The rockefeller university

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major responder to the pathogenic DNA of viruses and bacteria. Upon DNA binding, cGAS becomes enzymatically active to generate the second messenger cGAMP, leading to activation of inflammatory genes, type I interferon production, autophagy, and cell death. Following genotoxic stress, cGAS can also respond to endogenous DNA, deriving from mitochondria, endogenous retroelements, and chromosomes to affect cellular signaling, secretion, and cell fate decisions. However, under unperturbed conditions, signaling from self-DNA is largely, but not completely, inhibited. Here we review how endogenous DNA is exposed to cGAS, how signaling is attenuated but activated under pathological conditions, and how low-level signaling under unperturbed conditions might prime antipathogenic responses.

Recent reports have shown that intracellular, (super)paramagnetic ferritin nanoparticles can gate TRPV1, a non-selective cation channel, in a magnetic field. Here, we report the effects of differing field strength and frequency as well as chemical inhibitors on channel gating using a Ca2+-sensitive promoter to express a secreted embryonic alkaline phosphatase (SEAP) reporter. Exposure of TRPV1-ferritin-expressing HEK-293T cells at 30 degrees C to an alternating magnetic field of 501 kHz and 27.1 mT significantly increased SEAP secretion by similar to 82% relative to control cells, with lesser effects at other field strengths and frequencies. Between 30-32 degrees C, SEAP production was strongly potentiated 3.3-fold by the addition of the TRPV1 agonist capsaicin. This potentiation was eliminated by the competitive antagonist AMG-21629, the NADPH oxidase assembly inhibitor apocynin, and the reactive oxygen species (ROS) scavenger N-acetylcysteine, suggesting that ROS contributes to magnetogenetic TRPV1 activation. These results provide a rational basis to address the heretofore unknown mechanism of magnetogenetics.

A few weeks ago, which ranked one of the deadliest weeks in New York City with nearly 3000 COVID-19 deaths,1 I had a chance encounter on the street with a former patient, Mr. K. I had taken care of him in the emergency room five months ago. He is in his mid-fifties, lives in a homeless shelter, and works as a busboy. Not having a primary care doctor, he uses the emergency room (ER) often to manage complications of his diabetes. A few days before we ran into each other on the street, he went back to the ER because he noticed blood in his urine but was turned away because he did not have typical symptoms of COVID-19. Instead, he was offered a virtual care option—that is, asked to speak to a doctor on video. Being uninsured, financially distressed, and having recently lost his job due to restaurant closures, he had no idea where to start.

Detection methods for Demodex musculi were historically unreliable, and testing was rarely performed because its prevalence in laboratory mice was underestimated. Although infestations are unapparent in most mouse strains, D. musculi burdens are higher and clinical signs detected in various immunodeficient strains. The parasite's influence on the immune system of immunocompetent mice is unknown. We characterized mite burden (immunocompetent and immunodeficient strains) and immunologic changes (immunocompetent strains only) in naive Swiss Webster (SW; outbred), C57BL/6NCrl (B6; Th1 responder), BALB/cAnNCrl (BALB/c; Th2 responder) and NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG; immunodeficient) mice after exposure to Demodex-infested NSG mice. Infested and uninfested age-matched mice of each strain (n = 5) were euthanized 14, 28, 56, and 112 d after exposure. Mite burden was determined through PCR analysis and skin histopathology; B-cell and CD4(+) and CD8(+) T-cell counts and activation states (CD25 and CD69) were evaluated by using flow cytometry; CBC counts were performed; and serum IgE levels were measured by ELISA. Mite burden and PCR copy number correlated in NSG mice, which had the highest mite burden, but not in immunocompetent strains. Infested immunocompetent animals developed diffuse alopecia by day 112, and both BALB/c and C57BL/6 mice had significantly increased IgE levels. These findings aligned with the skewed Th1 or Th2 immunophenotype of each strain. BALB/c mice mounted the most effective host response, resulting in the lowest mite burden of all immunocompetent strains at 112 d after infestation without treatment. Clinically significant hematologic abnormalities were absent and immunophenotype was unaltered in immunocompetent animals. Topical treatment with imidacloprid-moxidectin (weekly for 8 wk) was effective at eradicating mites by early as 7 d after treatment. IgE levels decreased substantially in infested BALB/c mice after treatment. These findings demonstrate a need for D. musculi surveillance in mouse colonies, because the infestation may influence the use of infested mice in select studies.

Perturbations in metabolic processes are associated with diseases such as obesity, type 2 diabetes mellitus, certain infections and some cancers. A resurgence of interest in creatine biology is developing, with new insights into a diverse set of regulatory functions for creatine. This resurgence is primarily driven by technological advances in genetic engineering and metabolism as well as by the realization that this metabolite has key roles in cells beyond the muscle and brain. Herein, we highlight the latest advances in creatine biology in tissues and cell types that have historically received little attention in the field. In adipose tissue, creatine controls thermogenic respiration and loss of this metabolite impairs whole-body energy expenditure, leading to obesity. We also cover the various roles that creatine metabolism has in cancer cell survival and the function of the immune system. Renewed interest in this area has begun to showcase the therapeutic potential that lies in understanding how changes in creatine metabolism lead to metabolic disease. Creatine is well known to have a key role in energy buffering; however, new work is showing that creatine also has roles in diverse cell types and physiological conditions that are distinct from this classic role. This Review discusses the role of creatine in adipocyte thermogenesis, immunity and cancer cell survival.

This year is a plague year. The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is burning across the globe as we anxiously await an effective vaccine or drug to control it. Another plague, of a much older kind — one that is not curable with vaccines or medicine — is currently raging in Africa (Fig. 1) and the Middle East. Seasons of unusually heavy rains, driven by climate change (see go.nature.com/3fchnrm), have created population explosions of swarming desert locusts (Schistocerca gregaria). Swarms can contain billions of insects and cover hundreds of square kilometres. These insects strip vegetation and crops, threatening the precarious existence of subsistence farmers and contributing to food insecurity in vulnerable regions. The only effective weapon for fighting such locust plagues is the aerial spraying of pesticides, but the swarms are fast-moving and unpredictable, and spraying devastates beneficial insects.

The activation of behaviour in a daily rhythm governed by the light cycle is a universal phenomenon among humans, laboratory mammals and other vertebrates. For mice, the active period is during the dark. We have quantified the increase in activity when the lights shut off (Light to Dark, L to D) using a generalized CNS arousal assay with 20 ms resolution, rather than traditional running wheels. Data analysis yielded the rare demonstration of an equation which precisely tracks this behavioural transition and, surprisingly, its reverse during D to L. This behavioural dynamic survives in constant darkness (experiment 2) and is hormone-sensitive (experiment 3). Finally (experiment 4), mice on a light schedule analogous to one which proved troublesome for U.S. Navy sailors, had dysregulated activity bursts which did not conform to the transitions between D and L. These experiments show the lawfulness of a behavioural phase transition and the consequence of deviating from that dynamic pattern. And, in a new way, they bring mathematics to the realm of behavioural neuroscience.

Although there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and correlate with recovery from infection. To examine the human antibody response to HBV, we screened 124 vaccinated and 20 infected, spontaneously recovered individuals. The selected individuals produced shared clones of broadly neutralizing antibodies (bNAbs) that targeted 3 non-overlapping epitopes on the HBV S antigen (HBsAg). Single bNAbs protected humanized mice against infection but selected for resistance mutations in mice with prior established infection. In contrast, infection was controlled by a combination of bNAbs targeting non-overlapping epitopes with complementary sensitivity to mutations that commonly emerge during human infection. The co-crystal structure of one of the bNAbs with an HBsAg peptide epitope revealed a stabilized hairpin loop. This structure, which contains residues frequently mutated in clinical immune escape variants, provides a molecular explanation for why immunotherapy for HBV infection may require combinations of complementary bNAbs.

Nucleosome positioning and stability affect gene regulation in eukaryotic chromatin. Histone H2A.Z is an evolutionally conserved histone variant that forms mobile and unstable nucleosomes in vivo and in vitro. In the present study, we reconstituted nucleosomes containing human H2A.Z.1 mutants, in which the N-terminal or C-terminal half of H2A.Z.1 was replaced by the corresponding canonical H2A region. We found that the N-terminal portion of H2A.Z.1 is involved in flexible nucleosome positioning, whereas the C-terminal portion leads to weak H2A.Z.1-H2B association in the nucleosome. These results indicate that the N-terminal and C-terminal portions are independently responsible for the H2A.Z.1 nucleosome characteristics.