An analysis of cross-reactive viral binding and neutralization of emerging SARS-CoV-2 variants suggests that the mRNA-1273 and NVX-CoV2373 vaccines elicit immune responses that are effective at ...neutralizing the B.1.429 variant but less effective in recognizing the B.1.351 variant.
We describe complex organic mixture analysis by 21 tesla (T) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Ultrahigh mass-resolving power (m/Δm 50% > 2 700 000 at m/z 400) ...and mass accuracy (80 ppb rms) enable resolution and confident identification of tens of thousands of unique elemental compositions. We demonstrate 2.2-fold higher mass-resolving power, 2.6-fold better mass measurement accuracy, and 1.3-fold more assigned molecular formulas compared to our custom-built, state-of-the-art 9.4 T FT-ICR mass spectrometer for petroleum and dissolved organic matter (DOM) analyses. Analysis of a heavy petroleum distillate exemplifies the need for ultrahigh-performance mass spectrometry (49 040 assigned molecular formulas for 21 T versus 29 012 for 9.4 T) and extends the identification of previously unresolved Oo, SsOo, and NOo classes. Mass selective ion accumulation (20 Thompson isolation) of an asphalt volcano sample yields 462 resolved mass spectral peaks at m/z 677 and reveals previously unresolved CcHhNnOoSs mass differences at high mass (m/z > 600). Similar performance gains are realized in the analysis of dissolved organic matter, where doubly charged Oo species are resolved from singly charged SOo species, which requires a mass-resolving power greater than 1 400 000 (at m/z 600). This direct comparison reveals the continued need for higher mass-resolving power and better mass accuracy for comprehensive molecular characterization of the most complex organic mixtures.
Noninvasive human neuroimaging has yielded many discoveries about the brain. Numerous methodological advances have also occurred, though inertia has slowed their adoption. This paper presents an ...integrated approach to data acquisition, analysis and sharing that builds upon recent advances, particularly from the Human Connectome Project (HCP). The 'HCP-style' paradigm has seven core tenets: (i) collect multimodal imaging data from many subjects; (ii) acquire data at high spatial and temporal resolution; (iii) preprocess data to minimize distortions, blurring and temporal artifacts; (iv) represent data using the natural geometry of cortical and subcortical structures; (v) accurately align corresponding brain areas across subjects and studies; (vi) analyze data using neurobiologically accurate brain parcellations; and (vii) share published data via user-friendly databases. We illustrate the HCP-style paradigm using existing HCP data sets and provide guidance for future research. Widespread adoption of this paradigm should accelerate progress in understanding the brain in health and disease.
These pediatric hypertension guidelines are an update to the 2004 "Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents." Significant changes ...in these guidelines include (1) the replacement of the term "prehypertension" with the term "elevated blood pressure," (2) new normative pediatric blood pressure (BP) tables based on normal-weight children, (3) a simplified screening table for identifying BPs needing further evaluation, (4) a simplified BP classification in adolescents ≥13 years of age that aligns with the forthcoming American Heart Association and American College of Cardiology adult BP guidelines, (5) a more limited recommendation to perform screening BP measurements only at preventive care visits, (6) streamlined recommendations on the initial evaluation and management of abnormal BPs, (7) an expanded role for ambulatory BP monitoring in the diagnosis and management of pediatric hypertension, and (8) revised recommendations on when to perform echocardiography in the evaluation of newly diagnosed hypertensive pediatric patients (generally only before medication initiation), along with a revised definition of left ventricular hypertrophy. These guidelines include 30 Key Action Statements and 27 additional recommendations derived from a comprehensive review of almost 15 000 published articles between January 2004 and July 2016. Each Key Action Statement includes level of evidence, benefit-harm relationship, and strength of recommendation. This clinical practice guideline, endorsed by the American Heart Association, is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient diagnoses and outcomes, support implementation, and provide direction for future research.
Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and ...generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial.
Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle.
Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis.
Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.
Traditional cosmological hydrodynamics simulations fail to spatially resolve the circumgalactic medium (CGM), the reservoir of tenuous gas surrounding a galaxy and extending to its virial radius. We ...introduce the technique of Enhanced Halo Resolution (EHR), enabling more realistic physical modeling of the simulated CGM by consistently forcing gas refinement to smaller scales throughout the virial halo of a simulated galaxy. We investigate the effects of EHR in the tempest simulations, a suite of enzo-based cosmological zoom simulations following the evolution of an L* galaxy, resolving spatial scales of 500 comoving pc out to 100 comoving kpc in galactocentric radius. Among its many effects, EHR (1) changes the thermal balance of the CGM, increasing its cool gas content and decreasing its warm/hot gas content; (2) preserves cool gas structures for longer periods; and (3) enables these cool clouds to exist at progressively smaller size scales. Observationally, this results in a boost in "low ions" like H i and a drop in "high ions" like O vi throughout the CGM. These effects of EHR do not converge in the tempest simulations, but extrapolating these trends suggests that the CGM is actually a mist consisting of ubiquitous, small, long-lived, cool clouds suspended in a medium at the halo virial temperature. We find that EHR produces the above effects by (1) better sampling the distribution of CGM phases, enabling runaway cooling in the dense, cool tail of the phase distribution; and (2) preventing cool gas clouds from artificially mixing with the ambient hot halo and evaporating.
The Human Connectome Project (HCP) was launched in 2010 as an ambitious effort to accelerate advances in human neuroimaging, particularly for measures of brain connectivity; apply these advances to ...study a large number of healthy young adults; and freely share the data and tools with the scientific community. NIH awarded grants to two consortia; this retrospective focuses on the “WU-Minn-Ox” HCP consortium centered at Washington University, the University of Minnesota, and University of Oxford. In just over 6 years, the WU-Minn-Ox consortium succeeded in its core objectives by: 1) improving MR scanner hardware, pulse sequence design, and image reconstruction methods, 2) acquiring and analyzing multimodal MRI and MEG data of unprecedented quality together with behavioral measures from more than 1100 HCP participants, and 3) freely sharing the data (via the ConnectomeDB database) and associated analysis and visualization tools. To date, more than 27 Petabytes of data have been shared, and 1538 papers acknowledging HCP data use have been published. The “HCP-style” neuroimaging paradigm has emerged as a set of best-practice strategies for optimizing data acquisition and analysis. This article reviews the history of the HCP, including comments on key events and decisions associated with major project components. We discuss several scientific advances using HCP data, including improved cortical parcellations, analyses of connectivity based on functional and diffusion MRI, and analyses of brain-behavior relationships. We also touch upon our efforts to develop and share a variety of associated data processing and analysis tools along with detailed documentation, tutorials, and an educational course to train the next generation of neuroimagers. We conclude with a look forward at opportunities and challenges facing the human neuroimaging field from the perspective of the HCP consortium.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic oral agents indicating promising effects on cardiovascular and renal end points. However, the renoprotective effects ...of SGLT2 inhibitors are not fully understood. Also, metabolic effects of SGLT2 inhibition on other organ systems, such as effects on hepatic steatosis, are not fully understood. This study sought to address these questions by treating 18-wk-old uninephrectomized
mice with the selective SGLT2 inhibitor dapagliflozin. Untreated
mice developed progressive albuminuria, glomerular mesangial matrix expansion, and fatty liver associated with increased renal expression of TGFβ1, PAI-1, type IV collagen and fibronectin, and liver deposition of fibronectin, type I and III collagen, and laminin. Treatment with dapagliflozin (1 mg·kg
·day
) via gel diet from 18 to 22 wk of age not only reduced blood glucose (371.14 ± 55.02 mg/dl in treated
vs. 573.53 ± 21.73 mg/dl in untreated
,
< 0.05) and Hb A
levels (9.47 ± 0.79% in treated
vs. 12.1 ± 0.73% in untreated
,
< 0.05) but also ameliorated the increases in albuminuria and markers of glomerulosclerosis and liver injury seen in untreated
mice. Furthermore, both renal expressions of NF-kB p65, MCP-1, Nox4, Nox2, and p47phox and urine TBARS levels and liver productions of myeloperoxidase and reactive oxygen species, the markers of tissue inflammation and oxidative stress, were increased in untreated
mice, which were reduced by dapagliflozin administration. These results demonstrate that dapagliflozin not only improves hyperglycemia but also slows the progression of diabetes-associated glomerulosclerosis and liver fibrosis by improving hyperglycemia-induced tissue inflammation and oxidative stress.
Integration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology and organism behaviour. Colonic sensory neurons activate reflex pathways and give ...rise to conscious sensation, but the diversity and division of function within these neurons is poorly understood. The identification of signalling pathways contributing to visceral sensation is constrained by a paucity of molecular markers. Here we address this by comprehensive transcriptomic profiling and unsupervised clustering of individual mouse colonic sensory neurons.
Unbiased single-cell RNA-sequencing was performed on retrogradely traced mouse colonic sensory neurons isolated from both thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia associated with lumbar splanchnic and pelvic spinal pathways, respectively. Identified neuronal subtypes were validated by single-cell qRT-PCR, immunohistochemistry (IHC) and Ca
-imaging.
Transcriptomic profiling and unsupervised clustering of 314 colonic sensory neurons revealed seven neuronal subtypes. Of these, five neuronal subtypes accounted for 99% of TL neurons, with LS neurons almost exclusively populating the remaining two subtypes. We identify and classify neurons based on novel subtype-specific marker genes using single-cell qRT-PCR and IHC to validate subtypes derived from RNA-sequencing. Lastly, functional Ca
-imaging was conducted on colonic sensory neurons to demonstrate subtype-selective differential agonist activation.
We identify seven subtypes of colonic sensory neurons using unbiased single-cell RNA-sequencing and confirm translation of patterning to protein expression, describing sensory diversity encompassing all modalities of colonic neuronal sensitivity. These results provide a pathway to molecular interrogation of colonic sensory innervation in health and disease, together with identifying novel targets for drug development.
We provide evidence that creditors play an active role in the governance of corporations well outside of payment default states. By examining the Securities and Exchange Commission's filings of all ...U. S. nonfinancial firms from 1996 through 2008, we document that, in any given year, between 10% and 20% of firms report being in violation of a financial covenant in a credit agreement. We show that violations are followed immediately by a decline in acquisitions and capital expenditures, a sharp reduction in leverage and shareholder payouts, and an increase in CEO turnover. The changes in the investment and financing behavior of violating firms coincide with amended credit agreements that contain stronger restrictions on firm decision-making; changes in the management of violating firms suggest that creditors also exert informal influence on corporate governance. Finally, we show that firm operating and stock price performance improve post-violation. We conclude that actions taken by creditors increase the value of the average violating firm.
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