The rockefeller university

Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX deletion from mouse cells altered the repair of telomeric double-strand breaks (DSBs) and induced ALT-like phenotypes, including ALT-associated promyelocytic leukemia (PML) bodies (APBs), telomere sister chromatid exchanges (T-SCEs), and extrachromosomal telomeric signals (ECTSs). Mechanistically, we show that ATRX affects telomeric DSB repair by promoting cohesion of sister telomeres and that loss of ATRX in ALT cells results in diminished telomere cohesion. In addition, we document a role for DAXX in the repair of telomeric DSBs. Removal of telomeric cohesion in combination with DAXX deficiency recapitulates all telomeric DSB repair phenotypes associated with ATRX loss. The data reveal that ATRX has an effect on telomeric DSB repair and that this role involves both telomere cohesion and a DAXX-dependent pathway.

The Hawai'ian honeycreepers (drepanids) are a classic example of adaptive radiation: they adapted to a variety of novel dietary niches, evolving a wide range of bill morphologies. Here we investigated genomic diversity, demographic history, and genes involved in bill morphology phenotypes in 2 honeycreepers: the 'akiapla'au (Hemignathus wilsoni) and the Hawai'i 'amakihi (Chlorodrepanis virens). The 'akiapla'au is an endangered island endemic, filling the "woodpecker" niche by using a unique bill morphology, while the Hawai'i 'amakihi is a dietary generalist common on the islands of Hawai'i and Maui. We de novo sequenced the 'akiapla'au genome and compared it to the previously sequenced 'amakihi genome. The 'akiapla'au is far less heterozygous and has a smaller effective population size than the 'amakihi, which matches expectations due to its smaller census population and restricted ecological niche. Our investigation revealed genomic islands of divergence, which may be involved in the honeycreeper radiation. Within these islands of divergence, we identified candidate genes (including DLK1, FOXB1, KIF6, MAML3, PHF20, RBP1, and TIMM17A) that may play a role in honeycreeper adaptations. The gene DLK1, previously shown to influence Darwin's finch bill size, may be related to honeycreeper bill morphology evolution, while the functions of the other candidates remain unknown.

Introduction Primary care remains an underused venue for prevention and management of paediatric overweight and obesity. A prior trial demonstrated a significant impact of paediatrician/nurse practitioner (Ped/NP)-and registered dietitian (RD)-delivered motivational interviewing (MI) on child body mass index (BMI). The study described here will test the effectiveness of an enhanced version of this primary care-based MI counselling intervention on child BMI. Methods and analysis This cluster randomised effectiveness trial includes 24 Ped/NPs from 18 paediatric primary care practices that belong to the American Academy of Pediatrics (AAP) national Pediatric Research in Office Settings (PROS) practice-based research network. To date, practices have been randomised (nine to intervention and nine to usual care). Intervention Ped/NPs have been trained in MI, behavioural therapy, billing/coding for weight management and study procedures. Usual care Ped/NPs received training in billing/coding and study procedures only. Children 3-11 years old with BMI >= the 85th percentile were identified via electronic health records (EHRs). Parents from intervention practices have been recruited and enrolled. Over about 2 years, these parents are offered approximately 10 MI-based counselling sessions (about four in person sessions with their child's Ped/NP and up to six telephonic sessions with a trained RD). The primary outcome is change in child BMI (defined as per cent from median BMI for age and sex) over the study period. The primary comparison is between eligible children in intervention practices whose parents enrol in the study and all eligible children in usual care practices. Data sources will include EHRs, billing records, surveys and counselling call notes. Ethics and dissemination Institutional Review Board approval was obtained from the AAP. All Ped/NPs provided written informed consent, and intervention group parents provided consent and Health Insurance Portability and Accountability Act (HIPAA) authorisation. Findings will be disseminated through peer-reviewed publications, conference presentations and appropriate AAP channels.

Over the last 50 years, the concept of stress has evolved significantly, and our understanding of the underlying neurobiology has expanded dramatically. Rather than consider stress biology to be relevant only under unusual and threatening conditions, we conceive of it as an ongoing, adaptive process of assessing the environment, coping with it, and enabling the individual to anticipate and deal with future challenges. Though much remains to be discovered, the fundamental neurocircuitry that underlies these processes has been broadly delineated, key molecular players have been identified, and the impact of this system on neuroplasticity has been well established. More recently, we have come to appreciate the critical interaction between the brain and the rest of the body as it pertains to stress responsiveness. Importantly, this system can become overloaded due to ongoing environmental demands on the individual, be they physical, physiological, or psychosocial. The impact of this overload is deleterious to brain health, and it results in vulnerability to a range of brain disorders, including major depression and cognitive deficits. Thus, stress biology is one of the best understood systems in affective neuroscience and is an ideal target for addressing the pathophysiology of many brain-related diseases. The story we present began with the discovery of glucocorticoid receptors in hippocampus and has extended to other brain regions in both animal models and the human brain with the further discovery of structural and functional adaptive plasticity in response to stressful and other experiences.

Melanocytes are the neural crest-derived pigment-producing cells of the skin that possess dendrites. Yet little is known about how melanocyte dendrites receive and process information from neighboring cells. Here, using a co-culture system to interrogate the interaction between melanocyte dendrites and keratinocytes, we show that signals from neighboring keratinocytes trigger local compartmentalized Ca2+ transients within the melanocyte dendrites. The localized dendritic Ca2+ transients could be triggered by two keratinocyte-secreted factors, endothelin and acetylcholine, which acted via specific melanocyte receptors. Furthermore, compartmentalized Ca2+ transients were also generated on discrete dendritic spine-like structures on the melanocytes. These spines were also present in intact human skin. Our findings provide insights into how melanocyte dendrites communicate with neighboring cells and offer a new model system for studying compartmentalized signaling in dendritic structures.

Purpose of review Several anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency, and targeting different HIV-1 envelope epitopes have entered clinical trials. bNAbs are being evaluated for their potential as long-acting alternatives to antiretrovirals in HIV-1 prevention and therapy, and for potential role in strategies aiming at long-term viral remission. Here, we discuss recent findings from bNAb clinical studies. Recent findings bNAbs targeting distinct HIV-1 envelope epitopes have shown, in general, favorable safety profiles, and engineered bNAb variants have demonstrated improved pharmacokinetics. Single bNAb infusions transiently decreased viremia with subsequent selection of escape variants, while a combination of two bNAbs successfully maintained viral suppression in individuals harboring antibody-sensitive viruses after antiretroviral therapy (ART) was discontinued. Studies in animal models suggest that bNAbs can modulate immune responses and potentially interfere with the establishment or composition of the latent reservoir, and ongoing clinical studies aim to assess potential bNAb-mediated effects on HIV-1 persistence and host immune responses. Early clinical studies support additional evaluation of bNAbs. Antibodies may offer advantages over standard ART for HIV-1 prevention and therapy, and as components of immunologic strategies to achieve sustained virologic control. The evaluation of engineered bNAbs with multispecificity, extended half-lives and increased potency, as well as alternative bNAb-delivery systems are being pursued.

Social memory processing requires functional CA2 neurons, however the specific mechanisms that regulate their activity are poorly understood. Here, we document that SorCS2, a member of the family of the Vps10 family of sorting receptors, is highly expressed in pyramidal neurons of CA2, as well as ventral CA1, a circuit implicated in social memory. SorCS2 specifically localizes to the postsynaptic density and endosomes within dendritic spines of CA2 neurons. We have discovered that SorCS2 is a selective regulator of NMDA receptor surface trafficking in hippocampal neurons, without altering AMPA receptor trafficking. In addition, SorCS2 regulates dendritic spine density in CA2 neurons where SorCS2 expression is enriched, but not in dorsal CA1 neurons, which normally express very low levels of this protein. To specifically test the role of SorCS2 in behavior, we generated a novel SorCS2-deficient mouse, and identify a significant social memory deficit, with no change in sociability, olfaction, anxiety, or several hippocampal-dependent behaviors. Mutations in sorCS2 have been associated with bipolar disease, schizophrenia, and attention deficient-hyperactivity disorder, and abnormalities in social memory are core components of these neuropsychiatric conditions. Thus, our findings provide a new mechanism for social memory formation, through regulating synaptic receptor trafficking in pyramidal neurons by SorCS2.

Aerobic glycolysis or the Warburg effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although the WE is ubiquitous, its biological role remains controversial, and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, here we evolved resistance to koningic acid (KA), a natural product that specifically inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme, during the WE. We found that KA-resistant cells lose the WE but continue to conduct glycolysis and surprisingly remain dependent on glucose as a carbon source and also on central carbon metabolism. Consequently, this altered state of glycolysis led to differential metabolic activity and requirements, including emergent activities in and dependences on fatty acid metabolism. These findings reveal that aerobic glycolysis is a process functionally distinct from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.

Background Congenital heart disease (CHD) affects 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently. De novo variants are estimated to contribute to approximately 8% of sporadic CHD. Methods CHD is genetically heterogeneous, making pathway enrichment analysis an effective approach to explore and statistically validate CHD-associated genes. In this study, we performed novel gene and pathway enrichment analyses of high-impact de novo variants in the recently published whole-exome sequencing (WES) data generated from a cohort of CHD 2645 parent-offspring trios to identify new CHD-causing candidate genes and mutations. We performed rigorous variant- and gene-level filtrations to identify potentially damaging variants, followed by enrichment analyses and gene prioritization. Results Our analyses revealed 23 novel genes that are likely to cause CHD, including HSP90AA1, ROCK2, IQGAP1, and CHD4, and sharing biological functions, pathways, molecular interactions, and properties with known CHD-causing genes. Conclusions Ultimately, these findings suggest novel genes that are likely to be contributing to CHD pathogenesis.

Here we show that the variance over time of all-India daily rainfall (AIR) can be related to the mean over time of AIR by a seasonally varying power law. Outside of the peak monsoon months of July and August, AIR variance increases in proportion to a positive power of mean daily rainfall. During July and August, monthly averages of AIR show little association with the corresponding variances. This power-law relationship of temporal variance to temporal mean is known in biological sciences as Taylor's law (TL) and in physical sciences as fluctuation scaling. We explain the seasonal variation in TL qualitatively by independent and identically distributed random sampling. Accounting for day-to-day correlation in AIR is sufficient to match quantitatively the observed power-law behavior. Our findings provide a quantitative month-specific assessment of the variability of AIR that could prove useful for the design of crop insurance and social safety nets for the large fraction of the population of the Indian subcontinent that depends on rainfed agriculture.