Twisted bilayer graphene (TBG) provides a unique framework to elucidate the interplay between strong correlations and topological phenomena in two-dimensional systems. The existence of multiple ...electronic degrees of freedom—charge, spin, and valley—gives rise to a plethora of possible ordered states and instabilities. Identifying which of them are realized in the regime of strong correlations is fundamental to shed light on the nature of the superconducting and correlated insulating states observed in the TBG experiments. Here, we use unbiased, sign-problem-free quantum Monte Carlo simulations to solve an effective interacting lattice model for TBG at charge neutrality. Besides the usual cluster Hubbard-like repulsion, this model also contains an assisted-hopping interaction that emerges due to the nontrivial topological properties of TBG. Such a nonlocal interaction fundamentally alters the phase diagram at charge neutrality, gapping the Dirac cones even for infinitesimally small interactions. As the interaction strength increases, a sequence of different correlated insulating phases emerge, including a quantum valley Hall state with topological edge states, an intervalley-coherent insulator, and a valence bond solid. The charge-neutrality correlated insulating phases discovered here provide the sought-after reference states needed for a comprehensive understanding of the insulating states at integer fillings and the proximate superconducting states of TBG.
Herein we describe a general, mild and scalable method for deuterium incorporation by potassium methoxide/hexamethyldisilane-mediated dehalogenation of arylhalides. With CD3CN as a deuterium source, ...a wide array of heteroarenes prevalent in pharmaceuticals and bearing diverse functional groups are labeled with excellent deuterium incorporation (>60 examples). The ipso-selectivity of this method provides precise access to libraries of deuterated indoles and quinolines. The synthetic utility of our method has been demonstrated by the incorporation of deuterium into complex natural and drug-like compounds.
Inflammasomes are cytosolic multiprotein complexes that initiate host defense against bacterial pathogens by activating caspase-1–dependent cytokine secretion and cell death. In mice, specific ...nucleotide-binding domain, leucine-rich repeat-containing family, apoptosis inhibitory proteins (NAIPs) activate the nucleotide-binding domain, leucine-rich repeat-containing family, CARD domain-containing protein 4 (NLRC4) inflammasome upon sensing components of the type III secretion system (T3SS) and flagellar apparatus. NAIP1 recognizes the T3SS needle protein, NAIP2 recognizes the T3SS inner rod protein, and NAIP5 and NAIP6 recognize flagellin. In contrast, humans encode a single functional NAIP, raising the question of whether human NAIP senses one or multiple bacterial ligands. Previous studies found that human NAIP detects both flagellin and the T3SS needle protein and suggested that the ability to detect both ligands was achieved by multiple isoforms encoded by the single human NAIP gene. Here, we show that human NAIP also senses the Salmonella Typhimurium T3SS inner rod protein PrgJ and that T3SS inner rod proteins from multiple bacterial species are also detected. Furthermore, we show that a single human NAIP isoform is capable of sensing the T3SS inner rod, needle, and flagellin. Our findings indicate that, in contrast to murine NAIPs, promiscuous recognition of multiple bacterial ligands is conferred by a single human NAIP.
The acidification caused by the dissolution of anthropogenic carbon dioxide (CO₂) in the ocean changes the chemistry and hence the bioavailability of iron (Fe), a limiting nutrient in large oceanic ...regions. Here, we show that the bioavailability of dissolved Fe may decline because of ocean acidification. Acidification of media containing various Fe compounds decreases the Fe uptake rate of diatoms and coccolithophores to an extent predicted by the changes in Fe chemistry. A slower Fe uptake by a model diatom with decreasing pH is also seen in experiments with Atlantic surface water. The Fe requirement of model phytoplankton remains unchanged with increasing CO₂. The ongoing acidification of seawater is likely to increase the Fe stress of phytoplankton populations in some areas of the ocean.
Objective
Proinflammatory molecules promote osteoclast‐mediated bone erosion by up‐regulating local RANKL production. However, recent evidence suggests that combinations of cytokines, such as tumor ...necrosis factor (TNF) plus interleukin‐6 (IL‐6), induce RANKL‐independent osteoclastogenesis. The purpose of this study was to better understand TNF/IL‐6–induced osteoclast formation and to determine whether RANK is absolutely required for osteoclastogenesis and bone erosion in murine inflammatory arthritis.
Methods
Myeloid precursors from wild‐type (WT) mice or mice with either germline or conditional deletion of Rank, Nfatc1, Dap12, or Fcrg were treated with either RANKL or TNF plus IL‐6. Osteoprotegerin, anti–IL‐6 receptor (anti–IL‐6R), and hydroxyurea were used to block RANKL, the IL‐6R, and cell proliferation, respectively. Clinical scoring, histologic assessment, micro–computed tomography, and quantitative polymerase chain reaction (qPCR) were used to evaluate K/BxN serum–transfer arthritis in WT and RANK‐deleted mice. Loss of Rank was verified by qPCR and by osteoclast cultures.
Results
TNF/IL‐6 generated osteoclasts in vitro that resorbed mineralized tissue through a pathway dependent on IL‐6R, NFATc1, DNAX‐activation protein 12, and cell proliferation, but independent of RANKL or RANK. Bone erosion and osteoclast formation were reduced, but not absent, in arthritic mice with inducible deficiency of RANK. TNF/IL‐6, but not RANKL, induced osteoclast formation in bone marrow and synovial cultures from animals deficient in Rank. Multiple IL‐6 family members (IL‐6, leukemia inhibitory factor, oncostatin M) were up‐regulated in the synovium of arthritic mice.
Conclusion
The persistence of bone erosion and synovial osteoclasts in Rank‐deficient mice, and the ability of TNF/IL‐6 to induce osteoclastogenesis, suggest that more than one cytokine pathway exists to generate these bone‐resorbing cells in inflamed joints.
Plasma branched-chain amino acids (BCAAs, including leucine, isoleucine and valine) were recently related to risk of type 2 diabetes (T2D). Dietary intake is the only source of BCAAs; however, little ...is known about whether habitual dietary intake of BCAAs affects risk of T2D.
We assessed associations between cumulative consumption of BCAAs and risk of T2D among participants from three prospective cohorts: the Nurses' Health Study (NHS; followed from 1980 to 2012); NHS II (followed from 1991 to 2011); and the Health Professionals Follow-up Study (HPFS; followed from 1986 to 2010).
We documented 16 097 incident T2D events during up to 32 years of follow-up. After adjustment for demographics and traditional risk factors, higher total BCAA intake was associated with an increased risk of T2D in men and women. In the meta-analysis of all cohorts, comparing participants in the highest quintile with those in the lowest quintile of intake, hazard ratios (95%confidence intervals) were for leucine 1.13 (1.07-1.19), for isoleucine 1.13 (1.07-1.19) and for valine 1.11 (1.05-1.17) (all P for trend < 0.001). In a healthy subsample, higher dietary BCAAs were significantly associated with higher plasma levels of these amino acids (P for trend = 0.01).
Our data suggest that high consumption of BCAAs is associated with an increased risk of T2D.
Awareness with paralysis is a devastating complication for patients receiving mechanical ventilation and risks long-term psychological morbidity. Data from the emergency department (ED) demonstrate a ...high rate of longer-acting neuromuscular blocking agent use, delayed analgosedation, and a lack of sedation depth monitoring. These practices are discordant with recommendations for preventing awareness with paralysis. Despite this, awareness with paralysis has not been rigorously studied in the ED population. Our objective is to assess the prevalence of awareness with paralysis in ED patients receiving mechanical ventilation.
This was a single-center, prospective, observational cohort study on 383 mechanically ventilated ED patients. After extubation, we assessed patients for awareness with paralysis by using the modified Brice questionnaire. Three expert reviewers independently adjudicated awareness with paralysis. We report the prevalence of awareness with paralysis (primary outcome); the secondary outcome was perceived threat, a mediator for development of posttraumatic stress disorder.
The prevalence of awareness with paralysis was 2.6% (10/383). Exposure to rocuronium at any point in the ED was significantly different between patients who experienced awareness with paralysis (70%) versus the rest of the cohort (31.4%) (unadjusted odds ratio 5.1; 95% confidence interval 1.30 to 20.1). Patients experiencing awareness with paralysis had higher mean values on the threat perception scale, denoting a higher degree of perceived threat, compared with patients who did not experience awareness with paralysis (13.4 SD 7.7 versus 8.5 SD 6.2; mean difference 4.9; 95% confidence interval 0.94 to 8.8).
Awareness with paralysis occurs in a significant minority of ED patients who receive mechanical ventilation. Potential associations of awareness with paralysis with ED care and increased perceived threat warrant further evaluation.
Aberrant NLRP3 inflammasome activation contributes to the development of endotoxemia. The importance of negative regulation of NLRP3 inflammasomes remains poorly understood. Here, we show that the E3 ...ubiquitin ligase Cbl-b is essential for preventing endotoxemia induced by a sub-lethal dose of LPS via a caspase-11/NLRP3-dependent manner. Further studies show that NLRP3 undergoes both K63- and K48-linked polyubiquitination. Cbl-b binds to the K63-ubiquitin chains attached to the NLRP3 leucine-rich repeat domain (LRR) via its ubiquitin-associated region (UBA) and then targets NLRP3 at K496 for K48-linked ubiquitination and proteasome-mediated degradation. We also identify RNF125 as an additional E3 ubiquitin ligase that initiates K63-linked ubiquitination of the NLRP3 LRR domain. Therefore, NLRP3 is sequentially ubiquitinated by K63- and K48-linked ubiquitination, thus keeping the NLRP3 inflammasomes in check and restraining endotoxemia.
Chronic inflammation associated with ulcerative colitis predisposes individuals to increased colon cancer risk. The aim of these studies was to identify microRNAs that are aberrantly regulated during ...inflammation and may participate in transformation of colonic epithelial cells in the inflammatory setting.
We have use quantitative PCR arrays to compare microRNA (miRNA) expression in tumors and control colonic epithelial cells isolated from distal colons of chronically inflamed mice and APC(Min/+) mice. Rank order statistics was utilized to identify differentially regulated miRNAs in tumors that arose due to chronic inflammation and/or to germline APC mutation. Eight high priority miRNAs were identified: miR-215, miR-137, miR-708, miR-31, and miR-135b were differentially expressed in APC tumors and miR-215, miR-133a, miR-467d, miR-218, miR-708, miR-31, and miR-135b in colitis-associated tumors. Four of these (miR-215, miR-708, miR-31, and miR-135b) were common to both tumors types, and dysregulation of these miRNAs was confirmed in an independent sample set. Target prediction and pathway analysis suggests that these microRNAs, in the aggregate, regulate signaling pathways related to MAPK, PI3K, WNT, and TGF-β, all of which are known to be involved in transformation.
We conclude that these four miRNAs are dysregulated at some very early stage in transformation of colonic epithelial cells. This response is not dependent on the mechanism of initiation of transformation (inflammation versus germline mutation), suggesting that the miRNAs that we have identified are likely to regulate critical signaling pathways that are central to early events in transformation of colonic epithelial cells.
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