Genetic insights on sleep schedules: this time, it's PERsonal.

The study of circadian rhythms is emerging as a fruitful opportunity for understanding cellular mechanisms that govern human physiology and behavior, fueled by evidence directly linking sleep disorders to genetic mutations affecting circadian molecular pathways. Familial advanced sleep-phase disorder (FASPD) is the first recognized Mendelian circadian rhythm trait, and affected individuals exhibit exceptionally early sleep-wake onset due to altered post-translational regulation of period homolog 2 (PER2). Behavioral and cellular circadian rhythms are analogously affected because the circadian period length of behavior is reduced in the absence of environmental time cues, and cycle duration of the molecular clock is likewise shortened. In light of these findings, we review the PER2 dynamics in the context of circadian regulation to reveal the mechanism of sleep-schedule modulation. Understanding PER2 regulation and functionality may shed new light on how our genetic composition can influence our sleep-wake behaviors

Episodic neurologic disorders: syndromes, genes, and mechanisms.

Many neurologic diseases cause discrete episodic impairment in contrast with progressive deterioration. The symptoms of these episodic disorders exhibit striking variety. Herein we review what is known of the phenotypes, genetics, and pathophysiology of episodic neurologic disorders. Of these, most are genetically complex, with unknown or polygenic inheritance. In contrast, a fascinating panoply of episodic disorders exhibit Mendelian inheritance. We classify episodic Mendelian disorders according to the primary neuroanatomical location affected: skeletal muscle, cardiac muscle, neuromuscular junction, peripheral nerve, or central nervous system (CNS). Most known Mendelian mutations alter genes that encode membrane-bound ion channels. These mutations cause ion channel dysfunction, which ultimately leads to altered membrane excitability as manifested by episodic disease. Other Mendelian disease genes encode proteins essential for ion channel trafficking or stability. These observations have cemented the channelopathy paradigm, in which episodic disorders are conceptualized as disorders of ion channels. However, we expand on this paradigm to propose that dysfunction at the synaptic and neuronal circuit levels may underlie some episodic neurologic entities

Solving the mystery of human sleep schedules one mutation at a time.

Sleep behavior remains one of the most enigmatic areas of life. The unanswered questions range from "why do we sleep?" to "how we can improve sleep in today's society?" Identification of mutations responsible for altered circadian regulation of human sleep lead to unique opportunities for probing these territories. In this review, we summarize causative circadian mutations found from familial genetic studies to date. We also describe how these mutations mechanistically affect circadian function and lead to altered sleep behaviors, including shifted or shortening of sleep patterns. In addition, we discuss how the investigation of mutations can not only expand our understanding of the molecular mechanisms regulating the circadian clock and sleep duration, but also bridge the pathways between clock/sleep and other human physiological conditions and ailments such as metabolic regulation and migraine headaches

Episodic and electrical nervous system disorders caused by nonchannel genes.

As noted in the separate introduction to this special topic section, episodic and electrical disorders can appear quite different clinically and yet share many overlapping features, including attack precipitants, therapeutic responses, natural history, and the types of genes that cause many of the genetic forms (i.e., ion channel genes). Thus, as we mapped and attempted to clone genes causing other episodic disorders, ion channels were always outstanding candidates when they mapped to the critical region of linkage in such a family. However, some of these disorders do not result from mutations in channels. This realization has opened up large and exciting new areas for the pathogenesis of these disorders. In some cases, the mutations occur in genes of unknown function or without understanding of molecular pathogenesis. Recently, emerging insights into a fascinating group of episodic movement disorders, the paroxysmal dyskinesias, and study of the causative genes and proteins are leading to the emerging concept of episodic electric disorders resulting from synaptic dysfunction. Much work remains to be done, but the field is evolving rapidly. As it does, we have come to realize that the molecular pathogenesis of electrical and episodic disorders is more complex than a scenario in which such disorders are simply due to mutations in the primary determinants of membrane excitability (channels)

The rare semi-leptonic BcB_c decays involving orbitally excited final mesons

The rare processes $B_c\to D_{(s)J} ^{(*)}\mu\bar{\mu}$, where $D_{(s)J}^{(*)}$ stands for the final meson $D_{s0}^*(2317)$, $D_{s1}(2460,2536)$,~$D_{s2}^*(2573)$, $D_0^*(2400)$, $D_{1}(2420,2430)$ or~$D_{2}^*(2460)$, are studied within the Standard Model. The hadronic matrix elements are evaluated in the Bethe-Salpeter approach and furthermore a discussion on the gauge-invariant condition of the annihilation hadronic currents is presented. Considering the penguin, box, annihilation, color-favored cascade and color-suppressed cascade contributions, the observables $\text{d}Br/\text{d}Q^2$, $A_{LPL}$, $A_{FB}$ and $P_L$ are calculated

Very large G protein-coupled receptor 1 regulates myelin-associated glycoprotein via Gαs/Gαq-mediated protein kinases A/C.

VLGR1 (very large G protein-coupled receptor 1), also known as MASS1 (monogenic audiogenic seizure susceptible 1), is an orphan G protein-coupled receptor that contains a large extracellular N terminus with 35 calcium-binding domains. A truncating mutation in the Mass1 gene causes autosomal recessive, sound-induced seizures in the Frings mouse. However, the function of MASS1 and the mechanism underlying Frings mouse epilepsy are not known. Here, we found that MASS1 protein is enriched in the myelinated regions of the superior and inferior colliculi, critical areas for the initiation and propagation of audiogenic seizures. Using a panel of myelin antibodies, we discovered that myelin-associated glycoprotein (MAG) expression is dramatically decreased in Frings mice. MASS1 inhibits the ubiquitylation of MAG, thus enhancing the stability of this protein, and the calcium-binding domains of MASS1 are essential for this regulation. Furthermore, MASS1 interacts with Gαs/Gαq and activates PKA and PKC in response to extracellular calcium. Suppression of signaling by MASS1 RNAi or a specific inhibitor abrogates MAG up-regulation. We postulate that MASS1 senses extracellular calcium and activates cytosolic PKA/PKC pathways to regulate myelination by means of MAG protein stability in myelin-forming cells of the auditory pathway. Further work is required to determine whether MAG dysregulation is a cause or consequence of audiogenic epilepsy and whether there are other pathways regulated by MASS1

Roles of continental mid-lithosphere discontinuity in the craton instability under variable tectonic regimes

This is the dataset for the paper "Roles of continental mid-lithosphere discontinuity in the craton instability under variable tectonic regimes"

Sick and tired: how molecular regulators of human sleep schedules and duration impact immune function.

Why do we need to sleep? What regulates when we sleep? And what dictates the number of hours we require? These are often viewed as three separate biological questions. Here, we propose they share molecular etiologies, whereby regulators of sleep schedules and sleep duration also govern the physiological purposes of sleep. To support our hypothesis, we review Mendelian human genetic variants sufficient to advance sleep-wake onset (PER2) and shorten sleep length (DEC2), and evaluate their emerging roles in immune responses that may rely on a sound night of slumber

Genetic basis of human circadian rhythm disorders.

Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health