The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly ...contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD's performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people.
Repeat expansions are responsible for over 40 monogenic disorders, and undoubtedly more pathogenic repeat expansions remain to be discovered. Existing methods for detecting repeat expansions in ...short-read sequencing data require predefined repeat catalogs. Recent discoveries emphasize the need for methods that do not require pre-specified candidate repeats. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide repeat expansion detection. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference repeat expansions not discoverable via existing methods.
Ankrd11 is a potential chromatin regulator implicated in neural development and autism spectrum disorder (ASD) with no known function in the brain. Here, we show that knockdown of Ankrd11 in ...developing murine or human cortical neural precursors caused decreased proliferation, reduced neurogenesis, and aberrant neuronal positioning. Similar cellular phenotypes and aberrant ASD-like behaviors were observed in Yoda mice carrying a point mutation in the Ankrd11 HDAC-binding domain. Consistent with a role for Ankrd11 in histone acetylation, Ankrd11 was associated with chromatin and colocalized with HDAC3, and expression and histone acetylation of Ankrd11 target genes were altered in Yoda neural precursors. Moreover, the Ankrd11 knockdown-mediated decrease in precursor proliferation was rescued by inhibiting histone acetyltransferase activity or expressing HDAC3. Thus, Ankrd11 is a crucial chromatin regulator that controls histone acetylation and gene expression during neural development, thereby providing a likely explanation for its association with cognitive dysfunction and ASD.
•Ankrd11 regulates proliferation and neurogenesis in the embryonic brain•Ankrd11 mutation causes cortical abnormalities and ASD-like behavior•Ankrd11 is associated with chromatin and colocalizes with HDAC3•Ankrd11 mutation alters histone acetylation and gene expression in neural precursors
Gallagher et al. identify the ASD-associated protein Ankrd11 as a transcriptional coregulator essential for embryonic cortical development. Ankrd11 regulates histone acetylation and gene expression and thus controls precursor proliferation and neuronal genesis and positioning. Ankrd11 mutant mice display abnormal cortical development and ASD-like behaviors, thereby modeling the human situation.
To fight infections, macrophages undergo a metabolic shift whereby increased glycolysis fuels antimicrobial inflammation and killing of pathogens. Here we demonstrate that the pathogen Candida ...albicans turns this metabolic reprogramming into an Achilles' heel for macrophages. During Candida-macrophage interactions intertwined metabolic shifts occur, with concomitant upregulation of glycolysis in both host and pathogen setting up glucose competition. Candida thrives on multiple carbon sources, but infected macrophages are metabolically trapped in glycolysis and depend on glucose for viability: Candida exploits this limitation by depleting glucose, triggering rapid macrophage death. Using pharmacological or genetic means to modulate glucose metabolism of host and/or pathogen, we show that Candida infection perturbs host glucose homeostasis in the murine candidemia model and demonstrate that glucose supplementation improves host outcomes. Our results support the importance of maintaining glucose homeostasis for immune cell survival during Candida challenge and for host survival in systemic infection.
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•The macrophage Warburg effect becomes a liability during microbial challenge•In vitro, Candida competes for glucose, triggering massive macrophage death•In vivo, Candida infection promotes disruption of host glucose homeostasis•A glucose-rich diet improves host outcomes in systemic fungal infection
Glucose is essential for innate immune cells to mount effective anti-fungal responses. Tucey et al. show that, for infected macrophages, dependence on glucose becomes their downfall: the human fungal pathogen Candida albicans rapidly consumes glucose, causing macrophages to die. In mice, maintaining host glucose homeostasis is important to prevent life-threatening fungal infection.
Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of ...lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown.
To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1).
ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle.
In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1α knockout allele. Transgenic overexpression of HIF-1α in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1α increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue.
HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase inactivation may contribute to atherosclerosis in patients with sleep apnea.
Atomic frequency standards are used to generate accurate and precise time and frequency, enabling many communications, synchronization, and navigation systems in modern life. GPS and other satellite ...navigation systems, voice and data telecommunications, and timestamping of financial transactions all rely on precise time and frequency enabled by atomic frequency standards. This review provides a snapshot and an outlook of commercial and emerging atomic frequency standards. We provide a concise summary of the performance and physics of operation of current atomic frequency standards. In addition, we discuss examples of emerging frequency standard technologies and prototype demonstrations with a focus on technologies expected to provide commercial or military utility within the next decade. We include a comparison of performance versus size and power for current atomic frequency standards. We develop and discuss an empirical relationship between frequency standard performance and product size.
Phase transitions are ubiquitous in nature, and can be arranged into universality classes such that systems having unrelated microscopic physics show identical scaling behaviour near the critical ...point. One prominent universal element of many continuous phase transitions is the spontaneous formation of topological defects during a quench through the critical point. The microscopic dynamics of defect formation in such transitions are generally difficult to investigate, particularly for superfluids. However, Bose-Einstein condensates (BECs) offer unique experimental and theoretical opportunities for probing these details. Here we present an experimental and theoretical study of the BEC phase transition of a trapped atomic gas, in which we observe and statistically characterize the spontaneous formation of vortices during condensation. Using microscopic theories that incorporate atomic interactions and quantum and thermal fluctuations of a finite-temperature Bose gas, we simulate condensation and observe vortex formation in close quantitative agreement with our experimental results. Our studies provide further understanding of the development of coherence in superfluids, and may allow for direct investigation of universal phase transition dynamics.
Rydberg atom electric field sensors are projected to enable novel capabilities for resilient communications and sensing. This quantum sensor is small-size, highly sensitive, and broadly tunable, and ...it has the potential for performing precision vector electric field and angle-of-arrival measurements. While these atomic electric field sensors will not replace traditional receivers in commodity applications for RF signal reception, these sensors could be an enabling technology in niche application spaces. This review outlines the principles of operation of atomic electric field sensors and compares their performance capabilities to traditional RF receivers. It also highlights recent research and development efforts in atomic electric field sensing and identifies applications for which these sensors are projected to impact communications and remote sensing.
We found a p.Ala406Val (c.1217C > T) mutation in MORC2 in three individuals, from two families. All three individuals were evaluated and clinical electrophysiology was completed. The neuropathy began ...in childhood to early adulthood, with distal weakness progressing to proximal weakness. Vinblastine (for Hodgkin lymphoma) acutely worsened the weakness in one patient. This finding confirms that that the p.Ala406Val mutation in MORC2 causes severe neuropathy. In addition, we report the first case of vinblastine neurotoxicity in Charcot‐Marie‐Tooth disease type 2Z.
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