The rockefeller university

Background Hidradenitis suppurativa (HS) is now recognized as a systemic inflammatory disease, sharing molecular similarities with psoriasis. Direct comparison of the systemic inflammation in HS with psoriasis is lacking. Objectives To evaluate the serum proteome of HS and psoriasis, and to identify biomarkers associated with disease severity. Methods In this cross-sectional study, 1536 serum proteins were assessed using the Olink Explore (Proximity Extension Assay) high-throughput panel in patients with moderate-to-severe HS (n = 11), patients with psoriasis (n = 10) and age- and body mass index-matched healthy controls (n = 10). Results HS displayed an overall greater dysregulation of circulating proteins, with 434 differentially expressed proteins (absolute fold change >= 1 center dot 2; P <= 0 center dot 05) in patients with HS vs. controls, 138 in patients with psoriasis vs. controls and 503 between patients with HS and patients with psoriasis. Interleukin (IL)-17A levels and T helper (Th)1/Th17 pathway enrichment were comparable between diseases, while HS presented greater tumour necrosis factor- and IL-1 beta-related signalling. The Th17-associated markers peptidase inhibitor 3 (PI3) and lipocalin 2 (LCN2) were able to differentiate psoriasis from HS accurately. Both diseases presented increases of atherosclerosis-related proteins. Robust correlations between clinical severity scores and immune and atherosclerosis-related proteins were observed across both diseases. Conclusions HS and psoriasis share significant Th1/Th17 enrichment and upregulation of atherosclerosis-related proteins. Despite the greater body surface area involved in psoriasis, HS presents a greater serum inflammatory burden.

Associative learning allows animals to adapt their behavior in response to environmental cues. For example, sensory cues associated with food availability can trigger overconsumption even in sated animals. However, the neural mechanisms mediating cue-driven non-homeostatic feeding are poorly understood. To study this, we recently developed a behavioral task in which contextual cues increase feeding even in sated mice. Here, we show that an insular cortex to central amygdala circuit is necessary for conditioned overconsumption, but not for homeostatic feeding. This projection is marked by a population of glutamatergic nitric oxide synthase1 (Nos1)-expressing neurons, which are specifically active during feeding bouts. Finally, we show that activation of insular cortex Nos1 neurons suppresses satiety signals in the central amygdala. The data, thus, indicate that the insular cortex provides top-down control of homeostatic circuits to promote overconsumption in response to learned cues.

We talk to Mirjana (Mira) Lilic and Elizabeth (Liz) Campbell about their paper, "Structural basis of transcriptional activation by the Mycobacterium tuberculosis intrinsic antibiotic-resistance transcription factor WhiB7,'' the collaborations that made it happen, and the people who mentored and motivated them along the way.

Microbes use signaling factors for intraspecies and interspecies communications. While many intraspecies signaling factors have been found and characterized, discovery of factors for interspecies communication is lagging behind. To facilitate the discovery of such factors, we explored the potential of a mixed microbial culture (MMC) derived from wheatgrass, in which heterogeneity of this microbial community might elicit signaling factors for interspecies communication. The stability of Wheatgrass MMC in terms of community structure and metabolic output was first characterized by 16S ribosomal RNA amplicon sequencing and liquid chromatography/mass spectrometry (LC/MS), respectively. In addition, detailed MS analyses led to the identification of 12hydroxystearic acid (12-HSA) as one of the major metabolites produced by Wheatgrass MMC. Stereochemical analysis revealed that Wheatgrass MMC produces mostly the (R)-isomer, although a small amount of the (S)isomer was also observed. Furthermore, 12-HSA was found to modulate planktonic growth and biofilm formation of various marine bacterial strains. The current study suggests that naturally derived MMCs could serve as a simple and reproducible platform to discover potential signaling factors for interspecies communication. In addition, the study indicates that hydroxylated long-chain fatty acids, such as 12-HSA, may constitute a new class of interspecies signaling factors.

Turnover of cellular organelles, including endoplasmic reticulum (ER) and mitochondria, is orchestrated by an efficient cellular surveillance system. We have identified a mechanism for dual regulation of ER and mitochondria under stress. It is known that AMFR, an ER E3 ligase and ER-associated degradation (ERAD) regulator, degrades outer mitochondrial membrane (OMM) proteins, MFNs (mitofusins), via the proteasome and triggers mitophagy. We show that destabilized mitochondria are almost devoid of the OMM and generate "mitoplasts". This brings the inner mitochondrial membrane (IMM) in the proximity of the ER. When AMFR levels are high and the mitochondria are stressed, the reticulophagy regulatory protein RETREG1 participates in the formation of the mitophagophore by interacting with OPA1. Interestingly, OPA1 and other IMM proteins exhibit similar RETREG1-dependent autophagosomal degradation as AMFR, unlike most of the OMM proteins. The "mitoplasts" generated are degraded by reticulo-mito-phagy - simultaneously affecting dual organelle turnover.

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease. Despite major advances in the diagnosis and treatment of viral causes of hepatitis (Vilarinho and Lifton, 2016), the incidence of chronic liver disease continues to rise worldwide, affecting up to 1.5 billion people globally (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators, 2018) and leading to similar to 2 million deaths annually (Moon et al., 2020). Because the demand for liver transplantation far exceeds the supply of available donor organs, understanding the pathogenesis of advanced liver disease and its complications will be required to develop new therapies to reduce adverse disease outcomes. Portal hypertension-increased hepatic resistance to blood flow entering the liver-is a major contributor to the morbidity and mortality of liver disease owing to development of

The nuclear pore complex (NPC) is the massive protein assembly that regulates the transport of macromolecules between the nucleus and the cytoplasm. Recent breakthroughs have provided major insights into the structure of the NPC in different eukaryotes, revealing a previously unsuspected diversity of NPC architectures. In parallel, the NPC has been shown to be a key player in regulating essential nuclear processes such as chromatin organization, gene expression, and DNA repair. However, our knowledge of the NPC structure has not been able to address the molecular mechanisms underlying its regulatory roles. We discuss potential explanations, including the coexistence of alternative NPC architectures with specific functional roles.

The way in which interactions between mechanics and biochemistry lead to the emergence of complex cell and tissue organization is an old question that has recently attracted renewed interest from biologists, physicists, mathematicians and computer scientists. Rapid advances in optical physics, microscopy and computational image analysis have greatly enhanced our ability to observe and quantify spatiotemporal patterns of signalling, force generation, deformation, and flow in living cells and tissues. Powerful new tools for genetic, biophysical and optogenetic manipulation are allowing us to perturb the underlying machinery that generates these patterns in increasingly sophisticated ways. Rapid advances in theory and computing have made it possible to construct predictive models that describe how cell and tissue organization and dynamics emerge from the local coupling of biochemistry and mechanics. Together, these advances have opened up a wealth of new opportunities to explore how mechanochemical patterning shapes organismal development. In this roadmap, we present a series of forward-looking case studies on mechanochemical patterning in development, written by scientists working at the interface between the physical and biological sciences, and covering a wide range of spatial and temporal scales, organisms, and modes of development. Together, these contributions highlight the many ways in which the dynamic coupling of mechanics and biochemistry shapes biological dynamics: from mechanoenzymes that sense force to tune their activity and motor output, to collectives of cells in tissues that flow and redistribute biochemical signals during development.

Streptococcus suis, a ubiquitous bacterial colonizer in pigs, has recently extended host range to humans, leading to a global surge of deadly human infections and three large outbreaks since 1998. To better understand the mechanisms for the emergence of cross-species transmission and virulence in human, we have sequenced 366 S. suis human and pig isolates from 2005 to 2016 and performed a large-scale phylogenomic analysis on 1,634 isolates from 14 countries over 36 years. We show the formation of a novel human-associated clade (HAC) diversified from swine S. suis isolates. Phylogeographic analysis identified Europe as the origin of HAC, coinciding with the exportation of European swine breeds between 1960s and 1970s. HAC is composed of three sub-lineages and contains several healthy-pig isolates that display high virulence in experimental infections, suggesting healthy-pig carriers as a potential source for human infection. New HAC-specific genes are identified as promising markers for pathogen detection and surveillance. Our discovery of a human-associated S. suis clade provides insights into the evolution of this emerging human pathogen and extend our understanding of S. suis epidemics worldwide.

Pain contributes substantially to reduced quality of life in individuals living with hidradenitis suppurativa (HS). Although improved understanding of HS pathogenesis and treatment has resulted in improved evidence-based HS management guidelines, comprehensive pain management guidelines have yet to be developed. Few HS-specific data exist to guide pharmacologic analgesia; however, recognizing HS pain as either acute or chronic and predominantly nociceptive (aching and gnawing pain due to tissue damage) versus neuropathic (burning-type pain due to somatosensory nervous system dysfunction) provides a conceptual framework for applying outside pain management practices to HS management. This article incorporates the best available evidence from the HS and pain literature to propose an HS pain algorithm that integrates psychological, pharmacologic, and complementary and alternative treatment modalities.