Loss Of Rhythm Research Articles

Abstract 760: Alteration to transcriptional rhythmicity in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet

Abstract Biological clocks, existing in all human organ systems, cycle every 24 hours in a diurnal pattern and control the daily rhythms of human life (e.g., eating vs. fasting, sleep vs. wakefulness), which is essential for health and wellbeing. Disruption of the biological clocks, either by genetic or environmental alteration, disturbs circadian rhythms, which may lead to chronic diseases. Childhood obesity is a risk factor for breast cancer in adult women. Lifestyle changes in the modern world (e.g., energy-dense diets) serve as environmental factors that contribute to alterations in biological clocks and obesity. The present study examined transcriptional rhythmic changes in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet (HFD). Three-week-old female mice (FVB background) were randomly assigned into three groups - wild-type (WT) mice fed the AIN93G diet and MMTV-PyMT mice fed the AIN93G diet or an HFD for three weeks. At the end of the study, mammary glands were collected every 4 hours over a period of 24 hours (Zeitgeber time 0-24 hours) for RNA-sequencing analysis. The mammary weight was 0.45±0.02, 0.59±0.02, and 0.67±0.02 g for WT mice fed the AIN93G diet and MMTV-PyMT mice fed the AIN93G and HFD, respectively (means ± SEM, all p<0.05 when three groups were compared each other). The rhythmicity analysis using R showed that greater than 1,000 transcripts were classified as “loss of rhythm” when MMTV-PyMT mice (both AIN93G-fed and HFD-fed groups) were compared to WT mice fed the AIN93G diet. Eighteen transcripts were classified as “loss of rhythm” in MMTV-PyMT mice when the HFD was compared to AIN93G diet. Hierarchical clustering analysis showed differentially expressed genes that were significantly altered and KEGG enrichment analysis showed the most upregulated and downregulated metabolic pathways in treatment groups than in the control group at each time point over the 24-hour period. These findings indicates that genetic alterations may have a greater effect than dietary effects on transcriptional rhythmicity in mammary glands from pubertal mice. Citation Format: Lin Yan, Daniel G. Palmer, Huawei Zeng. Alteration to transcriptional rhythmicity in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 760.

Thousands of oscillating LncRNAs in the mouse testis

The long noncoding RNAs (lncRNAs) are involved in numerous fundamental biological processes, including circadian regulation. Although recent studies have revealed insights into the functions of lncRNAs, how the lncRNAs regulate circadian rhythms still requires a deeper investigation. In this study, we generate two datasets of RNA-seq profiles of the mouse (Mus musculus) testis under light-dark (LD) cycle. The first dataset included 18,613 unannotated transcripts measured at 12 time points, each with duplicate samples, under LD conditions; while the second dataset included 21,414 unannotated transcripts measured at six time points, each with three replicates, under desynchronized and control conditions. We identified 5964 testicular lncRNAs in each dataset by BLASTing these transcripts against the known mouse lncRNAs from the NONCODE database. MetaCycle analyses were performed to identify 519, 475, and 494 rhythmically expressed mouse testicular lncRNAs in the 12-time-point dataset, the six-time-point control dataset, and the six-time-point desynchronized dataset, respectively. A comparison of the expression profiles of the lncRNAs under desynchronized and control conditions revealed that 427 rhythmically expressed lncRNAs from the control condition became arrhythmic under the desynchronized condition, suggesting a possible loss of rhythmicity. In contrast, 446 arrhythmic lncRNAs from the control condition became rhythmic under the desynchronized condition, suggesting a possible gain of rhythmicity. Interestingly, 48 lncRNAs were rhythmically expressed under both desynchronized and control conditions. These oscillating lncRNAs were divided into morning lncRNAs, evening lncRNAs, and night lncRNAs based on their time-course expression patterns. We interrogated the promoter regions of these rhythmically expressed mouse testicular lncRNAs to predict their possible regulation by the E-box, D-box, or RORE promoter motifs. GO and KEGG analyses were performed to identify the possible biological functions of these rhythmically expressed mouse testicular lncRNAs. Further, we conducted conservation analyses of the rhythmically expressed mouse testicular lncRNAs with lncRNAs from humans, rats, and zebrafish, and uncovered three mouse testicular lncRNAs conserved across these four species. Finally, we computationally predicted the conserved lncRNA-encoded peptides and their 3D structures from each of the four species. Taken together, our study revealed thousands of rhythmically expressed lncRNAs in the mouse testis, setting the stage for further computational and experimental validations.

Flavoring Agents in E-cigarette Liquids: A Comprehensive Analysis of Multiple Health Risks.

The availability of a wide range of flavored e-cigarettes is one of the primary reasons for vaping initiation and persistent use among adolescents and young people. This plethora of flavors available on the market are crafted using different flavoring agents such as cinnamaldehyde, vanillin, benzaldehyde, ethyl maltol, menthol, and dimethylpyrazine. Recent studies have brought to light the potential risks associated with e-cigarette flavoring agents and their effects on various organ systems, both with and without nicotine. Research has demonstrated that flavoring agents can induce inflammation, endothelial dysfunction, epithelial barrier disruption, oxidative stress, DNA damage, electrophysiological alterations, immunomodulatory effects, and behavioral changes, even independently of nicotine. Notably, these negative outcomes adversely affect cardiovascular system by reducing cell viability, decreasing endothelial nitric oxide synthase, nitric oxide bioavailability, soluble guanylyl cyclase activity and cyclic guanosine monophosphate accumulation, impairing endothelial proliferation and tube formation, and altering vasoreactivity resulting in vascular dysfunction. In the heart, these agents decrease parasympathetic activity, induce depolarization of resting membrane potential, loss of rhythmicity, increase isovolumic relaxation time, and change in ventricular repolarization and ventricular tachyarrhythmias. It is found that the specific response elicited by flavoring agents in different organ systems varies depending on the flavor used, the concentration of the flavoring agent, and the duration of exposure. However, the literature on the effects of flavoring agents is currently limited, emphasizing the need for more preclinical and randomized clinical trials to gain a deeper understanding and provide further evidence of the harmful effects of flavored e-cigarette use. In summary, recent research suggests that flavoring agents themselves can have detrimental effects on the body. To fully comprehend these effects, additional preclinical and clinical studies are needed to explore the risks associated with flavored e-cigarette usage.

Loss ofDiel Circadian Clock Gene Cycling Is a Part ofGrape Berry Ripening.

Diel cycles of gene expression are thought to adapt plants to 24-h changes in environmental conditions. The circadian clock contributes to this process, but less is known about circadian programs in developing reproductive organs. While model plants and controlled conditions have contributed greatly to our knowledge of circadian clock function, there is a need to better understand its role in crop plants under field conditions with fluctuating light and temperature. In this study, we investigated changes in the circadian clock during the development of grape berries of Vitis vinifera L. We found that the transcripts of circadian clock homologs had high-amplitude oscillations prior to, but not during, ripening. As ripening progressed, the amplitude and rhythmicity of the diel oscillations decreased until most transcripts tested had no significant fluctuation over the 24-h cycle. Despite this loss of rhythmicity, the majority of circadian clock genes investigated were expressed at or near their abundance at the nadir of their pre-ripening oscillation although the berries remained transcriptionally active. From this, it can be concluded that cycling of the canonical circadian clock appears unnecessary for berry ripening. Our data suggest that changes in circadian clock dynamics during reproductive organ development may have important functional consequences.

Genetic and environmental circadian disruption induce weight gain through changes in the gut microbiome

ObjectiveInternal clocks time behavior and physiology, including the gut microbiome, in a circadian (∼24 h) manner. Mismatch between internal and external time, e.g. during shift work, disrupts circadian system coordination promoting the development of obesity and type 2 diabetes (T2D). Conversely, body weight changes induce microbiota dysbiosis. The relationship between circadian disruption and microbiota dysbiosis in metabolic diseases, however, remains largely unknown. MethodsCore and accessory clock gene expression in different gastrointestinal (GI) tissues were determined by qPCR in two different models of circadian disruption - mice with Bmal1 deficiency in the circadian pacemaker, the suprachiasmatic nucleus (Bmal1SCNfl/-), and wild-type mice exposed to simulated shift work (SSW). Body composition and energy balance were evaluated by nuclear magnetic resonance (NMR), bomb calorimetry, food intake and running-wheel activity. Intestinal permeability was measured in an Ussing chamber. Microbiota composition and functionality were evaluated by 16S rRNA gene amplicon sequencing, PICRUST2.0 analysis and targeted metabolomics. Finally, microbiota transfer was conducted to evaluate the functional impact of SSW-associated microbiota on the host's physiology. ResultsBoth chronodisruption models show desynchronization within and between peripheral clocks in GI tissues and reduced microbial rhythmicity, in particular in taxa involved in short-chain fatty acid (SCFA) fermentation and lipid metabolism. In Bmal1SCNfl/- mice, loss of rhythmicity in microbial functioning associates with previously shown increased body weight, dysfunctional glucose homeostasis and adiposity. Similarly, we observe an increase in body weight in SSW mice. Germ-free colonization experiments with SSW-associated microbiota mechanistically link body weight gain to microbial changes. Moreover, alterations in expression of peripheral clock genes as well as clock-controlled genes (CCGs) relevant for metabolic functioning of the host were observed in recipients, indicating a bidirectional relationship between microbiota rhythmicity and peripheral clock regulation. ConclusionsCollectively, our data suggest that loss of rhythmicity in bacteria taxa and their products, which likely originates in desynchronization of intestinal clocks, promotes metabolic abnormalities during shift work.

Circadian rhythms in the plant host influence rhythmicity of rhizosphere microbiota

BackgroundRecent studies demonstrated that microbiota inhabiting the plant rhizosphere exhibit diel changes in abundance. To investigate the impact of plant circadian rhythms on bacterial and fungal rhythms in the rhizosphere, we analysed temporal changes in fungal and bacterial communities in the rhizosphere of Arabidopsis plants overexpressing or lacking function of the circadian clock gene LATE ELONGATED HYPOCOTYL (LHY).ResultsUnder diel light–dark cycles, the knock-out mutant lhy-11 and the gain-of-function mutant lhy-ox both exhibited gene expression rhythms with altered timing and amplitude compared to wild-type plants. Distinct sets of bacteria and fungi were found to display rhythmic changes in abundance in the rhizosphere of both of these mutants, suggesting that abnormal patterns of rhythmicity in the plant host caused temporal reprogramming of the rhizosphere microbiome. This was associated with changes in microbial community structure, including changes in the abundance of fungal guilds known to impact on plant health. Under constant environmental conditions, microbial rhythmicity persisted in the rhizosphere of wild-type plants, indicating control by a circadian oscillator. In contrast, loss of rhythmicity in lhy-ox plants was associated with disrupted rhythms for the majority of rhizosphere microbiota.ConclusionsThese results show that aberrant function of the plant circadian clock is associated with altered rhythmicity of rhizosphere bacteria and fungi. In the long term, this leads to changes in composition of the rhizosphere microbiome, with potential consequences for plant health. Further research will be required to understand the functional implications of these changes and how they impact on plant health and productivity.

Age and Chronodisruption in Mouse Heart: Effect of the NLRP3 Inflammasome and Melatonin Therapy.

Age and age-dependent inflammation are two main risk factors for cardiovascular diseases. Aging can also affect clock gene-related impairments such as chronodisruption and has been linked to a decline in melatonin synthesis and aggravation of the NF-κB/NLRP3 innate immune response known as inflammaging. The molecular drivers of these mechanisms remain unknown. This study investigated the impact of aging and NLRP3 expression on the cardiac circadian system, and the actions of melatonin as a potential therapy to restore daily rhythms by mitigating inflammaging. We analyzed the circadian expression and rhythmicity of clock genes in heart tissue of wild-type and NLRP3-knockout mice at 3, 12, and 24 months of age, with and without melatonin treatment. Our results support that aging, NLRP3 inflammasome, and melatonin affected the cardiac clock genes expression, except for Rev-erbα, which was not influenced by genotype. Aging caused small phase changes in Clock, loss of rhythmicity in Per2 and Rorα, and mesor dampening of Clock, Bmal1, and Per2. NLRP3 inflammasome influenced the acrophase of Clock, Per2, and Rorα. Melatonin restored the acrophase and the rhythm of clock genes affected by age or NLRP3 activation. The administration of melatonin re-established murine cardiac homeostasis by reversing age-associated chronodisruption. Altogether, these results highlight new findings about the effects aging and NLRP3 inflammasome have on clock genes in cardiac tissue, pointing to continuous melatonin as a promising therapy to placate inflammaging and restore circadian rhythm in heart muscle. Additionally, light microscopy analysis showed age-related morphological impairments in cardiomyocytes, which were less severe in mice lacking NLRP3. Melatonin supplementation preserved the structure of cardiac muscle fibers in all experimental groups.

Macrophage circadian rhythms are differentially affected based on stimuli.

Macrophages are white blood cells that play disparate roles in homeostasis and immune responses. They can reprogram their phenotypes to pro-inflammatory (M1) or anti-inflammatory (M2) states in response to their environment. About 8-15% of the macrophage transcriptome has circadian oscillations, including genes closely related to their functioning. As circadian rhythms are associated with cellular phenotypes, we hypothesized that polarization of macrophages to opposing subtypes might differently affect their circadian rhythms. We tracked circadian rhythms in RAW 264.7 macrophages using luminescent reporters. Cells were stably transfected with Bmal1:luc and Per2:luc reporters, representing positive and negative components of the molecular clock. Strength of rhythmicity, periods and amplitudes of time series were assessed using multiple approaches. M1 polarization decreased amplitudes and rhythmicities of Bmal1:luc and Per2:luc, but did not significantly affect periods, while M2 polarization increased periods but caused no substantial alterations to amplitudes or rhythmicity. As macrophage phenotypes are also altered in the presence of cancer cells, we tested circadian effects of conditioned media from mouse breast cancer cells. Media from highly aggressive 4T1 cells caused loss of rhythmicity, while media from less aggressive EMT6 cells yielded no changes. As macrophages play roles in tumors, and oncogenic features are associated with circadian rhythms, we tested whether conditioned media from macrophages could alter circadian rhythms of cancer cells. Conditioned media from RAW 264.7 cells resulted in lower rhythmicities and periods, but higher amplitudes in human osteosarcoma, U2OS-Per2:luc cells. We show that phenotypic changes in macrophages result in altered circadian characteristics and suggest that there is an association between circadian rhythms and macrophage polarization state. Additionally, our data demonstrate that macrophages treated with breast cancer-conditioned media have circadian phenotypes similar to those of the M1 subtype, and cancer cells treated with macrophage-conditioned media have circadian alterations, providing insight to another level of cross-talk between macrophages and cancer.

Demystifying the Relevance of Size Amongst Macro- and Micro-Corticotropinoma: Experience in 206 Patients.

Objective:In individuals with adrenocorticotrophic hormone (ACTH)-dependent Cushing’s syndrome (CS), to estimate the differences between micro-corticotropinoma (size ≤6 mm and 6-10 mm), macro-corticotropinoma (>10 mm) and ectopic Cushing’s syndrome (ECS), in relation to their epidemiological, clinical and biochemical parameters.Methods:In individuals with CS, the clinical and hormonal parameters, and magnetic resonance imaging of sella were collected from 1984 to 2019. A total of 138 cases of micro-corticotropinoma, 47 cases of macro-corticotropinoma and 21 cases of ECS were compared.Results:Except for size, there were no differences in biochemical and hormonal parameters of macro- and micro-corticotropinoma, irrespective of their size (≤6 mm, 6-10 mm and >10 mm). In comparison to Cushing’s disease (CD), individuals with ECS had a male predominance (F:M ratio of 2.4:1 vs. 0.5:1), shorter duration from onset of symptoms to diagnosis (24 vs. 12 months). They also had a higher ACTH (139 vs. 65.8 pg/ml), 0800h cortisol (1200 vs. 880 nmol/l), 2300h cortisol (1100 vs. 700 nmol/l) and cortisol levels after high dose dexamethasone suppression test (1050 vs. 244.5 nmol/l).Conclusion:The biochemical phenotype of macro-corticotropinoma resembles that of micro-corticotropinoma despite their larger tumour size, suggesting that the former is relatively less functional. Micro-corticotropinoma ≤6 mm and 6-10 mm have a similar clinical and biochemical profile. As compare to CD, ECS is characterised by a higher disease burden as reflected in their higher cortisol, more autonomicity and loss of rhythmicity.

Arabidopsis thaliana PRR7 Provides Circadian Input to the CCA1 Promoter in Shoots but not Roots.

The core of the plant circadian clock involves multiple interlocking gene expression loops and post-translational controls along with inputs from light and metabolism. The complexity of the interactions is such that few specific functions can be ascribed to single components. In previous work, we reported differences in the operation of the clocks in Arabidopsis shoots and roots, including the effects of mutations of key clock components. Here, we have used luciferase imaging to study prr7 mutants expressing CCA1::LUC and GI::LUC markers. In mature shoots expressing CCA1::LUC, loss of PRR7 radically altered behaviour in light:dark cycles and caused loss of rhythmicity in constant light but had little effect on roots. In contrast, in mature plants expressing GI::LUC, loss of PRR7 had little effect in light:dark cycles but in constant light increased the circadian period in shoots and reduced it in roots. We conclude that most or all of the circadian input to the CCA1 promoter in shoots is mediated by PRR7 and that loss of PRR7 has organ-specific effects. The results emphasise the differences in operation of the shoot and root clocks, and the importance of studying clock mutants in both light:dark cycles and constant light.

Deregulation of Ca2+-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes.

Various types of cells demonstrate ubiquitous rhythmicity registered as simple and complex Ca2+-oscillations, spikes, waves, and triggering phenomena mediated by G-protein and tyrosine kinase coupled receptors. Phospholipase C/IP3-receptors (PLC/IP3R) and endothelial NO-synthase/Ryanodine receptors (NOS/RyR)–dependent Ca2+ signaling systems, organized as multivariate positive feedback generators (PLC-G and NOS-G), underlie this rhythmicity. Loss of rhythmicity at obesity may indicate deregulation of these signaling systems. To issue the impact of cell size, receptors’ interplay, and obesity on the regulation of PLC-G and NOS-G, we applied fluorescent microscopy, immunochemical staining, and inhibitory analysis using cultured adipocytes of epididumal white adipose tissue of mice. Acetylcholine, norepinephrine, atrial natriuretic peptide, bradykinin, cholecystokinin, angiotensin II, and insulin evoked complex [Ca2+]i responses in adipocytes, implicating NOS-G or PLC-G. At low sub-threshold concentrations, acetylcholine and norepinephrine or acetylcholine and peptide hormones (in paired combinations) recruited NOS-G, based on G proteins subunits interplay and signaling amplification. Rhythmicity was cell size- dependent and disappeared in hypertrophied cells filled with lipids. Contrary to control cells, adipocytes of obese hyperglycemic and hypertensive mice, growing on glucose, did not accumulate lipids and demonstrated hormonal resistance being non responsive to any hormone applied. Preincubation of preadipocytes with palmitoyl-L-carnitine (100 nM) provided accumulation of lipids, increased expression and clustering of IP3R and RyR proteins, and partially restored hormonal sensitivity and rhythmicity (5–15% vs. 30–80% in control cells), while adipocytes of diabetic mice were not responsive at all. Here, we presented a detailed kinetic model of NOS-G and discussed its control. Collectively, we may suggest that universal mechanisms underlie loss of rhythmicity, Ca2+-signaling systems deregulation, and development of general hormonal resistance to obesity.

Circadian rhythms in septic shock patients

BackgroundDespite the intensive efforts to improve the diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate whether the rhythmicity of clock gene expression is altered in patients with septic shock.MethodsThis prospective pilot study was performed at the university hospital Charité–Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK). We included 20 patients with septic shock between May 2014 and January 2018, from whom blood was drawn every 4 h over a 24-h period to isolate CD14-positive monocytes and to measure the expression of 17 clock and clock-associated genes. Of these patients, 3 whose samples expressed fewer than 8 clock genes were excluded from the final analysis. A rhythmicity score SP was calculated, which comprises values between -1 (arrhythmic) and 1 (rhythmic), and expression data were compared to data of a healthy study population additionally.Results77% of the measured clock genes showed inconclusive rhythms, i.e., neither rhythmic nor arrhythmic. The clock genes NR1D1, NR1D2 and CRY2 were the most rhythmic, while CLOCK and ARNTL were the least rhythmic. Overall, the rhythmicity scores for septic shock patients were significantly (p < 0.0001) lower (0.23 ± 0.26) compared to the control group (12 healthy young men, 0.70 ± 0.18). In addition, the expression of clock genes CRY1, NR1D1, NR1D2, DBP, and PER2 was suppressed in septic shock patients and CRY2 was significantly upregulated compared to controls.ConclusionMolecular rhythms in immune cells of septic shock patients were substantially altered and decreased compared to healthy young men. The decrease in rhythmicity was clock gene-dependent. The loss of rhythmicity and down-regulation of clock gene expression might be caused by sepsis and might further deteriorate immune responses and organ injury, but further studies are necessary to understand underlying pathophysiological mechanisms.Trail registration Clinical trial registered with www.ClinicalTrials.gov (NCT02044575) on 24 January 2014.

A Susceptible Period of Photic Day-Night Rhythm Loss in Common Marmoset Social Behavior Development.

The prevalence of neurodevelopmental psychiatric disorders such as pervasive developmental disorders is rapidly increasing worldwide. Although these developmental disorders are known to be influenced by an individual’s genetic background, the potential biological responses to early life’s environmental exposure to both physical and psychological factors must also be considered. Many studies have acknowledged the influence of shorter time for rest at night and the simultaneous occurrence of various kinds of complications involving developmental disorders. In a prior study, we examined how a common marmoset’s (Callithrix jacchus) psychosocial development was affected when it was reared under constant daylight from birth and then reared individually by humans nursing them under constant light (LL) during their juvenile development stages. The behaviors of these marmosets were compared with those of normal day-night cycle (LD) marmosets using a multivariate analysis based on principal component analysis (PCA). That study found that LL marmosets relatively elicited egg-like calls (Ecall) and side-to-side shakes of the upper body with rapid head rotation through adulthood frequently. Based on the PCA, these behaviors were interpreted as “alert” or “hyperactive” states. However, we did not clarify susceptible periods of the photic rhythm loss experience and the psychological development output. In this study we summarize the following studies in our model animal colonies involving 30 animals (11 female, 19 males) to further explore critical age states of inquiry about each social behavior profiling. We compared social behaviors of three age stages, juvenile, adolescent and young adult equivalent to one another in four LL experience conditions, LL (postnatal day (P) 0 to around 150), Middle (P60–149, 90 days), Late (P150–239, 90 days), and LD (no experience). In the most representative 1st and 2nd principal component scores, the shifting to higher frequency of alert behaviors developed at the adult stage in LL, Middle, then Late in turn. The no LL experience group, LD, generally featured higher frequency of local preference of high position compared to LL experience present groups, in adulthood. This limited model primate study might inspire different developmental age sensitive mechanisms of neuronal network to control socio-emotional functions by utilizing the multivariate visualization method, BOUQUET. This study could potentially contribute to nurturing educational designs for social developmental disorders.

The time it takes; How do we understand personal growth in an age of instant solutions

ABSTRACT One source of the mental health challenges facing contemporary people, especially younger people, is the increasing commodification of experience: phases of life, human encounters and so on, which were once part of a connected narrative are seen as items to be purchased/acquired/accumulated by a curiously contentless desiring ego. But the effect of this is a sense of pervasive loss – characterised as loss of rhythm, narrative and future. There is a loss of connection with the processes and agencies of the natural world, a loss of a continuous narrative of the self and a loss of a manageable or desirable future (individual and social). Creating the conditions for mental health (not simply providing ambulance services) requires cultural resistance in all these areas; it is important to identify and nurture signs of such resistance as part of any strategy for improving mental health.

Disruption of Circadian Rhythms: A Crucial Factor in the Etiology of Infertility.

Infertility represents a growing health problem in industrialized countries. Thus, a greater understanding of the molecular networks involved in this disease could be critical for the development of new therapies. A recent finding revealed that circadian rhythmicity disruption is one of the main causes of poor reproductive outcome. The circadian clock system beats circadian rhythms and modulates several physiological functions such as the sleep-wake cycle, body temperature, heart rate, and hormones secretion, all of which enable the body to function in response to a 24 h cycle. This intricated machinery is driven by specific genes, called “clock genes” that fine-tune body homeostasis. Stress of modern lifestyle can determine changes in hormone secretion, favoring the onset of infertility-related conditions that might reflect disfunctions within the hypothalamic–pituitary–gonadal axis. Consequently, the loss of rhythmicity in the suprachiasmatic nuclei might affect pulsatile sexual hormones release. Herein, we provide an overview of the recent findings, in both animal models and humans, about how fertility is influenced by circadian rhythm. In addition, we explore the complex interaction among hormones, fertility and the circadian clock. A deeper analysis of these interactions might lead to novel insights that could ameliorate the therapeutic management of infertility and related disorders.

Effect of different music genres on gait patterns in Parkinson's disease.

The timing and size of repetitive, internally generated, automatic sequences of movements are particularly affected in Parkinson's disease. The most evident consequence of this deficit is the alteration of gait patterns, with a loss of rhythmicity, shorter steps, slower walking, and trunk instability. Several studies have highlighted a potential benefit of listening to music on the normalization of walking patterns. However, most of these studies investigated the effect of a single specific music. We hypothesized that different musical genres may induce different modifications of spatiotemporal parameters and trunk oscillations during walking. In this study, we enrolled healthy young subjects, healthy elderly, and patients with Parkinson's disease. They were asked to walk listening, by a wireless headset, one of six different music tracks (related to four different musical genres) while wearing an inertial measurement unit at pelvis level used to assess their walking patterns. The main effect of music tracks resulted statistically significant in all the gait parameters (p < 0.05), but for symmetry of lower trunk movements. This effect was independent by group. The only significant interaction between music and group, in fact, was found for pelvis obliquity range of motion (p = 0.019). Post hoc analyses showed as classical music reduced speed and trunk tilting (p < 0.01), whereas the range of pelvic obliquity movements in frontal plane were increased by rock, motivational, and heavy metal songs (p < 0.015). In conclusion, the gait patterns were altered by listening music depending by the musical genre, and these adaptations occurred similarly among the three groups, including patients with Parkinson's disease.

2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice

Aryl hydrocarbon receptor (AhR) activation is reported to alter the hepatic expression of circadian clock regulators, however the impact on clock-controlled metabolism has not been thoroughly investigated. This study examines the effects of AhR activation on hepatic transcriptome and metabolome rhythmicity in male C57BL/6 mice orally gavaged with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4 days for 28 days. TCDD diminished the rhythmicity of several core clock regulators (e.g. Arntl, Clock, Nr1d1, Per1, Cry1, Nfil3) in a dose-dependent manner, involving either a ≥ 3.3-fold suppression in amplitude or complete loss of oscillation. Accordingly, protein levels (ARNTL, REV-ERBα, NFIL3) and genomic binding (ARNTL) of select regulators were reduced and arrhythmic following treatment. As a result, the oscillating expression of 99.6% of 5,636 clock-controlled hepatic genes was abolished including genes associated with the metabolism of lipids, glucose/glycogen, and heme. For example, TCDD flattened expression of the rate-limiting enzymes in both gluconeogenesis (Pck1) and glycogenesis (Gys2), consistent with the depletion and loss of rhythmicity in hepatic glycogen levels. Examination of polar hepatic extracts by untargeted mass spectrometry revealed that virtually all oscillating metabolites lost rhythmicity following treatment. Collectively, these results suggest TCDD disrupted circadian regulation of hepatic metabolism, altering metabolic efficiency and energy storage.

Efectos de un programa de restricciones ambientales en el aprendizaje de la digitación en la flauta en secundaria: una aproximación desde el aprendizaje motor

Los efectos de los patrones funcionales surgidos durante la adquisición bimanual de los movimientos de los dedos tocando flauta dulce bajo restricciones informacionales auditivas y visuales en la tarea instrumental, pueden contribuir a mejorar variables importantes relacionadas con la sincronización, precisión de la ejecución, pérdida de ritmo, entre otras variables. 147 alumnos de 3º curso de educación secundaria se sometieron a 5 variaciones de un programa de aprendizaje de flauta durante 12 sesiones de práctica. Los resultados muestran una resistencia al deterioro frente al resto de grupos en la prueba de retención, en variables importantes instrumentales como es el error de nota al grupo al que se aplicaron restricciones totales (GE1), aunque uno de los grupos sometido a restricciones parciales (GE3) también obtuvo mejoras estadísticamente significativas respecto al resto de grupos en otra variable importante como es la sincronización.

Artificial Light at Night (ALAN), an alarm to ovarian physiology: A study of possible chronodisruption on zebrafish (Danio rerio)

The ALAN is drawing the attention of researchers and environmentalists for its ever-increasing evidence on its capacity of “desynchronization” of organismal physiology. Photoperiod and circadian cycles are critical parameters to influence the biology of reproduction in several animals, including fish. The present study is the first proof of the development of an ovarian tumour with the effect of light in zebrafish (Danio rerio), an excellent model for circadian-related studies. Results of three experimental conditions, continuous light for one week, LLW, one month, LLM, and for one year, LLY revealed a clear desynchronization of clock associated genes (Clock1a, Bmal1a, Per2, and Cry2a). Interestingly, loss of rhythmicity and low concentration of melatonin found in these conditions in whole brain, retina, ovary, and serum through ELISA. RNA-Seq data of ovarian samples revealed the upregulation of Mid2, Tfg, Irak1, Pim2, Tradd, Tmem101, Nfkbib genes and ultimately increase the expression of NF-κB, a cellular transformer for tumourigenesis, confirmed by the western blot. The appearance of TNFα, inflammatory cytokines and activator of NF-κB also increased. Histology approved the formation of thecoma and granulosa cell tumour in the one year exposed ovarian sample. The whole transcriptome data analysis revealed 1791 significantly upregulated genes in an ovarian tumour. Among these genes, DAVID functional annotation tool identified 438 genes, directly linked to other physiological disorders. This study evidenced of an ovarian tumour induced by ALAN in zebrafish.

Suprachiasmatic Nucleus Interaction with the Arcuate Nucleus; Essential for Organizing Physiological Rhythms

The suprachiasmatic nucleus (SCN) is generally considered the master clock, independently driving all circadian rhythms. We recently demonstrated the SCN receives metabolic and cardiovascular feedback adeptly altering its neuronal activity. In the present study, we show that microcuts effectively removing SCN-arcuate nucleus (ARC) interconnectivity in Wistar rats result in a loss of rhythmicity in locomotor activity, corticosterone levels, and body temperature in constant dark (DD) conditions. Elimination of these reciprocal connections did not affect SCN clock gene rhythmicity but did cause the ARC to desynchronize. Moreover, unilateral SCN lesions with contralateral retrochiasmatic microcuts resulted in identical arrhythmicity, proving that for the expression of physiological rhythms this reciprocal SCN-ARC interaction is essential. The unaltered SCN c-Fos expression following glucose administration in disconnected animals as compared to a significant decrease in controls demonstrates the importance of the ARC as metabolic modulator of SCN neuronal activity. Together, these results indicate that the SCN is more than an autonomous clock, and forms an essential component of a larger network controlling homeostasis. The present novel findings illustrate how an imbalance between SCN and ARC communication through circadian disruption could be involved in the etiology of metabolic disorders.