The rockefeller university

Cell fate determination requires faithful execution of gene expression programs, which are increasingly recognized to respond to metabolic inputs. In particular, the family of alpha-ketoglutarate (alpha KG)-dependent dioxygenases, which include several chromatin-modifying enzymes, are emerging as key mediators of metabolic control of cell fate. alpha KG-dependent dioxygenases consume the metabolite alpha KG (also known as 2-oxoglutarate) as an obligate cosubstrate and are inhibited by succinate, fumarate, and 2-hydroxyglutarate. Here, we review the role of these metabolites in the control of dioxygenase activity and cell fate programs. We discuss the biochemical and transcriptional mechanisms enabling these metabolites to control cell fate and review evidence that nutrient availability shapes tissue-specific fate programs via alpha KG-dependent dioxygenases.

The Niemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by the lack or decreased activity of the acid sphingomyelinase enzyme or a deficiency of the Niemann-Pick C intracellular cholesterol transporter protein. As a result of the defect, sphingomyelin and cholesterol accumulate in the lysosomes of the cells. The most common presentation symptom of the disease is abdominal protrusion due to hepatosplenomegaly. The most severe symptoms are the consequences of progressive neurodegeneration. Genetic testing is essential to confirm the diagnosis, which also allows for prenatal genetic testing in the affected families. Early detection of the disease is extremely important as therapeutic options are expanding. Thanks to substrate reduction and enzyme replacement therapies, hepatosplenomegaly can be reduced, and progression of neurological symptoms can be reversed. Through two case reports, the author presents the main types, clinical manifestations, and molecular genetic background of this rare metabolic disorder. The author describes the diagnostic and therapeutic approaches to Niemann-Pick disease.

Hidradenitis suppurativa (HS) is a chronic and often debilitating inflammatory condition characterized by frequent nodules, abscesses, sinus tracts, and scars impacting the intertriginous areas. Many patients with HS often report limited treatment success and symptom coverage with conventional therapies. Recent studies have reported the widespread use of complementary and alternative medicine (CAM) among patients with HS. In this study, our aim was to examine current physician practice patterns, opinions, and comfort with recommending CAM. Our results indicate that provider comfort and opinions on CAM varied based on the provider's experiences, demographics, and the CAM modality itself. Overall, nearly two-thirds (n = 30, 61.2%) of respondents agreed that CAM and conventional medicine were more effective together than either alone. Meanwhile, 44.9% (n = 22) of respondents routinely recommend CAM while 64.6% (n = 31) of respondents reported that they are routinely asked about CAM. The majority (n = 41, 83.7%) of respondents indicated a lack of scientific evidence in the medical literature as a barrier to recommending CAM along with efficacy concerns (n = 34, 69.4%) and ability to recommend reputable CAM products (n = 32, 65.3%) and practitioners (n = 32, 65.3%). Future investigations are warranted to establish a better understanding of the efficacy and benefit of CAM methods in conjunction with conventional methods.

Animal nervous systems remodel following stress. Although global stress-dependent changes are well documented, contributions of individual neuron remodeling events to animal behavior modification are challenging to study. In response to environmental insults, C. elegans become stress-resistant dauers. Dauer entry induces amphid sensory organ remodeling in which bilateral AMsh glial cells expand and fuse, allowing embedded AWC chemosensory neurons to extend sensory receptive endings. We show that amphid remodeling correlates with accelerated dauer exit upon exposure to favorable conditions and identify a G protein-coupled receptor, REMO-1, driving AMsh glia fusion, AWC neuron remodeling, and dauer exit. REMO-1 is expressed in and localizes to AMsh glia tips, is dispensable for other remodeling events, and promotes stress-induced expression of the remodeling receptor tyrosine kinase VER-1. Our results demonstrate how single-neuron structural changes affect animal behavior, identify key glial roles in stress-induced nervous system plasticity, and demonstrate that remodeling primes animals to respond to favorable conditions.

Polymerase sliding clamps are ring-shaped proteins that encircle duplex DNA and hold polymerases to DNA for high processivity during synthesis. The crystal structure of clamp-DNA complex reveals that the DNA is highly tilted through the clamp with extensive interaction with the clamp inner surface. In contrast to the tilted clamp-DNA interaction without DNA polymerases, recent structures of replicative polymerases of bacteria, eukaryotes, and archaea that are bound to the clamp and DNA show that the polymerase positions DNA straight through the clamp without direct protein-DNA contacts. Instead, the clamp-to-DNA interaction is mediated by one or two layers of water. Hence, clamps 'water skate' on DNA during function with replicative polymerases from all domains of life, providing a nearly frictionless bearing for fast and processive DNA synthesis.

The development of safe and effective vaccines against viruses is central to disease control. With advancements in DNA synthesis technology, the production of synthetic viral genomes has fueled many research efforts that aim to generate attenuated viruses by introducing synonymous mutations. Elucidation of the mechanisms underlying virus attenuation through synonymous mutagenesis is revealing interesting new biology that can be exploited for vaccine development. Here, we review recent advancements in this field of synthetic virology and focus on the molecular mechanisms of attenuation by genetic recoding of viruses. We highlight the action of the zinc finger antiviral protein (ZAP) and RNase L, two proteins involved in the inhibition of viruses enriched for CpG and UpA dinucleotides, that are often the products of virus recoding algorithms. Additionally, we discuss current challenges in the field as well as studies that may illuminate how other host functions, such as translation, are potentially involved in the attenuation of recoded viruses.

The authors show that zonation extends to hepatic immune cells and that this spatial patterning is mediated by microbiome sensing by liver sinusoidal endothelial cells, and provide evidence that immune zonation is required to protect the host from the dissemination of blood-borne pathogens. The liver connects the intestinal portal vasculature with the general circulation, using a diverse array of immune cells to protect from pathogens that translocate from the gut(1). In liver lobules, blood flows from portal triads that are situated in periportal lobular regions to the central vein via a polarized sinusoidal network. Despite this asymmetry, resident immune cells in the liver are considered to be broadly dispersed across the lobule. This differs from lymphoid organs, in which immune cells adopt spatially biased positions to promote effective host defence(2,3). Here we used quantitative multiplex imaging, genetic perturbations, transcriptomics, infection-based assays and mathematical modelling to reassess the relationship between the localization of immune cells in the liver and host protection. We found that myeloid and lymphoid resident immune cells concentrate around periportal regions. This asymmetric localization was not developmentally controlled, but resulted from sustained MYD88-dependent signalling induced by commensal bacteria in liver sinusoidal endothelial cells, which in turn regulated the composition of the pericellular matrix involved in the formation of chemokine gradients. In vivo experiments and modelling showed that this immune spatial polarization was more efficient than a uniform distribution in protecting against systemic bacterial dissemination. Together, these data reveal that liver sinusoidal endothelial cells sense the microbiome, actively orchestrating the localization of immune cells, to optimize host defence.

Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4(+) T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFN.2 and IFN. that reduced viral replication in vitro by 50% (IC50) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4(+) T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFN.2 and IFN. resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant.

This cross-sectional survey characterizes the knowledge, attitudes, and practices of international experts in the management of pain in patients with hidradenitis suppurativa.