Effects of chronodisruption and alcohol consumption on gene expression in reward-related brain areas in female rats.

Circadian dysfunction caused by exposure to aberrant light-dark conditions is associated with abnormal alcohol consumption in humans and animal models. Changes in drinking behavior have been linked to alterations in clock gene expression in reward-related brain areas, which could be attributed to either the effect of chronodisruption or alcohol. To date, however, the combinatory effect of circadian disruption and alcohol on brain functions is less understood.

Changes in Active Site Loop Conformation Relate to the Transition toward a Novel Enzymatic Activity.

Enzymatic promiscuity, the ability of enzymes to catalyze multiple, distinct chemical reactions, has been well documented and is hypothesized to be a major driver of the emergence of new enzymatic functions. Yet, the molecular mechanisms involved in the transition from one activity to another remain debated and elusive. Here, we evaluated the redesign of the active site binding cleft of lactonase Pox using structure-based design and combinatorial libraries.

Changes in Active Site Loop Conformation Relate to the Transition toward a Novel Enzymatic Activity.

Enzymatic promiscuity, the ability of enzymes to catalyze multiple, distinct chemical reactions, has been well documented and is hypothesized to be a major driver for the emergence of new enzymatic functions. Yet, the molecular mechanisms involved in the transition from one activity to another remain debated and elusive. Here, we evaluated the redesign of the active site binding cleft of the lactonase Pox using structure-based design and combinatorial libraries.

The effects of circadian desynchronization on alcohol consumption and affective behavior during alcohol abstinence in female rats.

Disruption of circadian rhythmicity distorts physiological and psychological processes and has major consequences on health and well-being. A chronic misalignment within the internal time-keeping system modulates alcohol consumption and contributes to stress-related psychiatric disorders which are known to trigger alcohol misuse and relapse. While there is growing evidence of the deleterious impact of circadian disruption on male physiology and behavior, knowledge about the effect in females remains limited.

Anti-SARS-CoV-2 immunoadhesin remains effective against Omicron and other emerging variants of concern.

Blocking the interaction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with its angiotensin-converting enzyme 2 (ACE2) receptor was proved to be an effective therapeutic option. Various protein binders as well as monoclonal antibodies that effectively target the receptor-binding domain (RBD) of SARS-CoV-2 to prevent interaction with ACE2 were developed. The emergence of SARS-CoV-2 variants that accumulate alterations in the RBD can severely affect the efficacy of such immunotherapeutic agents, as is indeed the case with Omicron that resists many of the previously isolated monoclonal antibodies.

Sexually dimorphic role of circadian clock genes in alcohol drinking behavior.

Sex differences in alcohol use and abuse are pervasive and carry important implications for the prevention and treatment of alcohol use disorder (AUD), yet insight into underlying sexually dimorphic mechanisms is limited. Growing experimental and clinical evidence points to an important influence of circadian rhythms and circadian clock genes in the control of alcohol drinking behavior and AUD. Sex differences in the expression of circadian rhythms and in the molecular circadian clock that drive these rhythms have been reported in humans and animals.

Characterization of Affective Behaviors and Motor Functions in Mice With a Striatal-Specific Deletion of and .

The expression of circadian clock genes, either centrally or in the periphery, has been shown to play an integral role in the control of behavior. Brain region-specific downregulation of clock genes revealed behavioral phenotypes associated with neuropsychiatric disorders and neurodegenerative disease. The specific function of the clock genes as well as the underlying mechanisms that contribute to the observed phenotypes, however, are not yet fully understood.

Thermoregulatory significance of immobility in the forced swim test.

The forced swim test (FST) is a widely used animal model of depression and antidepressant drug screen. Rats are forced to swim on two test days in a restricted space from which there is no escape. On the first test day the rats attempt to escape and then become largely immobile; on the second test day the onset of immobility is more rapid.

Bmal1 in the striatum influences alcohol intake in a sexually dimorphic manner.

Alcohol consumption has been strongly associated with circadian clock gene expression in mammals. Analysis of clock genes revealed a potential role of Bmal1 in the control of alcohol drinking behavior. However, a causal role of Bmal1 and neural pathways through which it may influence alcohol intake have not yet been established.

Exposure to Valproic-Acid Alters Circadian Organisation and Clock-Gene Expression: Implications for Autism Spectrum Disorders.

Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterised by restrictive patterns of behaviour and alterations in social interaction and communication. Up to 80% of children with ASD exhibit sleep-wake cycle disturbances, emphasising the pressing need for novel approaches in the treatment of ASD-associated comorbidities. While sleep disturbances have been identified in ASD individuals, little has been done to assess the contribution of the circadian system to these findings.

The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4.

The integrated stress response (ISR) is activated in response to diverse stress stimuli to maintain homeostasis in neurons. Central to this process is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Here, we report a critical role for ISR in regulating the mammalian circadian clock.

mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction.

Mammalian/mechanistic target of rapamycin (mTOR) signaling controls cell growth, proliferation, and metabolism in dividing cells. Less is known regarding its function in postmitotic neurons in the adult brain. Here we created a conditional knockout mouse model to address this question.

Biological Clocks and Rhythms of Anger and Aggression.

The body's internal timekeeping system is an under-recognized but highly influential force in behaviors and emotions including anger and reactive aggression. Predictable cycles or rhythms in behavior are expressed on several different time scales such as circadian (, or approximately 24-h rhythms) and infradian (exceeding 24 h, such as monthly or seasonal cycles). The circadian timekeeping system underlying rhythmic behaviors in mammals is constituted by a network of clocks distributed throughout the brain and body, the activity of which synchronizes to a central pacemaker, or master clock.

Individual differences in circadian locomotor parameters correlate with anxiety- and depression-like behavior.

Disrupted circadian rhythms are a core feature of mood and anxiety disorders. Circadian rhythms are coordinated by a light-entrainable master clock located in the suprachiasmatic nucleus. Animal models of mood and anxiety disorders often exhibit blunted rhythms in locomotor activity and clock gene expression.

Structural Basis for Receptor Selectivity by the Whitewater Arroyo Mammarenavirus.

Whitewater Arroyo virus belongs to the "New World" group of mammarenaviruses that reside in rodent reservoirs and are prevalent in North and South Americas. Clades B and A/B of New World mammarenaviruses use transferrin receptor 1 (TfR1) for entry. While all of these viruses use rodent-derived TfR1 orthologs, some can also use the human-TfR1 and thereby infect humans.

Neurodegeneration and the Circadian Clock.

Despite varied etiologies and symptoms, several neurodegenerative diseases-specifically, Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HDs)-share the common feature of abnormal circadian rhythms, such as those in behavior (e.g., disrupted sleep/wake cycles), physiological processes (e.

Effects of bilateral anterior agranular insula lesions on food anticipatory activity in rats.

Food anticipatory activity (FAA) refers to a daily rhythm of locomotor activity that emerges under conditions of food restriction, whereby animals develop an intense, predictable period of activity in the few hours leading up to a predictable, daily delivery of food. The neural mechanisms by which FAA is regulated are not yet fully understood. Although a number of brain regions appear to be involved in regulating the development and expression of FAA, there is little evidence to date concerning the role of the anterior agranular insular cortex (AICa).

Mapping of the Lassa virus LAMP1 binding site reveals unique determinants not shared by other old world arenaviruses.

Cell entry of many enveloped viruses occurs by engagement with cellular receptors, followed by internalization into endocytic compartments and pH-induced membrane fusion. A previously unnoticed step of receptor switching was found to be critical during cell entry of two devastating human pathogens: Ebola and Lassa viruses. Our recent studies revealed the functional role of receptor switching to LAMP1 for triggering membrane fusion by Lassa virus and showed the involvement of conserved histidines in this switching, suggesting that other viruses from this family may also switch to LAMP1.

Mapping the co-localization of the circadian proteins PER2 and BMAL1 with enkephalin and substance P throughout the rodent forebrain.

Despite rhythmic expression of clock genes being found throughout the central nervous system, very little is known about their function outside of the suprachiasmatic nucleus. Determining the pattern of clock gene expression across neuronal subpopulations is a key step in understanding their regulation and how they may influence the functions of various brain structures. Using immunofluorescence and confocal microscopy, we quantified the co-expression of the clock proteins BMAL1 and PER2 with two neuropeptides, Substance P (SubP) and Enkephalin (Enk), expressed in distinct neuronal populations throughout the forebrain.

Exploring the role of locomotor sensitization in the circadian food entrainment pathway.

Food entrainment is the internal mechanism whereby the phase and period of circadian clock genes comes under the control of daily scheduled food availability. Food entrainment allows the body to efficiently realign the internal timing of behavioral and physiological functions such that they anticipate food intake. Food entrainment can occur with or without caloric restriction, as seen with daily schedules of restricted feeding (RF) or restricted treat (RT) that restrict food or treat intake to a single feeding time.

The aging clock: circadian rhythms and later life.

Circadian rhythms play an influential role in nearly all aspects of physiology and behavior in the vast majority of species on Earth. The biological clockwork that regulates these rhythms is dynamic over the lifespan: rhythmic activities such as sleep/wake patterns change markedly as we age, and in many cases they become increasingly fragmented. Given that prolonged disruptions of normal rhythms are highly detrimental to health, deeper knowledge of how our biological clocks change with age may create valuable opportunities to improve health and longevity for an aging global population.

Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease.

Circadian clock proteins form an autoregulatory feedback loop that is central to the endogenous generation and transmission of daily rhythms in behavior and physiology. Increasingly, circadian rhythms in clock gene expression are being reported in diverse tissues and brain regions that lie outside of the suprachiasmatic nucleus (SCN), the master circadian clock in mammals. For many of these extra-SCN rhythms, however, the region-specific implications are still emerging.