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The journal of Biological and Medical Rhythm Research

ISSN: 0742-0528 (Print) 1525-6073

Seven-day human biological rhythms: An expedition in search oftheir origin, synchronization, functional advantage, adaptive value and clinical relevance

Alain E. Reinberg, Laurence Dejardin, Michael H. Smolensky & Yvan Touitou

Seven-day human biological rhythms: An expedition in search of their origin, synchronization, functional advantage, adaptive value and clinical relevance

Alain E. Reinberg3, Laurence Dejardinab, Michael H. Smolenskyc and Yvan Touitoua

Unite de Chronobiologie, Fondation Adolphe de Rothschild, Paris Cedex, France; bHopital Frangais Saint Louis, Jerusalem, Israel; ‘Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, USA

ABSTRACT

ARTICLE HISTORY

Received 24 August 2016 Accepted 12 September 2016

KEYWORDS

Adaptive capacity; chronotherapy; circaseptan rhythms; clinical applications; functional value; Hebraic week; 7-day rhythms

This fact-finding expedition explores the perspectives and knowledge of the origin and functional relevance of the 7 d domain of the biological time structure, with special reference to human beings.

These biological rhythms are displayed at various levels of organization in diverse species — from the unicellular sea algae of Acetabularia and Goniaulax to plants, insects, fish, birds and mammals, including man — under natural as well as artificial, i.e. constant, environmental conditions.

Nonetheless, very little is known about their derivation, functional advantage, adaptive value, synchronization and potential clinical relevance.

About 7 d cosmic cycles are seemingly too weak, and the 6 d work/1 d rest week commanded from G-d through the Laws of Mosses to the Hebrews is too recent an event to be the origin in humans.

Moreover, human and insect studies conducted under controlled constant conditions devoid of environmental, social and other time cues report the persistence of 7 d rhythms, but with a slightly different (free-running) period (t), indicating their source is endogenous.

Yet, a series of human and laboratory rodent studies reveal certain mainly non-cyclic exogenous events can trigger 7 d rhythm-like phenomena. However, it is unknown whether such triggers unmask, amplify and/or synchronize previous non-overtly expressed oscillations. Circadian (~24 h), circa-monthly (~30 d) and circannual (~1 y) rhythms are viewed as genetically based features of life forms that during evolution conferred significant functional advantage to individual organisms and survival value to species.

No such advantages are apparent for endogenous 7 d rhythms, raising several questions: What is the significance of the 7 d activity/rest cycle, i.e. week, storied in the Book of Genesis and adopted by the Hebrews and thereafter the residents of nearby Mediterranean countries and ultimately the world?

Why do humans require 1 d off per 7 d span? Do 7 d rhythms bestow functional advantage to organisms?

Is the magic ascribed to the number 7 of relevance?

We hypothesize the 7 d time structure of human beings is endogenous in origin — a hypothesis that is affirmed by a wide array of evidence — and synchronized by sociocultural factors linked to the Saturday (Hebrews) or Sunday (Christian) holy day of rest. We also hypothesize they are representative, at least in part, of the biological requirement for rest and repair 1 d each 7 d, just as the circadian time structure is representative, in part, of the biological need for rest and repair each 24 h.

Introduction

The biology of life forms is organized with both an anatomical and temporal structure, the latter defined by endogenous rhythms of several period (t) domains that correspond to various prominent environmental cycles present during evolution (Halberg, 1960a).

Circadian rhythms are associated with and entrained by the 24 h light (L)/dark (D) cycle arising from the rotation of the earth around its axis (Aschoff, 1965; Brown, 1960; Bunning, 1963; Sweeney, 1987; Wever, 1979), circa-monthly (~30 d) ones associated and entrained by lunar phases arising from the rotation of the satellite around the earth every 29.53 d (Reinberg et al., 2016), and seasonal and circannual ones, respectively, associated with and entrained by seasonal and annual changes in the daily photoperiod caused by rotation of the earth around its sun (Bunning, 1963; Pengelley, 1974; Reinberg & Smolensky, 1983).

These bioperiodicities are viewed as beneficial traits that during evolution conveyed functional advantage (FA) and adaptive value (AV) to individual organisms and survival value (SV) to species. The derivation and biological value of cyclic 7 d phenomena are much less clear.

Are theyrepresentative of a genetic trait common to all species and thus persistent in constant environmental conditions, or are they instead the consequence of external cosmic and earthly cycles, magical aspect of the number 7, relatively recent in human history 6 d work/1 d rest religious and cultural 7 d “week,” or specific exogenous non-cyclic triggers that evoke acute or chronic 7 d oscillatory responses?

The purpose of this article is to first report illustrative findings of 7 d biological cycles across species, particularly human beings, based on our review of journal articles, and also proceedings of chronobiology conferences where much of the information has been reported, and thereafter to explore their origin, including the possible role of religious, social and economic influences, and potential FA, AV, SV and clinical relevance.

Terminology

Different terms and expressions, e.g. ~7 d, ~1 wk and circaseptan, are used in publications to denote temporal variation of identical t. We prefer ~7 d because it is straight forward in meaning. Circaseptan (Halberg et al., 1977) is old, i.e. midtwentieth century, jargon of the field of chrono-biology that nowadays is appreciated only by a select few. According to Prosser (1986), the phrase biological adaptation can have different meanings depending on the context of its usage; therefore, it can be imprecise, especially when discussing chronobiologic matters.

We use the phrases of functional advantage (FA) and functional value (FV) when referring to the biological time structure in its totality or one or more specific domains that favor in the usual cyclic environment normal/ optimal life processes and functioning of individual organisms. We use the phrase adaptive value (AV) to refer to the capacity of individuals afforded by the biological time structure or one or more of its specific time domains to respond successfully to the usual and mostly predictable-in-time biological, chemical, physical and other ambient challenges.

In line with Prosser (1986), we use the phrase survival value (SV) when referring to genetic trait(s) relating to the biological time structure in its entirety or one or more of its domains that favors perpetuation of species.

Our expedition in search of the origin, synchronization, FA, and AV of human 7 d rhythms is broad-based and multidisciplinary and includes the potential role of certain religious doctrine, which is atypical of biological papers. Respecting the religious convention of the devout, we print the Name of the Lord as “G-d” to avoid the sin of erasing or defacing the Name. Finally, we use the King James’ version of the Bible (www.davince. com) when citing Biblical passages and psalms.

Examples of 7 d cyclic phenomena across species

Seven-day cyclic phenomena have been much less studied than circadian and circannual rhythms, and typically findings are based on relatively small sample-sized investigations. Nonetheless, many diverse species are known to express them, from the simple unicellular Gonyaulax polyedra (Cornelissen et al., 1986; Halberg et al., 1985; Hastings & Keynan, 1965) and Acetabularia (Berger et al., 1990; Schweiger, 1969; Schweiger & Schweiger, 1965; Schweiger et al., 1986), the latter having an evolutionary history of >400 million years (Puiseux-Dao, 1970), to plants, insects, fish, birds and mammals, e.g. laboratory rodents, horses and humans.

Plants, insects, fish and birds

Imbibition (water uptake) of pole bean seeds, Phaseolus vulgaris, displays 7 d bioperiodicity with a peak prior to each lunar phase, the most prominent one displayed before the full moon (Brown & Chow, 1973; Spruyt et al., 1987). Such temporal variation is also reported in the IgY (functional equivalent to mammalian IgG) content of the chicken egg yolk (He et al., 2014). In insects studied under constant darkness, oviposition, intermolt interval (stadia) and growth of the Springtail Folso mia candida (Collembola: Isotomidae) and activity level of the beach beetle Chaerodes trachyscelides White display ~7 d variability (Chiba et al., 1973; Cutkomp et al., 1987; Meyer-Rochow & Brown, 1998). Certain hemolymph constituents of worker honey bees studied under normal ambient conditions also exhibit ~7 d cycles (Mikulecky & Bounias, 1997), and the tolerance (survival) of the face fly Musca autumnalis De Geer as well as Acetabularia mediterranea (Schweiger et al., 1986) to repeated phase shift of the ambient 24 h L/D synchronizer schedule is greatest when the interval approximates 7 d (Hayes et al., 1980, 1983, 1986). Similar findings are also reported for the Springtail Folsomia candida according to repeated phase shift of optimal and non-optimal ambient temperature; tolerance, i.e. life span duration, is best when the shift interval is 7 d (Marques et al., 1987). Furthermore, in continuous darkness melatonin production of isolated superperfused pineal glands of the pike fish Esox lucius L. exhibits rather prominent ~7 d oscillation (Cornelissen et al., 1995a).

Laboratory rodents

Evidence of 7 d rhythms is provided from study of laboratory rodents housed in a research environment that mimics the ambient 24 h L/D cycle. This includes pineal melatonin content (Sanchez de la Pena et al., 1986); corneal mitosis (Tsai et al., 1989); cardiac creatine phosphokinase enzyme activity (Marques et al., 1994); tolerance to whole body X-ray irradiation (Scheving et al., 1981); urinary sodium excretion during a high dietary salt regimen (Uezono et al., 1987); immune system (see overviews by Haus & Smolensky, 1999; Levi et al., 1982); death from experimentally induced malarial infection (Sanchez de la Pena et al., 1984); kidney (Levi & Halberg, 1982; Levi et al., 1982; Ratte et al., 1977), heart and pancreas (Kawahara et al., 1980, 1982) allograph rejection episodes; therapeutic effect of medications (Halberg, 1995; Levi & Halberg, 1982; Levi et al., 1982; Liu et al., 1986); time course of antibody response to vaccine-delivered antigens (DeLisi et al., 1983); and murine plasma and brain pregnenolone concentration of adrenalectomized and orchidectomized animals (Bourreau et al., 1987).

Domesticated horse

Statistically significant 7 d cycles in semen volume and sperm motility and spermatozoa concentration were detected in an intensive investigation of a famous Brazilian bred (Mangalarga) stallion (Araujo et al., 1996; Marques et al., 1996). In contrast, Piccione et al. (2004) found only weak and inconsistent expression of 7 d biochemical and physiologic rhythms of horses studied during exercise training.     

Human beings

A wide variety of ~7 d rhythms are reported, although typically based on small sample-size investigations, for young and adult human beings residing in the usual environment of today. For example, biological oscillations of ~1 wk have been demonstrated in systolic (S) blood pressure (BP) and diastolic (D) BP (SBP/DBP) during pregnancy (Ayala & Hermida, 1995); corticosteroid-binding activity of human breast milk of lactat-ing mothers (Agrimonti et al., 1984); BP, heart rate (HR) and body weight gain of neonates, including twins, following birth (Cornelissen et al., 2001; Garcia et al., 1994, 1995; Hurley et al., 1987; Wu et al., 1990); nutrient and calorie consumption of 4 y-old infants (Debry et al., 1975), and dentition, i.e. enamel deposition (striae of Retzius), of children (FitzGerald, 1998). Moreover, 7 d rhythms of cognitive functions are reported in school-aged children and adolescents of both genders and also adult men and women (Beugnet-Lambert et al., 1988; Guerin et al., 1993; Halberg & Reinberg, 1967; Leconte, 2011; Leconte & Lambert, 1990; Reinberg, 1997a, b, 1998; Testu, 1989; Vermeil, 1995). In adults, they are known for physical activity level (Otsuka et al., 1994); nighttime sleep duration (Hecht et al., 2002; Paine & Gander, 2016); core body temperature (Halberg et al., 1964); cell mitosis (Blank et al., 1995; Halberg, 1995); HR, DBP, SBP and day-night SBP ratio (Cornelissen et al., 1996; Otsuka et al., 2004; Shinagawa et al., 2002); positive and negative mood (Cornelissen et al., 2005); functional attributes of the immune and hemostatic systems (Haus, 2007; Haus & Smolensky, 1999; Kanabrocki et al., 1995; Levi et al., 1982); DBP and SBP response to cold pressor test (Lee et al., 2003); total calories and dietary constituent consumption (An, 2016); stress-associated evening/nighttime eating behavior (Huh et al., 2015); prostatic hyperplasia-associated nocturia (Cornelissen et al., 2004); urinary sodium excretion, occurring in antiphase with the 7 d periodicity in plasma aldosterone and in phase with that of plasma cortisol concentration, of men studied under long-term space flight simulation (Rakova et al., 2013; Titze et al., 2014); and thoracic impedance in certain heart failure patients (Kirchner et al., 2015). Additionally, ~7 d free-running rhythmicity in urinary cortisol concentration is reported in arthritic patients after ACTH (adrenocorticotropic hormone) treatment (Halberg et al., 1981) and HR, SBP and SBP in persistent vegetative-state patients (Guan et al.,

2011). In this regard, Peyro et al. (1999a, b, 2002) found 7 d SBP and DBP rhythms in intensive care unit comatose patients that were 3-fold greater in amplitude than their 24 h rhythms; interestingly, desynchronization of the acrophase (peak time, 0) of the SBP and DBP 7 d rhythms was predictive of nonsurvival. Finally, free-running ~7 d oscillation in oral and axillary temperature, HR, SBP, DBP, mean arterial BP and urinary norepinephrine concentration is expressed during temporal isolation — in the absence of known ambient plus usual social and clock-time cues (Levi & Halberg, 1982; Lucas et al., 1985; Montalbini et al., 1989; Sanchez de la Pena et al., 1989). These latter findings are consistent with the hypothesis that human 7 d rhythms are endogenous in origin.

Further support for this hypothesis comes from our analysis of the interplay of biological timekeeping between the ~24 h, ~7 d and ~30 d spectral domains of human beings while dwelling in temporal isolation, a topic not previously addressed. The change, lengthening or shortening, in t of the desynchronized rhythms under these study conditions varies according to spectral — circadian (~24 h) versus infradian (~7 and ~30 d) — domain. The t of rhythms of the circadian domain lengthens, while that of the rhythms of the infradian domain shortens (Halberg & Reinberg, 1967; Halberg et al., 1970). These findings imply the circadian and infra-dian rhythm domains, although governed by separate “clocks”, are inter-linked, participating together in the compensatory adjustment of the biological time structure at large to perturbation of usual environmental synchronizer time cues.

Findings of the longitudinal self-study by the Danish endocrinologist Christian Hamburger      (CH), who beginning when 43 y of age every day collected for 15 y his total 24 h urine voidings for measurement of volume (UV) and 17-ketosteroid (17-KS) concentration (index of androgen production), are also consistent with the hypothesis 7 d rhythms are endogenous in origin. Throughout the span of this self-study, CH maintained a disciplined 24 h and weekly routine, which according to information recorded in his daily diary included rest one-half day Saturdays and rest the full day Sundays. Time series analysis revealed not only statistically significant annual (Hamburger, 1954) but 7 d rhythms in UV and 17-KS, with the 0 of the 17-KS rhythm around midday Sunday and that of the 7 d UV rhythm around midnight Wednesday, the Д0 between the two 7 d rhythms thus being ~3.5 d (Halberg & Reinberg, 1967; Halberg et al., 1965; Hamburger, 1954; Hamburger et al., 1985). Detailed review of CH’s daily diary during the 15 y self-study span also revealed 7 d (and 3.5 d) patterning of his sexual activity (SA). SA was highest on Sundays, thus coinciding with the 0 ofhis 7 d rhythm of 17-KS, with a second smaller peak in SA on Thursdays, associated as well with a second smaller peak in 17-KS (Hamburger et al., 1985). Of further interest is the finding that both 17-KS and UV exhibited a t of precisely 7 d during the initial 12 y of the self-study, while that of the former changed during the last 3 y during which CH chronically selfmedicated himself with a fixed dose of testosterone at regular intervals. Indeed, the t of the 17-KS rhythm shortened to <7 d, thereby evidencing free-running behavior from the societal week, while that of the UV rhythm persisted unaltered with the t being exactly 7 d (Halberg & Reinberg, 1967; Halberg et al., 1965).

The human 7 d time structure

A glimpse of the 7 d human time structure comes from research conducted by Haus et al. (1988) that involved a total of 20 diurnally active medical laboratory staff 21-46 y of age. The main aim of these investigations was to establish day-of-week diagnostic reference criteria for improving the interpretation of patient clinical laboratory test values. Subjects were day-shift employees who worked Monday-Friday, with Saturday and Sunday off, unless circumstances in the hospital setting required their presence. Blood samples were withdrawn always in the morning between 07:30 and 08:30 h primarily Mondays, Wednesdays and Fridays throughout each of two 90 d studies conducted 1 y apart (Figure 1: Study A) that also included at their conclusion around-the-clock (24 h) blood sampling at 4 h intervals. Blood samples were analyzed for hematocrit, hemoglobin, red blood cell count, plasma cortisol, and serum alkaline phosphatase (alkaline Ptase), albumin, calcium, cholesterol, glucose, lactate dehydrogenase (LDH), phosphorus and total protein. Additional longitudinal investigations entailed two other diurnally active

Figure 1. Acrophase (0) and 95% confidence interval (CI) according to day of week (x-axis) of statistically significant (p < 0.05) 7 d rhythms. Study A: 12 blood variables of a group of 20 diurnally active men (M) and women (W) 21-46yofage who participated in two 90 d studies conducted 1 y apart. Serum variables were determined only for the blood samples of 11 subjects who participated in the y 2 study. Study B: 0 and 95% CI of plasma cortisol for one other 31 y-old diurnally active women (W), a medical staff member, who provided blood samples between 08:50 and 09:00 h primarily Mondays, Wednesdays and Fridays for 6 wk. Study C: 0 and 95% CI of urine volume and urinary cyclic AMP, creatinine and sodium concentration of the same female medical staff member who also provided daytime urine voids daily for 6 wk. Study D: 0 and 95% CI of urinary 17-KS concentration for one 37 y-old man (M), also a medical staff member, who collected his urine voids at ~4 h intervals every 24 h for 35 wk. The 0 of most plasma and serum variables as group phenomena (Study A) occur Tuesday-Thursday. The 0 of the plasma cortisol 7 d rhythm for the female medical staff member and group of 20 subjects is quite similar. The lower portion of the figure (Study C & D) shows the 0 and 95% CI of the 7 d urine rhythms of the woman and man of the medical staff; except for the 17-KS rhythm of the man, 0s occur Friday-Sunday. The rather large group 95% CI of each 0 is presumably due to (i) time series analysis method that assumes the curve pattern of the raw data closely resembles a cosine function; this is presumably true when the 95% CI is narrow (<2.5 d) but not when wide (>3.5 d, i.e. albumin and glucose); (ii) limited 3 d sampling/ wk; (iii) relatively small sample size; and/or (iv) difference between subjects in nature and strength of the 7 d synchronizer time cues, i.e. 7 d activity and rest regimen, among others. (Redrawn based on data from Haus et al., 1988).

medical staff members, a 31 y women who daily selfcollected her wake-time urine voids during 6 wk for later analysis of urine volume and cyclic adenosine monophosphate (cyclic AMP), creatinine, and sodium concentration (Figure 1: Study C) and a 37-y-old man who self-collected his urine voids at ~4 h intervals every 24 h during 35 wk for later analysis of 17-KS concentration (Figure 1: Study D). The 31 y women also provided blood samples between 08:50 and 09:00 h primarily Mondays, Wednesdays and Fridays during 6 wk for subsequent analysis of plasma cortisol (Figure 1: Study B).

Figure 1 presents the 0 and 95% confidence interval

(CI) per clinical laboratory variable. The 0 of the 7 d plasma cortisol rhythm for both the group of 20 subjects and the 31 y women is Monday-Tuesday, but for most of the other blood constituents of the group it is Tuesday, Wednesday or Thursday (hemoglobin, hematocrit, and red blood cell count and serum glucose, albumin, alkaline ptase, calcium, cholesterol, LDH and total protein). Finally, the 0 of all of the urine variables except 17-KS, which is Wednesday, is either Friday, Saturday or Sunday (urine volume and creatinine, cyclic AMP and sodium concentration).

Figure 2 graphically depicts the amplitude of both the 7 d and 24 h rhythms of each of the 12 plasma and serum variables of Study A whose 0 and 95% CI are shown in Figure 1. The amplitude of each of the studied 24 h rhythms was determined from time series analysis of data obtained from the two around-the-clock 24 h blood sampling studies that were conducted immediately following the conclusion of the two 90 d longitudinal investigations done 1 y apart from one another. The amplitude of the 7 d rhythm of red cell count, hemoglobin, plasma cortisol and plasma serum phosphorus is much smaller than that of the corresponding 24 h rhythm. The amplitude of the 7 d in comparison to the 24 h rhythm of the other serum variables is statistically comparable. Moreover, the amplitude (data not shown) of all of the 24 h urinary rhythms, except volume, is greater than all the respective 7 d ones. Low-amplitude 7 d rhythms in the same (Figure 1) and also other urinary variables, i.e. chloride, magnesium, potassium, uric acid, specific gravity and pH, most displaying a Sunday peak, are also reported based on time series data analysis of the laboratory determinations performed on ~2800 mostly consecutive voidings collected at 2-5 h intervals each 24 h during two different spans of a longitudinal self-study by a healthy male when between 21 and 26 y of age (Sothern et al., 1977).

Figure 2. Comparison of the 7 d versus 24 h amplitude (one-half peak-to-trough difference) values of 12 statistically significant 7 d and circadian rhythm clinical laboratory variables of the same group of 20 diurnally active men and women whose 0 and 95% CI are shown in Figure 1: Study A. Blood samples were collected always between 07:30 and 08:30 h — primarily Mondays, Wednesdays and Fridays — throughout two 90 d studies conducted 1 y apart that were each followed immediately by blood samplings at 4 h intervals for a full 24 h. The 7 d and 24 h amplitude values were derived by time series analyses. The amplitude of the 7 d rhythms in comparison to that of the 24 h ones is smaller for 5 variables and statistically equal for the 7 others (Modified from Haus et al., 1988).

Despite the research evidence from persons studied in temporal isolation that indicate 7 d rhythms are endogenous in origin, several publications report induction or enhancement of 7 d phenomena in humans and laboratory animals by environmental triggers as accommodative biological responses (Hildebrandt, 1977, 1984, 1993; Hildebrandt et al., 1982). This is exemplified by the findings of Pollmann (1984) demonstrating a 7 d cyclic pattern

Figure 3. Examples in humans and laboratory animals of 7 d cycles triggered by major maxillo-facial and renal surgery, serious infection, high-altitude (low-oxygen) partial pressure exposure, and physical and strength training. Time along the x-axis is referenced to the 1st day of the specified trigger. Evident in all examples is the prominent induced 7 d cycle, sometimes superimposed on a declining linear trend line (see Hildebrandt, 1984 for referenced findings; figure content modified and redrawn after Hildebrandt, 1984).

of inflammation superimposed upon the linear decline of tissue swelling following maxillo-facial surgery, with crests exhibited on days 7, 14 and 21 of healing, and those reported by Hildebrandt (1984) relating to both biological and cognitive variables (e.g. sleep-time HR, basal metabolic rate, locomotor activity, physical work capacity, grip strength, left ventricular function and reaction time) induced by rehabilitative and spa therapies, with the peak time, i.e. day of week, of the oscillation per patient determined by the day of week of treatment initiation. Other examples (Figure 3) include the 7 d cycling of body temperature of patients with scarlet fever (Hildebrandt, 1977), human reticulocyte count after high altitude exposure (Hildebrandt, 1984), indices of fitness and strength during and after physical and muscle strength training (Hildebrandt, 1984; Sasse, 1981), and HR and BP of neonates for as long as several weeks following birth (Garcia et al., 1994, 1995; Hurley et al., 1987). Acute human renal allograft rejection (AHRAR) events elicited both by cadaver and live donor organs, e.g. evidenced by plasma creatinine retention, also exhibit prominent 7 d patterning (Figure 4), with the particular day of the week when the cyclic AHRAR 7 d events manifest in individual organ recipients determined by the day of the week of surgical implantation. Indeed, of some 280 AHRAR incidents of four different studies entailing 628 patients (De Vecchi et al., 1979, 1981; Knapp & Pownall, 1980; Levi & Halberg, 1982), the risk of experiencing a rejection episode at an interval of 6-8 d and/or multiples of such following organ transplantation surgery is nearly 50% greater than the risk of experiencing one at an interval of 2-5 d and/or multiples of such following organ transplantation. In well-controlled laboratory animal experiments, rejection incidents of ~7 d interval were also demonstrated following heart, renal and pancreas transplantation; skin-to-muscle grafting (Cornelius et al., 1967; Kawahara et al., 1980, 1982; Ratte et al., 1977); and DNA synthesis of tubular epidermal cells following unilateral nephrectomy (Hubner, 1969; Figure 3). The chronobiologic mechanism of these overt 7 d triggered bioperiodicities is yet to be elucidated. Hildebrandt (1984) proposed such external triggers serve to amplify otherwise low-amplitude, perhaps ordinarily non-overt, rhythms. Thus, the triggers may serve to unmask and/or recruit and synchronize the expression of already existing endogenous 7 d biological oscillations.

Figure 4. Seven-day patterns of 212 renal rejection episodes experienced by a combined 579 kidney transplant patients of three transplant centers — Milan (Italy), Paris (France) and Minneapolis (Minnesota, USA) — during the late 1970s, before current generation effective anti-rejection therapies. Especially evident at every transplant center is the prominent first rejection episode ~7 d following allograph surgery. Additional rejection episodes thereafter at ~7 d intervals are detected in some patients, particularly ones of the Minneapolis center. Differences between centers in the later occurrence at 7 d intervals of rejection episodes are hypothesized to represent differences in transplant surgical procedures and/or specific post-surgical therapeutic interventions and their exact temporal (day-of-week) patterning (Redrawn and modified after Levi & Halberg, 1982; Levi et al., 1982).

7 d patterns in medical emergencies and health behaviors

Prominent 7 d patterns are occasionally exhibited by individual patients in the exacerbation of relatively rare medical conditions (Reimann, 1963, 1971), and in the human population at large they are rather consistently detected (occasionally also a 3.5 d cycle) not only in the occurrence of infectious, gastrointestinal, lung, mood (including suicidal intent), hemostatic and neurological disorders (Ajdacic-Gross et al., 2015; Baibergenova et al., 2005; Beauchamp et al., 2014; Brillman et al., 2005; Cugini et al., 1990; Halberg, 1995; Kao et al., 2010, 2014; Manfredini et al., 2015; Svanes et al., 1998; Walker et al., 2007) but life-threatening cardiac and vascular events. Hospital admissions for acute care of hypertension crises, severe angina pectoris, cardiac arrhythmias, heart failure exacerbation, acute aortic rupture or dissection, Takotsubo cardiomyopathy, myocardial infarction, sudden cardiac arrest, transient ischemic attack and stroke typically display a Monday peak (Arntz et al., 2000; Boari et al., 2011; Cantwell et al., 2015; Cornelissen et al., 1993; Diaz-Sandoval et al., 2008; Manfredini et al., 2010a, b, 2011; Nicolau et al., 1991; Vitale et al., 2015a; Witte et al., 2005). Additionally, statistically significant weekly and semi-weekly (3.5 d) patterns are detected in minor childhood (5-16 y of age) injuries of boys and girls combined and of boys, but not girls, with a midday Wednesday peak (Reinberg O et al., 2005).      Day-of-week differences are also reported in internet search activities that seek health information (Ayers et al., 2014a, b; Gabarron et al., 2015). Norwegian language internet inquiries over a 911 d span for medical information concerning sexually transmitted diseases — chlamydia, gonorrhea, herpes, human immunodeficiency virus and acquired immune deficiency syndrome — plus other diseases and medical conditions — influenza, diabetes and menopause — reveal prominent 7 d cyclicity, with peak search activity the first day or two of the traditional work week (Gabarron et al., 2015). 7 d patterns are also documented in “healthy contemplations” of residents of the USA as verified by analysis of Google search queries that include the word “healthy”; the number of internet inquiries between 2005 and 2012 was significantly greater Mondays and Tuesdays than the other days of the week (Ayers et al., 2014a). The initiation of quitting behavior by addicted tobacco smokers, quantified by the volume of their Google searches of related internet sites, also evidences strong day-of-week patterning, with the Monday query volume across all the major languages of the world -English, French, Mandarin/Cantonese, Portuguese, Russian and Spanish — 25% (95% CI, 24-26%) greater than the combined Tuesday through Sunday mean query volume (Ayers et al., 2014b). Gabarron et al. (2015) conjecture such 7 d cycles derive either from exogenous factors, i.e. concerns over well-being because of having engaged the preceding weekend in risky behaviors, or day-of-week difference of computer use, while Ayers et al. (2014a, b) contend they represent expression of an endogenous time structure.

Functional value of the human 7 d time structure

From a fatalistic perspective, the biological and metabolic costs of maintaining performance and readiness at a consistently high level throughout the entire 24 h (Ticher et al., 1995) and year (Pengelley, 1974; Reinberg, 1974), particularly by land-based animals, are much too great to sustain life (Reinberg, 1997b, 1998). In contrast, an endogenous oscillatory system entrained by ambient periodic time cues, e.g. L/D alternation each 24 h and change of photofraction during the ~30 d lunar and 365.25 d annual temporal domains, favors, among others, efficient resource utilization thereby conferring for individual organisms FA and AV, the latter entailing readiness to successfully respond to rather predictable-in-time occurring biological, chemical and physical environmental challenges (Halberg, 1960a, b; Reinberg & Smolensky, 1983; Smolensky & Reinberg, 1985; Zhao et al., 2003), and also SV through perpetuation of species (Nelson et al., 2002; Ortavant & Reinberg, 1980; Pengelley, 1974; Reinberg & Ashkenazi, 2003; Reinberg & Smolensky, 1983; Smolensky & Reinberg, 1985). The research of Ticher et al. (1995), who explored the coordinated staging of 168 different human circadian rhythms of diurnally active healthy young adults, illustrates the FA and AV of the circadian time structure. The 0 of most of the studied rhythms clusters between 15:00 and 19:00 h, while none occur between 05:00 and 07:00 h. Furthermore, the studied 37 physiologic and 32 cognitive rhythms collectively display close coupling in time as indicated by strong correlation (r = 0.78) of their circadian 0. Accordingly, the circadian time structure enables optimal response to “expected” cyclic environmental changes and challenges linked to the rotation during the 24 h of the earth about its axis. During evolution, circadian rhythms are presumed to have contributed significantly to the survival of species by conferring FA and AV to individual organisms and animals, although according to Ticher et al. (1995) given the man-made artificial conditions of today some analyzed rhythms may be vestigial, i.e. no longer of relevance to humans (Smolensky et al., 1972).

The biological time structure is composed of ultradian (0.5 h < т < 20 h), circadian (20 h < т < 28 h) and infradian (т > 28 h) domains (Halberg, 1960a); all of them impart FA, AV and SV to individuals and species, but with qualitative and quantitative differences. For example, plasma testosterone (pT) in men displays both circadian and circannual rhythms. However, there is no coupling between the 24 h pattern in pT, which displays a morning-time 0, and self-documented (entries into daily diaries) sexual activities (SA), which display a major nighttime and secondary midday peak, thereby inferring with reference to this time domain the androgen circadian rhythm bestows no apparent SV (Reinberg & Lagoguey, 1978; Reinberg et al., 1975, 1978). The situation is different for the annual time domain; the 0 of the annual patterns of pT and that of male SA is strongly associated in time. The 0 of the human pT rhythm that occurs in early autumn is strongly coupled in time with the 0 of the annual rhythm of human SA, based both on direct evidence, i.e. daily diary data of couples (Udry & Morris, 1967) and males (Reinberg & Lagoguey, 1978), and indirect evidence, i.e. seasonal pattern of conceptions, reported rapes and sexually transmitted diseases (Batchelet et al., 1973; Chandwani et al., 2004; Leffingwell, 1892; Lemmer, 2012; Roenneberg & Aschoff, 1990; Smolensky et al., 1972, 1981). Reinberg et al. (1988), on the other hand, found no temporal coincidence between the 0 of the annual variation in semen characteristics, i.e. volume, sperm count and sperm motility, and pT of men; the high-amplitude circannual rhythm in sperm count exhibited its 0 in April-May and trough in late summer-early autumn, while that of pT exhibited its 0 in autumn. However, sperm count is typically depressed by high SA (Li et al., 2009). Thus, the finding by Reinberg et al. (1988) of lowest, rather than expected greatest, sperm count in the fall, when pT concentration is highest during the year, is presumably the consequence of enhanced male SA then (Reinberg & Lagoguey, 1978; Reinberg et al., 1975; Smolensky et al., 1981).

The high SV of the circannual time structure is much more evident in species other than humans (Boissin & Canguilhem, 1998). Staging, i.e. timing of peak and trough values, of the rhythms of pT and SA (mating), which is synchronized by the annual photoperiod cycle, is strongly linked such that they crest at the same time, e.g. in the boar (January), deer (October), ferret (March-April), fox (January), hedgehog (February-March) and mink (February). Typically, short-gestation mammalian species conceive between late winter/early spring and the comparatively longer-day breeders early in autumn with birth in late spring, e.g. fox and hedgehog in March, mink in April and deer in May, when environmental conditions and food availability favor survival of newborns and thus perpetuation of species. Inter-species diversity in mating time during the year is related not only to inter-species difference in gestation duration but specific reproductive phenomena, like delayed ovulation and delayed ovo-implantation. The overall annual time structure of mammals is viewed as bestowing FA to individual animals, but with reference to the perpetuation of species, the annual rhythm of pT in males specifically contributes to SV (Ortavant & Reinberg, 1980). Admittedly, we focused only on pT as the major determinant of SA; for sure, other variables and processes are involved in both male and female animals (Halberg & Reinberg, 1967; Nelson et al., 2002; Ortavant & Reinberg, 1980; Pengelley, 1974; Reinberg & Smolensky, 1983; Roenneberg & Aschoff, 1990; Smolensky et al., 1972). Thus, the above-summarized findings are not intended to imply the annual rhythm in pT is the sole variable that determines season-specific mating behavior; although, the annual pT rhythm is a well-documented one. We wish to point out the endogenous ~30 d menstrual rhythm of women, which also confers SV, is integrated into the complex multiple т biological time structure (see review by Reinberg et al., 2016). This raises the question whether ~7 d rhythms are in any way of SV for the human or other species.

The 7 d week: Concept and origin

The concept, origin and definition of the “week” have a long and complex history. It entails Biblical scripture and religious dictates, rituals and practices, and perhaps even numerological mysticism.

Mystic and religious connotations of the number 7

The ancient philosopher Pythagoras of Samos (~570 to ~495 BC), as did many other scholars of his era, believed things and happenings have a numerical basis, i.e. all things are numbers. Numbers such as 7, 3, 4, 6, 12 and 13 were viewed not only as denoting counts and value but when associated with otherwise trivial phenomena bestowing some sort of ill-defined supernatural-like energy and power.   The number 7 is of great religious significance, appearing in the Bible some 735 times and when “7fold” and “7th” are included 860 times. The number 7 is the foundation of G-d’s word, tied directly to G-d’s Creation of all things and representing physical and spiritual completeness and perfection. Some well-known examples are the creation of Adam which according to Jewish tradition occurred October 7th, the first day of Tishri, that is, the 7th month of the Hebrew calendar. Circumcisim of the male child is to be done waiting 7 d after birth (Genesis 17:12). The word “created” is used 7 times describing G-d’s Creative work (Genesis 1:1,21 and 27 three times and 2:3 and 2:4). There are 7 d per week and G-d’s Sabbath is the 7th day. The Old Testament refers to 7 y of plenty and 7 y of famine in Egypt during the days of Joseph, and G-d refers to at least 7 men of G-d: Moses (Joshua 14:6), David (2 Chronicles 8:14), Samuel (1 Samuel 9:6, 14), Shemaiah (1 Kings 12:22), Elijah (1Kings 17:18), Elisha (2 Kings 5:8) and Igdaliah (Jeremiah 35:4). Noah took clean beasts of every kind into the ark in male and female pairs of 7s (Genesis 7:2), and 7 d after Noah entered the ark the flood came (Genesis 7:1-10). Peter stories the long-suffering of G-d’s waiting in the days of Noah with 7 d being the wait time, and only Noah and 7 members of his family survived the judgment of G-d (1 Peter 3:21). The Apostle Paul in the book of Hebrews uses 7 titles to reference Christ: “Heir of all things” (Hebrews 1:2), “Captain of our salvation” (2:10), “Apostle” (3:1), “Author of salvation” (5:9), “Forerunner” (6:20), “High Priest” (10:21) and “Author and finisher of our faith” (12:2).

The number 7 in Genesis is identified with something being “finished,” “complete” and/or “divine”. Moreover, it is revealed by G-d’s instructions that animals be at least 7 d of age before sacrifice in religious ceremony (Exodus 22:30); Naaman bathed in the Jordan River 7 times to achieve complete cleansing (2 Kings 5:10); and Joshua marched around Jericho for 7 d, and on the 7th day made 7 circuits, and 7 priests blew 7 trumpets outside the city walls to cause the Walls of Jericho to tumble down (Joshua 6:3-4). Other Biblical examples are the Apocalypse of John, the apostle who obsessively quotes the number 7. The Apocalypse was written for the “7 bishops of the 7 churches” in Asia (Chapters 1:1 & 1:11); “I saw 7 golden candelsticks” (1:12); “In his right hand 7 stars” (1:16); “The 7 stars are the angels of the 7 churches”; “The 7 candelsticks are the 7 churches” (1:20); “The book is sealed with the 7 seals” (Chapter 5); “A lamb having 7 horns and 7 eyes … the 7 Spirits of G-d” (5:6); “The 7th seal is opened”… angels with the 7 trumpets’ (Chapter 8); “Of the wild beast with 7 heads …” (Chapter 13). The number 7 is prominent also in Jewish religion and rituals. For example, 7 Laws of Noah known as the Noahide Laws; in the synagogue, 7 portions of the Torah, each preceded by a special blessing — 7 in total — are recited by 7 different members of the congregation on the 7th day (Shabbat) of each week, and at end of the Jewish year, after completing the reading of all designated portions of the Torah, the Torah is carried in joyous song and celebration (Simchat Torah) around the synagogue 7 times.

Quotations, stories, traditions and various phenomena frequently invoke the number 7 (http://mys ticalnumbers.com/number-7/). They include the 7 branched candelstick in the tabernacle; 7 heavens (here 7 is good); 7 deadly or capital sins (here 7 is bad); 7 mythical Hesperides (daughters of the night in Greek mythology); 9 muses generated by Zeus, but only 7 among them generated the 7 chords of the lyre (Greek mythology); 7 notes of the musical scale; 7 lucky Japanese deities; 7 Liberal Arts of Martianus Cepella (Fifth century) and medieval European universities; 7 Hills of Rome; 7 y to construct the Jewish Temple by Salomon; 7 valleys of the Baha’i Faith; bride and groom during Hindu wedding ceremony circling the holy fire 7 times and taking 7 steps together; Maya, birth mother of Siddhartha Gautama — the Buddha, died in joy and joined the deities 7 d after giving birth; in Islam some examples include the 7 verses of the first sura (chapter) of the Qur’an and rituals of the Hajj pilgrims that include walking around the Kaaba 7 times and throwing 7 pebbles at each of the three walls representing the devil; Chinese associate the 7 stars of the Great Bear with the 7 bodily as well as heart openings; and 7 Cherokee Indian clans, with seal of the Cherokee flag surrounded by 7 pointed stars and differently colored background flags representing war and peace depicting the 7 stars of the Big Dipper. In addition, there are 7 colors of the rainbow; 7 wonders of the world; 7 continents of the earth; House of 7 Gables (novel by Nathaniel Hawthorn); 7 Ravens and Snow White and the 7 Dwarfs (Grimm Brothers fairy tales); and Perrault’s Little Thumb (Le Petit Poucet), smallest of 7 brothers, with the reading of these fables today often done on the 7th day (day of leisure) of the week. Nonetheless, although the number 7 is given privileged and/or supernatural power in scripture, Greek mythology, other ancient writings and many aspects of everyday life, there is no evidence of any kind to support such. Moreover, its magical effect or/and aura, if any, is of no help to understanding of either the origin or biological significance of endogenous 7 d rhythms.

Biblical designation of time domains of biological relevance

Several Biblical inferences are of direct relevance to understanding the concept, origin and definition of several time domains of biological relevance. The first is the day-night L/D alternation. The Book of Genesis relates on the first day of Creation the darkness of night was separated from the light of the daytime: “And G-d called the light Day, and the darkness He called Night. And the evening and the morning were the first day” (Genesis 1:5). The significance of this passage is well appreciated by chronobiologists; this L/D alternation constitutes a prominent synchronizer of the 24 h time structure of almost all species, including ours. The second one is the 7 d week. With reference to the Creation, one of G-d’s commandments conveyed through Moses is 6 d of work must be followed by 1 d of rest. “Remember the Sabbath day, to keep it holy” (Exodus 20:9). “6 days shalt thou labor, and do all thy work” (Exodus 20:10). “But the 7th day is the Sabbath of the Lord thy G-d: in it thou shalt not do any work. . .. For in 6 days the Lord made heaven and earth, the sea, and all that in them and rested the 7th day: wherefore the Lord blessed the Sabbath day, and hallowed it” (Exodus 20:11). This religious commandment was obviously at the origin of the 7 d week and all associated predictable-in-time cyclic variation of the sociocultural environment. The third one pertains to the significance of both the ecologic and biological time structure according to the hours of the day and seasons of the year based on Ecclesiastes (3:1-22): “To every thing there is a season, and a time to every purpose under the heaven” (3:1); “A time to be born, and a time to die; a time to plant, and a time to pluck up that which is planted” (3:2); “A time to kill, and a time to heal; a time to break down, and a time to build up” (3:3); “A time to weep, and a time to laugh; a time to mourn, and a time to dance” (3:4); “. . .A time to keep silence, and a time to speak” (3:5); “A time to love, and a time to hate; a time of war, and a time of peace” (3:8).

We cite select scripture not only to emphasize the wisdom of the Bible, but to highlight the critical importance of the Hebraic religious week comprising 6 d of work alternating with 1 d of Sabbatic rest in giving rise to the 7 d periodic socioecologic behaviors of the Judeao-Christian culture that remain dominant today. This governing 7 d time domain of life that originated through the middle-eastern ancient Hebrews spread across settlements along and around the Mediterranean Sea and eventually throughout the Roman Empire when the Christian religion was formally adopted and promoted by Emperor Constantine ~300 AC (Maraval, 2011).

The Hebraic week

No clear evidence indicates the concept of the week, as now defined, existed in the near-eastern and middle-eastern non-Hebraic populations of the Mediterranean Sea region, i.e. Babylon, Egypt or elsewhere. People of Mari residing along the Euphrates River worked non-stop day after day; while some Babylonians observed a 5 d “week.” Although the Hebrews used a lunar calendar, the year consisting of 12 months was recognized and named, even by the Hebrews, according to Zodiac signs (Couderc, 1993; de Bourgoing, 2000; Guittard, 1973). Time spans <28-30 d, as subdivisions of the month, were denoted, e.g. by the Romans, by grouping 10 d or even 8 d clusters with designation of the time of a forthcoming event as the number of days from specified references — ides and calends, but in a backward rather than forward direction as done today (Guittard, 1973).

The 7 d week that included the rest day of Shabbat was a commandment from G-d to the     Hebrews; however, it does not seem to have been strongly respected by the Jews of Babylon until their 70 y of captivity (586-516 BC). This exile, which was interpreted as G-d’s punishment of a rebellious people, was discouraging: “We hunged our harps upon the willows in the midst thereof” (Psalm 137:2); “How shall we sing the Lord’s song in a strange land?” (Psalm 137:4); “If I forget thee, O Jerusalem, let my right hand forget her cunning” (Psalm, 137:5). Nevertheless, they were encouraged by the prophet Jeremiah to follow their routine way of life (Jeremiah 29:4-11). “Build ye houses, and dwell in them; and plant gardens, and eat the fruit of them” (Jeremiah 29:5); “And seek the peace of the city whither I have caused you to be carried away captives, and pray unto the Lord for it: for in the peace thereof shall ye have peace” (Jeremiah 29:7).

The great proportion of common people during this time had little education. Among the ancient Hebrews of Babylon, in contrast, the proportion of educated people who could count, read and write was quite high and thus capable of understanding the Mosaic laws. Jewish religious leaders wrote much of the literature, employed scribes to copy Scripture and taught followers to observe the Sabbath. Babylonia became the most important center of Jewish life during the Exile. Not only were rules more fully established regarding the 7 d week that included the 1 d of Shabbat but also those of the kashrut, i.e. Jewish religious dietary laws, and all other aspects of Jewish religious and moral behavior. However, we must emphasize the Shabbat was not an integral feature of Mesopotamian culture (Nouveau Dictionnaire Biblique, 1992), thereby confirming the 6 d of work/1 d of rest week followed by G-d to create the world, as storied in the Book of Genesis, and commanded to Moses is specifically and exclusively of Hebrew origin.

It is noteworthy the Babylonians accurately tracked, by training and reference drawings, the passage of time according to specific phases of the lunar cycle, each of ~7 d duration: day 1 = first visible crescent, day 7 = waxing half-moon, day 14 = full moon, day 21 = waning half-moon, day 28 = last visible crescent and day 29 = invisible moon (http://www.crowl.org/lawrence/time/days.html). Notable, also, is the religious significance of the moon to devout Jews in that the sages of the Talmud viewed the monthly renewal of the moon as a visible reminder of the magnificent wonders of G-d’s Creation and symbolic of the Divine Presence. Accordingly, in the distant past, the sky was scanned to determine exactly when to give thanks through blessing (kiddush levanah) for the entire “master piece of celesterial orchestration” (http://www.chabad.org/library/article_cdo/aid/ 1904288/jewish/Sanctification-of-the-Moon.htm). Thus, the progressive evolution of the lunar stages served as a visible calendar to the Hebrews to know when to observe the Shabbat and attend the prayer services of the local synagogue/temple. The secular and pagan populations also used the lunar calendar system to track time in days.

Dissemination of the 7 d Hebraic week as a basic unit of religious and associated social time to large extent depended on the geographic distribution of Jewish settlements. Questions of their location and size around the Mediterranean Sea and elsewhere still await precise answers. The Diaspora commenced during the eighth century BC, eight centuries before the reign of the Roman Emperor Titus (41-81 AC) and the destruction of the Temple in Jerusalem. Juster (quoted by De Fontette, 1982) suggests rather large communities of Jews existed in 500 different cities of the Roman Empire, which overall totaled 60 million people, of whom 5-6 million were Jews, including the 1.5 million Jews who resided in Palestine. In Rome, early in the first century AC, no distinction was made between Jews who did and did not accept Jesus as the Messiah (Poliakov, 1961). Both religious groups were viewed suspiciously because their weekly gatherings for prayer were interpreted as conspiracy against Roman rule. Both Jews and Christians were regarded as enemies, justification for their spectacular bloody death by forced battle with vicious wild animals in circus-like games (ludi circenses) attended by Roman citizens in huge numbers for entertainment (Coles, 2011; Kyle, 1998). At the Coliseum in Rome, alone, >500 000 Jews and Christians were assassinated for amusement, and similar bloody shows regularly took place in arenas throughout the Roman Empire resulting in the enduring image of the Roman arenas being sites of spectacular death and bloodshed. Despite such sustained criminal mass murder, Jewish and Christian communities survived, as did observance of the Hebraic 7 d week that included the holy day of rest — the Shabbat.         The story of Paul the Apostle, backed by Barnaby the Apostle, is of relevance to the acceptance of the 7 d Hebraic week. Peter and other apostles were the “stones” of the new church and as such they strove to convert Jews to Christianity. Paul, a highly educated scholar, was dedicated to Christianizing Jews as well as pagans and other gentiles/goyim that dwelled not only in the region of the Mediterranean Sea but throughout the Roman Empire. Paul wanted to demonstrate to Jews and goyim that Jesus was THE Messiah anticipated by the Biblical prophets. Paul, as an apostle, preached in the name of Jesus, not for himself. Because of the terms of the new covenant, Paul rejected several Jewish rites spelled out in the Torah, the Hebraic Bible, e.g. circumcision of males and the kashrut — Jewish religious dietary laws, including the forbidden consumption of certain types and/or parts of land and sea animals. However, taking into account the strongly established religious behaviors of the devout, Paul choose Shabbat to preach the new doctrine of Christianity in synagogues, knowing it to be the best time and place to encounter large numbers of Jews and non-Jews. Thus, the 7 d week was both maintained and supported by Paul and his followers. With the acceptance and growth of Christianity in Rome, the administrative center of the vast Roman Empire, the sanctioned day of rest was moved from Saturday to Sunday to emphasize Rome, rather than Jerusalem, as the spiritual capital. Interestingly, nowadays some Christian communities, e.g. Seventh-day Adventists, recognize Saturday as G-d’s day as a reminder of the Jewish roots of Christianity. Finally, Mohammad, the prophet of Islam, designated Friday as the day of the week when followers of the Muslim religion must pray at the mosque; however, Mohammad did not designate it as an entire day of rest. Thus, the Islamic Friday strongly differs from the Hebraic Shabbat and Christian holy day.

The Hebrews did not formally name the days of the week but simply numbered them from 1 to 7. The Greeks titled them after the sun, moon and the five known planets, which were in turn named after the deities Ares, Hermes, Zeus, Aphrodite and Cronus. The Greeks called the days of the week the Theon hemerai “days of the deities.” The Romans substituted their equivalent deities for Greek ones, i.e. Mars, Mercury, Jove (Jupiter), Venus and Saturn, even though the pagan celestial and Greco-Roman-based deities in ecclesiastical Latin are inconsistent with Christian doctrine. Dominica, the first day of the week, is that of the Lord. The 2nd through 6th weekdays, respectively, are dies lunae (Monday), — after the earth’s satellite, the Moon; dies martis (Tuesday) — after the planet Mars and Greek deity of war; dies mercurii (Wednesday) — after the planet Mercury and Geco-Roman deity of finance, trade and travel; dies jovis (Thursday) — after Zeus-Jupiter, the sky and thunder deity of the ancient Greeks; dies veneris (Friday) — after the planet Venus; and dies saturni (Saturday) — after the planet Saturn. Many different belief systems preserve or integrate directly or indirectly various common elements, terminologies and practices, thereby making it impossible to comprehend the derivation and rationale of the broad array of traditional behaviors and practices of the different religions, e.g. why the time-honored Hebrew words amen and hallelujah continue to be used today in Christian religious celebrations and why the Catholic Pope and all high ranked bishops today wear a Jewish kippah (presumably, Peter and the apostles did, although no one knows with certainty). Although the numerical ordering (naming) of the weekdays for Islam is also the cardinal numbers 1-6, there is no Islamic equivalent to Shabbat — a full 24 h span of rest; as previously discussed, only a fraction of every Friday is devoted to prayer at the mosque.

Nero (37-68 AC) was the first Roman emperor who formally differentiated Jews who followed the teachings of the Torah from Christians who accepted Jesus as the Messiah (De Fontette, 1982; Poliakov, 1961). Nonetheless, the Christianization of gentiles lead by Paul and Barnaby commencing in the 2nd half of the first century AC was a relatively slow process. By the third century, however, the political and economical influence of the Christian minority had increased sufficiently to convince Emperor Constantine (272337), the then ruler of the Roman Empire, to formally accept the Christian religion and promote its unrestricted practice according to the Edict of Milan in 313 (MacMullen, 1998; Maraval, 2011; Veyne, 2007). Nonetheless, historians disagree as to whether the Christianization of the Roman Empire was achieved peacefully (Veyne, 2007) or forcefully (MacMullen, 1998). In the latter case, viewed as a boomerang effect, the practice of Christianity was “paganized” through incorporation of symbols, signs, concepts and practices totally outside the message of Jesus as a means of converting vast numbers of individuals to the faith of the New Testament. Thus, the transfer and integration of old pagan customs, beliefs and behaviors flourished in the Roman Christian church, even at its highest level, leading to a strange mixture of incoherence. The names that early Christians gave to each day of the week, as earlier discussed, is a good example of such. It is worthy of emphasis that many pagans rejected the concept of the Hebrew’s Shabbat, during which work was forbidden, and considered it scandalous. Suetone (70-130 AC) stated: “Stay each 7th day doing nothing, is losing one-seventh of the life”, and Rutilius Claudius Namatianus (fifth century) stated: “The G-d that Jews are imitating when observing the Shabbat must have been a tired G-d” (De Fontette, 1982). Thus, the concept of the week that consisted of 6 d work alternating with 1 d rest was neither universally accepted nor practiced by everyone.

In keeping with the aim of the present paper, we wish to call attention to two facts regarding the concept of the week. First, Constantine in 321 mandated that Sunday must be observed as the weekly day of rest, except for agricultural field-workers when seasonally dictated. Actually, Sunday was the weekly pagan day devoted to the Sun deity, adopted by the Roman Empire as the substitute for the Hebrew’s Saturday Shabbat. Second, the Shabbat is more than a 24 h rest span programmed in time to enable recovery from the fatigue of 6 successive physically demanding days of work. For the devout Jew, it is a holy day, a sacred 24 h span of time, devoted to giving honor and prayer to G-d. Playing with words, Shabbat is a holy day associated with holiday, the meaning of the latter being vacation, i.e. vacant with reference to the Latin root vacuum, meaning empty = no work. In keeping with the traditional Hebrew way of thinking, the Shabbat is far more than a day to rest, since it also includes when looking backward appreciation and satisfaction of one’s accomplishments and achievements during the preceding 6 d of work. Thus, Shabbat is a kind of day of thanksgiving for the work one was allowed to accomplish the other non-holy days of the week. Consistent with G-d’s model of the 7 d week, as related in the Book of Genesis, during the 24 h of rest (Shabbat) man should devote no time to being “creative,” which perhaps explains the forward-in-time motivation for creative activity during the ensuing weekdays. However, as subsequently discussed, the feelings of accomplishment linked in the past to adherence to the week’s holy day are in the growing secular society of today increasingly being transformed and monetized. Indeed, for the skeptical and non-believers, both the 24 h day of rest and the nighttime sleep span have a negative connotation of squandering time. From a chronobiologic point of view, it is impossible to eliminate the 7 d component from the inherent organization of processes and functions of the biological time structure.

Valuation of the day of rest in modern times

With few exceptions, the wage paid per 1 h work is standardized according to occupation and task (Scherrer, 1981), but with the clock time and day during the 24 h and week, respectively, of toiling differently valued by employers and employees (Banks, 1956). In the United Kingdom, for example, a lower wage is paid for working convenient — daytime and weekday — than inconvenient — nighttime and weekend — shifts. As shown in Table 1, the hourly wage for work on Saturdays during the late 1970s in Great Britain was 1% times that for weekdays — Mondays through Fridays — and on Sundays twice as great or more (Wedderburn, 1981) .      Some 35 years ago, Wedderburn (1981) devised a clever method to objectively quantify the differential value of time. He surveyed a cohort of 132 shift and day workers of a wide range of occupations to estimate how much they expected to be paid per hour according to various presented work-time scenarios. The questionnaire divided the day into different 3 h segments. Respondents were asked to rank each one of them with a score of 0-9, the time segment off of work most desired rated highest as 9 and that least desired off of work rated lowest as 0 and all the other time segments rated accordingly. Saturday evening was rated highest for time off from work by both shift and day workers. Furthermore, both groups of workers valued time off during the evenings and weekends more than time off during the daytime and weekdays. Overall, the findings of Wedderburn’s study reveal Saturday is the day of week of greatest social value, which is consistent with the enhanced financial incentive for work on weekends than weekdays, although the hourly wages in Great Britain (as well as other countries) generally are higher for toiling Sundays than Saturdays (Table 1). This higher incentive for working nights and/or weekends can be interpreted as compensation for the extra difficulty of working those atypical times; however, it is also compensation for the deprivation of social opportunities when working then. The extra pay incentive, particularly for Sunday work, originally intended to compensate workers for being unable to observe the religious and/or sociocultural day of rest, in actuality has had the effect of encouraging Sunday work (Wedderburn, 1981), which as a cause or result is linked to declining church membership and attendance plus relaxation of laws restricting Sunday commerce. Thus, the present designation of Sunday as a day of rest, particularly in the Westernized world, is based mainly on a widely adopted sociocultural practice rather than persisting religious tradition, at least by non-believers. Today, the 7 d week composed of 1 d of rest, which is often disassociated from its Hebraic religious roots, is increasingly a sociocultural lifestyle preference that, nonetheless, even in the growing secular Western society, likely reinforces and synchronizes human 7 d rhythms of endogenous origin.

Of significant relevance to this discussion is the failure of past attempts to redefine the traditional 7 d week. The leaders of the French revolution in 1789 rejected the 7 d week founded on religious doctrine, promoting instead the decimalization of time, initially in the form of the 10 d “week” termed the decadi. Even highly fit individuals were unable to tolerate the tough, mainly physical, continuous 9 d work span with no interspaced off day. Thereafter, the 5 d “week”, termed the quintidi, was promoted, but it too was a disaster and rejected in favor of the traditional 7 d week (Couderc, 1993; de Bourgoing, 2000). Redefinition of the 7 d week was attempted also by the leaders of the Bolshevik revolution, who instituted a 5 d “week”, 1 d of which was for rest to achieve as a goal 20% of the work force having off 1 d per 5 d period. After an 11 y span (1929-1940) of dramatically compromised industrial production, Stalin abandoned the 5 d “week” in favor of the traditional 7 d one (Couderc, 1993).

Discussion

The ~7 d domain of the biological time structure has been little studied; thus, relatively little is known about its derivation, rationale (biological value), synchronization and in the case of human beings clinical relevance. Nonetheless, a broad array of research demonstrates persistent 7 d rhythms in different species under usual conditions of life as well as controlled conditions devoid of ambient and social time cues — from the simple single cell organisms of very long evolutionary history like Gonyaulax polyedra (Cornelissen et al., 1986; Halberg et al., 1985; Hastings & Keynan, 1965) and Acetabularia (Berger et al., 1990; Schweiger, 1969; Schweiger & Schweiger, 1965; Schweiger et al., 1986) to the more complex plant, insect (Brown & Chow, 1973; Chiba et al., 1973; Hayes et al., 1980, 1983, 1986; Meyer-Rochow

& Brown, 1998; Mikulecky & Bounias, 1997; Spruyt et al., 1987), fish (Cornelissen et al., 1995a), birds (He et al., 2014) and mammalian species, e.g. laboratory rodents (Bourreau et al., 1987; DeLisi et al., 1983; Levi et al., 1982; Marques et al., 1994; Sanchez de la Pena et al., 1984; Scheving et al., 1981; Tsai et al., 1989), horse (Marques et al., 1996; Piccione et al., 2004) and human beings (Cornelissen et al., 2005; Guan et al., 2011; Halberg, 1995; Halberg & Hamburger, 1964; Halberg & Reinberg, 1967; Halberg et al., 1964,1965, 1981; Hamburger, 1954; Hamburger et al., 1985; Haus, 2007; Haus & Smolensky, 1999; Hecht et al., 2002; Kanabrocki et al., 1995; Kirchner et al., 2015; Lee et al., 2003; Levi & Halberg, 1982; Lucas et al., 1985; Montalbini et al., 1989; Otsuka et al., 1994; Paine & Gander, 2016; Rakova et al., 2013; Reinberg O et al., 2005; Sanchez de la Pena et al., 1989; Titze et al., 2014), of more recent evolutionary time.

The primary purpose of our expedition has been to seek answers to the fundamental questions of the origin, synchronization, FA and AV of 7 d rhythms in life forms, and also in human beings their potential clinical significance.

The origin of 7 d bioperiodic phenomena is unknown; however, several theories have been advanced. One is they are the result of external triggers as accommodative biological responses. In this regard, several investigators (e.g. Cornelius et al., 1967; De Vecchi et al., 1979,1981; Garcia et al., 1994, 1995; Hildebrandt, 1977, 1984, 1993; Hildebrandt et al., 1982; Hubner, 1969; Kawahara et al., 1980, 1982; Knapp & Pownall, 1980; Levi & Halberg, 1982; Levi et al., 1982; Pollmann, 1984; Ratte et al., 1977; Sasse, 1981) have demonstrated the generation of cyclic or other ~7 d phenomena in humans and animals by external triggers. Another theory is they are caused and maintained by persistent cyclic cosmic phenomena. Cornelissen et al. (1993), Diaz-Sandoval et al. (2008), Halberg et al. (2000, 2010), Mikulecky & Mikulecky (2014), Revilla et al. (1996) and Uezono et al. (2001), based on statistical associations, suggest or conclude they derive from ~7 d and/ or ~3.5 d relatively weak geomagnetic cosmic cycles generated by the Sun and/or planets. However, statistical evidence of controlled experiments is lacking. In fact, the results of studies involving complex organisms — insects and human beings — conducted under constant conditions devoid of usual 24 h, lunar, and annual ambient and social time cues, but not necessarily ones of cosmic origin, are not consistent with the contention these rhythms are generated, maintained or synchronized by cyclic external cosmic electromagnetic or other phenomena (Chiba et al., 1973; Halberg, 1995; Levi & Halberg, 1982; Lucas et al., 1985; Meyer-Rochow & Brown, 1998; Montalbini et al., 1989; Sanchez de la Pena et al., 1989). Indeed, under these constant conditions, the rhythms free-run and display a т < 7 d. Admittedly, the ~30 d lunar cycle exhibits several distinct ~7 d phases that give rise to predictable variation in the time of moonrise and moonset, and thus nocturnal and diurnal moonlight photofraction and intensity, and specialized photoreceptors are capable of sensing such temporal signals (Ben Attia et al., 2016; Reinberg et al., 2016). Although pole bean seeds (Brown & Chow, 1973; Spruyt et al., 1987) and some nutritional rhythms of worker honey bees (Mikulecky & Bounias, 1997) exhibit 7 d cycles that are linked and seemingly synchronized by the four distinct ~7 d lunar phases, we know of no experiments that have tested the theory that anyone of the photic features of the lunar cycle is the source of the 7 d biological time structure in other life forms, particularly human beings.

Can it be assumed the 7 d bioperiodicites of today are representative of ones that were of FA, AV and/or SV to individual organisms and species in a milieu of cyclic environmental or cosmic phenomena that existed eons ago, during the early history of the earth, when the т of the rotation of the earth around its axis was <24 h (Wells, 1963)? The rotation of the earth around the sun has maintained a fixed т throughout geological time, precisely 365.256 d when calculated according to the day length being 24.0 h. The rotation of the Earth around its axis, however, has slowed during geological time. Evidence for this comes from fossilized coral beds formed by sea animals >400 million years ago in which each astonomical “day” is denoted by the deposition of a single calcium salt layer, the thickness of which varies according to time during the astonomical year. Analysis of these fossil records reveals the т of the earth’s rotation about its axis early in geological time was 21.9 h, corresponding to an astronomical year, defined by the rotation of the earth around the sun, of ~400 “days.” This means that long ago the duration of the 7 d week was 153.3 h (21.9 h • 7 d) compared to 168 h (24 h • 7 d) today, with each “year” then composed of ~57.18 wk compared to ~52.17 wk nowadays. Such change in the respective duration of the astronomical day and week does not exclude the expression of cyclic biological phenomena of presumed corresponding т. No doubt the L/D alternation with т of 21.9 h served as a prominent synchronizer of circadian (20 h < т < 28 h) rhythms that assumedly bestowed significant FA, AV and SV to simple organisms. Yet, no earth-borne or cosmic cyclic phenomena with a т of 153.3 h, equal to 6.38 d -the then duration of the “week”, are known to have existed at that time during evolution that might be expected to confer meaningful FA, AV and SV and thus be the basis today for the 7 d periodicity of organisms as an endogenous biological trait. The Ten Commandments guide the cultural, religious and moral behaviors of human beings. The one specifically devoted to the Shabbat that thus defines the Hebraic 6 d work/1 d rest week and that respects the work/rest pattern of G-d in creating the world is too recent an event in evolutionary time to explain why 7 d biological rhythms are an endogenous trait in humans and, of course, any of the other species of this planet. The Hebraic week gives rise to 7 d human behavioral and activity patterns, and although it may serve to provide synchronizer signals to biological processes of corresponding т, it cannot be the origin of the 7 d time structure.

Presently, there is no evidence that gives credence to the hypothesis 7 d rhythms impart SV to any species, and, additionally, no specific research has yet to identify their significance in conferring FA or AV to individual organisms. This is in contrast to the known FA and AV of rhythms of other ts. Circadian rhythms, for example, bestow not only FA through predictable-in-time oscillation of processes synchronized by the 24 h L/D cycle to ensure efficient utilization of energy resources during the activity span and conservation of them during the rest span, but also AV through differential readiness during the 24 h to respond to mostly predictable-in-time ambient biological, chemical and physical challenges (e.g. Halberg, 1960a; Ticher et al., 1995). Additionally, circannual rhythms are of both FA and AV by preparing life forms ahead of time for seasonal differences in environmental conditions and nutrient resources signaled through predictable-in-time change during the year in daily photofraction. Furthermore, the circannual time structure of almost all species is of SV through the temporal organization and coordination of the reproductive biology and mating behavior of males and females of both short-day and long-day breeders (Boissin & Canguilhem, 1998; Nelson et al., 2002; Ortavant & Reinberg, 1980; Pengelley, 1974; Reinberg & Ashkenazi, 2003; Reinberg & Smolensky, 1983; Smolensky & Reinberg, 1985). In a similar way, circa-monthly rhythms in reproductive endocrinology, functions and behaviors are of fundamental SV for many plant, fish and primate species, including humans (see Ben Attia et al., 2016; Reinberg et al., 2016; Smolensky et al., 1972).

It is of interest that Palmer et al. (1982) found the SA of young couples exhibits very prominent 7 d patterning. SA is markedly greater during the weekend (~38% of the total weekly SA) than weekdays, with the absolute peak in SA on Sunday. However, in the absence of evidence to the contrary, we assume this 1 wk temporal variation is unrelated to an endogenous 7 d time structure of SV achieved through natural selection during evolution. Rather, it is likely the consequence of temporal differences in the opportunity for SA during the course of the week. Along these lines, Jewish Law as conveyed by the Torah relates the expression of human sexuality (specifically sexual intercourse for procreation) is a mandate and first mitzvah, i.e. commandment by G-d and good deed, one of the holiest of all human endeavors. The Talmud (treatise Ketoubot) recommends workers engage in sexual intercourse twice on Shabbat, unless the female is in an “impure state” (during menses and 7 d thereafter), but once-a-day or less weekdays according to one’s specific occupation (http://www.chabad.org/theJewishWomen/arti clecdo/aid/1541/jewish/The-Mikvah.htm). Thus, it is likely the SA of devout Hebrews, especially in ancient times, exhibited a prominent 7 d pattern with a Saturday, rather than Sunday, peak as found in the study by Palmer et al. (1982) of young couples and other study samples of unspecified religious belief and practice.

The Laws of Moses are central to the health, wellbeing and cultural life of the Hebrews, and in this regard one of the authors of this article (Dejardin, 2012) explored their relevance to the prevention of the so-called “burn out” syndrome. The 24 h time structure of most, if not all, simple and complex life forms entails a circadian stage of elevated physical and metabolic activity, alternating with a circadian stage of rest, energy economy and rejuvenation/ repair, with each stage supported by numerous complementary periodic processes at all levels of biological organization. In humans, and most likely other organisms, this 24 h rest/activity pattern not only involves a circadian but a homeostatic component, i.e. representative of the progressive rise in physical, metabolic and other types of fatigue as a consequence of the diverse activities and associated energy expenditures of wakefulness (Borbely, 1980). In the 1960s, the model was termed “relaxation system” (Aschoff, 1965; Reinberg, 1997b). A large body of research documents the health and well-being of human beings are compromised when an insufficient amount time is devoted to sleep (Alvarez & Ayas, 2004; Killgore, 2010; Meerlo et al., 2008; Tobaldini et al., 2014), indicating the endogenous circadian processes of rest/sleep of humans, and presumably other organisms (e.g. Deurveilher et al., 2015; Periasamy et al., 2015; Vienne et al., 2016; Yaoita, 2016), are of critical importance for realization of the FA and AV of individual organisms. In line with this perspective, hibernation — a feature of the circannual time structure — in certain ways may be viewed as a specialized form of biological “rest.” Even though the circadian sleep/wake rhythm during hibernation may be disrupted and sleep appear to be a unique arousal-like state according to elec-troencephalographic criteria, biologically it is a stage of energy economy, comparable conceptually to the rest/sleep stage of the circadian time structure that confers FA, and for some species AV (Kilduff et al., 1993; Larkin & Heller, 1998; Larkin et al., 2002; Nelson et al., 2002; Siegel, 2009). The perspective that hibernation is an aspect of the circannual time structure is not new (Berger, 1975, 1984; Pengelley, 1974; Rial et al., 2010; Schmidt, 2014; Tu & McKnight, 2006); however, previously it was not conceptualized in terms of FA and AV.

As a working hypothesis, we propose the 7 d time structure of human beings and certain other life forms is simply the biological imperative for the bioperiodic, i.e. predictable-in-time, requirement for 1 d out of every 7 d for energy economy, rest and rejuvenation/repair that entails also an integrated homeostatic component, as in the case of the circadian time domain as modeled by Borbely (1980). This hypothesis is consistent not only with the biological utility of the Hebraic 7 d week that includes the Shabbat, the holy day of rest, but the almost universal acceptance of it in human life worldwide today. The 7 d cyclic-like pattern of activity and associated bedtime and rise times, with preference for later ones both Saturday and Sunday than weekdays, plus longer duration sleep on weekends, especially evident in adolescent and young adult evening chronotypes (de Souza & Hidalgo, 2015; Paine & Gander, 2016; Stowie et al., 2015; Vitale et al., 2015b) but also characteristic of other age and chronotype groups (Hecht et al., 2002), is assumed to be tied specifically to the sociocultural demands of modern life. On the other hand, could these Saturday and Sunday “behaviors”, what some refer to today as “recovery”, actually be representative of an endogenous 7 d time structure that in the past as well as today affords FA and AV to individuals, and when not respected compromises well-being and health (Fritz & Sonnentag, 2005; Kubo et al., 2011; Lee et al., 2015; Wang et al., 2015)? From our point of view, the failed experimental attempts by the leaders of the French Revolution to redefine the week as 10 d and then 5 d as well as the leaders of the Russian Revolution to redefine it as 5 d constitute population-based evidence that backs our proposed hypothesis of the biological basis for the 7 d time structure.

These failed attempts to redefine the duration of the week compel us to examine the widely held assumption anyone can perform work with equal proficiency at any time during the 24 h, week, month and year (Reinberg & Smolensky, 1983, 1994). Decades of shift work research have proven beyond doubt the fallacy of this belief (e.g. see Reinberg & Smolensky, 1983, 1994; Reinberg et al., 1981, 2015). Moreover, research findings reveal the absurdity of this notion, even in regard to the start and end times of the school day, temporal ordering of presented subject matter and number of days comprising the school week (Beugnet-Lambert et al., 1988; Cerasuolo et al., 2016; Fotinos & Testu, 1996; Guerin et al., 1993; Leconte, 2011; Testu, 1989; Vermeil, 1995). Preadolescents, adolescents and young adults tend to be evening chronotypes; compared to the adult population, they prefer later nocturnal bedtimes and later diurnal awakening times. Thus, the traditional school schedule that necessitates an early morning awakening results in a shorter than required sleep duration, i.e. sleep deprivation, the consequence being compromised school attention, learning and performance (e.g. Guerin et al., 1993; Haraszti et al., 2014; Martin et al., 2016; Touitou 1999, 2013; van der Vinne et al., 2015; Wolfson & Carskadon, 1998). The relevance of the circadian time structure of children to the school setting is increasingly gaining appreciation; pediatricians and school administrators recommend the school day commence at a chronobiologically more compatible (later clock) time (Be^oluk et al., 2011; Adolescent Sleep Working Group; Committee on Adolescence; Council on School Health, 2014; Owens et al., 2010; Touitou, 2013; Wheaton et al., 2015). Yet, almost no attention has been devoted to the 7 d time structure of school children as it pertains to the design of the school week.    Since the majority of the authors of the present article are French, we focus on the school week in France, which has been strongly shaped by religious, political and economic factors rather than the chronobiology of school children, a topic of increased scientific investigation nowadays (Arbabi et al., 2015; Be^oluk et al., 2011; Diaz-Morales & Escribano, 2015; Diaz-Morales et al., 2015; Escribano & Diaz-Morales, 2014; Guerin et al., 1993; Haraszti et al., 2014; Martin et al., 2016; Owens et al., 2010; Tonetti et al., 2015; Touitou, 1999, 2013; van der Heijden et al., 2010; van der Vinne et al., 2015; Wheaton et al., 2015; Wolfson & Carskadon, 1998).

At the beginning of the twentieth century, there was disagreement between the leaders of the French public and religious (Catholic) schools about the number and distribution of class days across the 7 d week. Then, children, no matter their religion, attended school free of charge 6 d per week, i.e. everyday but Sunday. In 1905, the French public school week was reorganized to 5 d with 2 d off, Sunday as before plus 1 d mid-week -initially Thursday but subsequently Wednesday -resulting in a so-called “broken” week, the weekday off being devoted to religious education when parents of children desired such. In 1936, mainly for political gain, the wages of civil servants were raised; however, teachers were excluded because of economic constraints. Instead, teachers were “compensated” by granting them an additional 1% months of vacation time. This so-termed avan-tage acquis (English: acquired advantage), which became a non-negotiable contractual right, necessitated the annual school term be shortened to 175 d and the school day lengthened. In 2007, the French Minister of Education, a naive political appointee even though having been awarded a university doctoral degree, mandated further reduction of the school week to 4 d — Monday-Tuesday and Thursday-Friday. This misguided mandate, which disregarded the chronobiologic and other determinants of the stamina and capability for sustained attention of children, necessitated that long hours be devoted daily to master materials both during and after formal school hours. As a consequence, ~50% of French school children developed symptoms of intolerance like those of “burn-out syndrome,” e.g. abnormal fatigue, poor attention and sleep disturbances. Additionally, test scores, as measures of learning, dramatically decreased. French chronobiologists, two being the co-authors of this article (AR & YT), were the first to proclaim publicly the broken 4 d week was a huge mistake (Touitou & Begue,

2010). Before being dismissed from his post, the Minister of Education accused the “chrono-some-things” of being trouble makers. Following subsequent implementation of a less fatiguing 4.5 d school week, student learning markedly improved. In summary, for children as it is for adults, population-based “trials” document the size of the week cannot be manipulated at will without increasing the risk of fatigue and other symptoms of intolerance. A school workload intended for presentation over 5-6 d when compressed into 4 d is not compensated by 3 d of rest. Moreover, the week cannot be “broken” into shorter intervals each of

2, 3 or 4 d duration; to optimize performance and well-being, it must be maintained as closely as possible to 7 d, e.g. 6 d of work alternating with

1 d of rest (Dejardin, 2012). Finally, even though the strength of the 7 d time structure, defined by the amplitude of its individual rhythms, of healthy organisms, including humans, under ordinary circumstances typically is not as great as that of the individual rhythms of the circadian time structure, it, nonetheless, seems to be of clinical relevance. Population-based studies reveal quite prominent day-of-week differences, among others, in the manifestation or exacerbation of infectious, gastrointestinal, lung, mood, hemostatic and neurological disorders (Ajdacic-Gross et al., 2015; Baibergenova et al., 2005; Beauchamp et al., 2014; Brillman et al., 2005; Cugini et al., 1990; Halberg, 1995; Kao et al., 2010, 2014; Manfredini et al., 2015; Svanes et al., 1998; Walker et al., 2007) plus serious and even life-threatening cardiac and vascular events, typically with peak incidence on Mondays (Arntz et al., 2000; Boari et al., 2011; Cantwell et al., 2015; Cornelissen et al., 1993; Diaz-Sandoval et al., 2008; Manfredini et al., 2010a, b, 2011; Nicolau et al., 1991; Vitale et al., 2015a; Witte et al., 2005). However, it’s unknown whether these and other weekly patterns of disease intensity and mortal events result from differences between weekdays and weekends in risky behaviors, endogenous 7 d rhythm of biological vulnerability, or both. Additionally, 7 d phenomena are observed in patient status following their “triggering,” e.g. by birth, infection or surgery and other medical interventions (Cornelius et al., 1967; De Vecchi et al., 1979, 1981; Garcia et al., 1994, 1995; Hildebrandt, 1977, 1984, 1993; Hildebrandt et al., 1982; Hurley et al., 1987; Knapp & Pownall, 1980; Levi & Halberg, 1982; Levi et al., 1982; Pollmann, 1984; Sasse, 1981). Moreover, increase in the prominence (amplitude) of 7 d rhythms may be indicative of pathology and risk state. Peyro et al. (1999a, b, 2002) found 7 d SBP and DBP rhythms measured directly from the radial and pulmonary arteries of intensive care unit comatose patients that were 3-fold greater in amplitude than their respective 24 h rhythms, with disparity in the 0 of the SBP and DBP 7 d rhythms predictive of impending mortality. The findings are similar for sudden infant death syndrome (SIDS) of premature infants; the amplitude ratio of the 7 d versus 24 h rhythm in respiratory rate and also oxygen saturation was found to be nearly 3-fold greater in at-risk than non-at-risk for SIDS infants (Halberg et al., 1991). These and other observations (Cornelissen et al., 1995b; Cornelius et al., 1967; De Vecchi et al., 1979, 1981; Kawahara et al., 1980, 1982; Knapp & Pownall, 1980; Levi & Halberg,

1982) raise the question of whether certain disease and risk states can be improved by applying 7 d chronotherapeutic, perhaps even chronopreven-tive, strategies rather than the current homeostatic-based ones. Although various circadian chronotherapies (De Giorgi et al., 2013; Hermida et al., 2016; Reinberg, 1983; Smolensky et al., 2015a, 2016) are now available to clinicians to optimize the beneficial effects of many classes of medications and better manage medical conditions that exhibit strong predictable-in-time 24 h variation (Smolensky et al., 2015b, c, 2016), to our knowledge there has been little exploration as yet of the utility of 7 d-modulated chronotherapy regimens to optimize the control of medical conditions that exhibit prominent day-of-week differences in disease pathology, symptom intensity and risk of life-ending events (Baselga & Tabernero, 2001; Blank et al., 1995; Halberg, 1995; Levi & Halberg, 1982; Levi et al., 1982; Liu et al., 1986). Certainly, this merits further research.

Concluding comments

Neither cosmic nor earth-borne signals seem to be of sufficient strength to give rise to the 7 d rhythms of life forms of various degree of complexity. Experiments conducted under conditions devoid of conventional environmental time cues, but not necessarily electromagnetic or other cosmic and earth-borne cycles, reveal persistence of 7 d bioperiodicity, but with a slightly altered т, resulting in free-running of the peak and trough relative to time of the week. This evidence motivates us to hypothesize weekly rhythms are endogenous in origin. Biologists commonly assess the utility of bioprocesses, functions and rhythms, either individually or collectively, according to their pertinence to the SV of species, admittedly a criterion that does not indicate 7 d rhythms of humans or other species are the consequence of past “selective” pressures. We understand the concepts of “adaptive value” and “functional advantage” may be differently interpreted (Prosser, 1986) and that they must be invoked with caution, especially given the anthropocentrism of many biologists (Reinberg & Ashkenazi, 2003; Smolensky & Reinberg, 1985). Unlike the endogenous circadian, circa-monthly and circannual rhythms, which as the end result of evolutionary forces confer FA and AV to individual organisms and SV to species (e.g. Ben Attia et al., 2016; Boissin & Canguilhem, 1998; Ortavant & Reinberg, 1980; Reinberg & Ashkenazi, 2003; Reinberg et al., 2016; Smolensky & Reinberg, 1985; Smolensky et al., 2015d; Ticher et al., 1995), there is no convincing evidence this is the case for weekly rhythms.                             

The question thus arises: What is the underlying rationale and mechanism of 7 d rhythms? The same question was asked decades ago about the 24 h activity/rest rhythm, but in the form of: Why do humans and other higher order diurnally and nocturnally active organisms need to sleep? Borbely (1980) proposed a two-process model of interacting homeostatic and oscillatory components to explain the rationale and mechanism of the 24 h sleep/wake rhythm of human beings, although in principle it seems applicable to other organisms, too. He hypothesized the progressive accumulation of an as yet unknown substance associated with activities of the wake span that interacts with the staging of endogenous circadian processes to initiate predictable-in-time sleep and associated restorative processes. As a complementary hypothesis, we propose the biological requirement for 1 d of rest per 6 d of work derives from one or more chemical substances that progressively accumulate in association with the 6 d work/active span, as an internal signal perceived by the brain — presumably the left hemisphere in right-sided dominant persons (Reinberg, 1997b; Springer & Deutsch, 1998), relative to the staging of an endogenous 7 d time structure. Human beings are a highly social species and as such social time cues can serve to synchronize human biological rhythms. This was clearly demonstrated to be the case for human circadian rhythms by Apfelbaum et al. (1969). In a group of healthy women housed together during isolation in an underground cave that precluded the perception of environmental and also clock time cues, the sleep/wake circadian rhythm of each subject desynchronized and free-ran with т Ф 24.0 h, but with differences in т between individual subjects. Sometime thereafter during the isolation experiment, the sleep/wake circadian rhythm resynchronized as a group phenomenon, with every subject displaying an identical т of 24.8 h. These observations indicate social factors are powerful synchronizers not only of the human circadian wake/sleep rhythm but the overall circadian system. With the findings of this study in mind, we hypothesize sociocultural time cues closely associated with the scheduled work and non-work (e.g. Hebraic Shabbat and Christian Sunday) days of the 7 d week resynchronize and reset the staging and т of human 7 d rhythms.

The work week of 6 d in duration, e.g. compared to one of 3, 4, 5, 8, 9 or 10 d, prior to the rest day seems to be optimal for humans. This perspective is factually substantiated. Among the subdivisions of the lunar month of ~29.5 d, only the 7 d period of the Hebraic week has survived human history. Its acceptance over such an extensive length of time suggests the 7 d week is not a chance “creation.” All attempts to reconfigure the duration of the week, including that by the French school system when instituting the broken 4 d one, ended disastrously because of physical and/or mental intolerance. Thus, we disagree with Zerubavel (1989), who without experimental evidence, considers that the week of 7 d duration arose by chance.

Finally, if one assumes 7 d rhythms are exclusively of endogenous origin, there is no need to separate such cyclic temporal phenomenon into two categories — spontaneous versus reactive — as proposed by Levi and Halberg (1982). Cyclic 7 d phenomena that are perceived to be reactive require both the triggering and staging of peak and/or trough times by one or more specific external signals of only occasional occurrence. However, it is unknown if the resultant overt 7 d phenomena represent the de novo elicitation of bioperiodicities or the recruitment and/or synchronization of very low-amplitude rhythms of such т that are otherwise under-expressed, repressed or masked (Mrosovsky, 1999; Page, 1989; Wever, 1985). If, indeed, the latter is the case, such overt cycles are perhaps expressions of the AV of the 7 d time structure by favorably enhancing the FA they provide to the individual organism, although the effect in some presumably rare instances may not be favorable but detrimental as exemplified by the serious about-weekly interval organ rejection episodes demonstrated by laboratory animal experiments and experienced by transplant patients (Cornelius et al., 1967; De Vecchi et al., 1979, 1981; Kawahara et al., 1980, 1982; Knapp & Pownall, 1980; Levi & Halberg, 1982; Levi et al., 1982; Ratte et al., 1977). This dichotomy of positive and negative outcome effects of the AV of the 7 d time structure brings to mind the perspectives of Selye (1950). Based only on homeostatic mechanisms and criteria, he viewed the “adaptive” response to “stress” as conferring immediate positive but also later potentially negative, even pathological, outcomes. We are of the opinion that spontaneous endogenously generated cyclic 7 d phenomena are synchronized and/or enhanced, not triggered, by periodic ambient signals, particularly sociocultural and other ecological features of the 6 d work/1 d -Saturday or Sunday — rest day. Even though the 7 d self-sustained oscillator system does not appear to be as strong, in terms of amplitude, as most circadian and certain circannual rhythms, its biological and clinical significance cannot be dismissed as earlier discussed.       We conclude our fact-seeking expedition to the time domain of 7 d rhythms with a rather provocative view about the magic of the number 7. We discussed partially for fun the perspective that it grants special magical power and effects to things, living or otherwise. The direction of such power and effect(s) is perceived as always emanating in direction from outside to inside. Why is it that the effect(s) of the number 7 upon human beings, in particular, not in the opposite direction? Did the 7 d week choose us or did we choose it? We feel intuitively — with the help of our left brain (Springer & Deutsch, 1998) — that 7 d rhythms are swinging within us, but we are blind to the detailed knowledge of them, making them still illusionary. Since prominent 7 d cyclic astronomical phenomena do not exist outside of us, our feeling about “7 somethings” seems to come from nowhere, apart from Wonderland, which is magic for those who ignore the fact that 7 d rhythms represent an integral endogenous component of the multi-spectral temporal organization of human and other life forms.

Acknowledgements

We express deep gratitude to Maxime Ouanounou, who helped us better understand various Jewish behavioral rites, and Linda Sackett-Lundeen, who helped with the construction of the illustrations and finalization of our article.

Declaration of interest

The authors have no conflicts of interest that influence the content of this review. This work was supported by the

Tremel-Pontremoli donation to support the research activities of the Unite de Chronobiologie at the Fondation Adolphe de Rothschild in Paris, France.

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