The coherent elastic scattering of neutrinos off nuclei has eluded detection for four decades, even though its predicted cross section is by far the largest of all low-energy neutrino couplings. This ...mode of interaction offers new opportunities to study neutrino properties and leads to a miniaturization of detector size, with potential technological applications. We observed this process at a 6.7σ̃ confidence level, using a low-background, 14.6-kilogram CsINa scintillator exposed to the neutrino emissions from the Spallation Neutron Source at Oak Ridge National Laboratory. Characteristic signatures in energy and time, predicted by the standard model for this process, were observed in high signal-to-background conditions. Improved constraints on nonstandard neutrino interactions with quarks are derived from this initial data set.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting ...their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.
Keywords: KEY WORDS Frank's sign; diagonal earlobe crease; coronary artery disease Author Affiliation: (1) Department of Medicine, University of California, San Francisco, San Francisco, CA, USA (2) ...Division of Cardiology at Zuckerberg San Francisco General Hospital, San Francisco, CA, USA (3) University of California, San Francisco, San Francisco, CA, USA (a) arturo.gasga@ucsf.edu Article History: Registration Date: 12/04/2020 Received Date: 04/18/2020 Accepted Date: 12/03/2020 Online Date: 01/22/2021 Byline:
Dual-phase xenon detectors lead the search for keV-scale nuclear recoil signals expected from the scattering of weakly interacting massive particle (WIMP) dark matter, and can potentially be used to ...study the coherent nuclear scattering of MeV-scale neutrinos. New capabilities of such experiments can be enabled by extending their nuclear recoil searches down to the lowest measurable energy. The response of the liquid xenon target medium to nuclear recoils, however, is not well characterized below a few keV, leading to large uncertainties in projected sensitivities. In this work, we report a new measurement of ionization signals from nuclear recoils in liquid xenon down to the lowest energy reported to date. At 0.3 keV, we find that the average recoil produces approximately one ionization electron; this is the first measurement of nuclear recoil signals at the single-ionization-electron level, approaching the physical limit of liquid xenon ionization detectors. We discuss the implications of these measurements on the physics reach of xenon detectors for nuclear-recoil-based WIMP dark matter searches and the detection of coherent elastic neutrino-nucleus scattering.
The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay ...for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios.
A measurement of the energy dependence of antineutrino disappearance at the Daya Bay reactor neutrino experiment is reported. Electron antineutrinos (ν¯(e)) from six 2.9 GW(th) reactors were ...detected with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls. Using 217 days of data, 41 589 (203 809 and 92 912) antineutrino candidates were detected in the far hall (near halls). An improved measurement of the oscillation amplitude sin(2)2θ(13)=0.090(-0.009)(+0.008) and the first direct measurement of the ν¯(e) mass-squared difference |Δm(ee)2|=(2.59(-0.20)(+0.19))×10(-3) eV2 is obtained using the observed ν¯(e) rates and energy spectra in a three-neutrino framework. This value of |Δm(ee)2| is consistent with |Δm(μμ)2| measured by muon neutrino disappearance, supporting the three-flavor oscillation model.
Summary Background Incisional hernia is a frequent complication of midline laparotomy and is associated with high morbidity, decreased quality of life, and high costs. We aimed to compare the large ...bites suture technique with the small bites technique for fascial closure of midline laparotomy incisions. Methods We did this prospective, multicentre, double-blind, randomised controlled trial at surgical and gynaecological departments in ten hospitals in the Netherlands. Patients aged 18 years or older who were scheduled to undergo elective abdominal surgery with midline laparotomy were randomly assigned (1:1), via a computer-generated randomisation sequence, to receive small tissue bites of 5 mm every 5 mm or large bites of 1 cm every 1 cm. Randomisation was stratified by centre and between surgeons and residents with a minimisation procedure to ensure balanced allocation. Patients and study investigators were masked to group allocation. The primary outcome was the occurrence of incisional hernia; we postulated a reduced incidence in the small bites group. We analysed patients by intention to treat. This trial is registered at Clinicaltrials.gov , number NCT01132209 and with the Nederlands Trial Register, number NTR2052. Findings Between Oct 20, 2009, and March 12, 2012, we randomly assigned 560 patients to the large bites group (n=284) or the small bites group (n=276). Follow-up ended on Aug 30, 2013; 545 (97%) patients completed follow-up and were included in the primary outcome analysis. Patients in the small bites group had fascial closures sutured with more stitches than those in the large bites group (mean number of stitches 45 SD 12 vs 25 10; p<0·0001), a higher ratio of suture length to wound length (5·0 1·5 vs 4·3 1·4; p<0·0001) and a longer closure time (14 6 vs 10 4 min; p<0·0001). At 1 year follow-up, 57 (21%) of 277 patients in the large bites group and 35 (13%) of 268 patients in the small bites group had incisional hernia (p=0·0220, covariate adjusted odds ratio 0·52, 95% CI 0·31–0·87; p=0·0131). Rates of adverse events did not differ significantly between groups. Interpretation Our findings show that the small bites suture technique is more effective than the traditional large bites technique for prevention of incisional hernia in midline incisions and is not associated with a higher rate of adverse events. The small bites technique should become the standard closure technique for midline incisions. Funding Erasmus University Medical Center and Ethicon.
Smad7 plays a protective role in chronic kidney disease; however, its role in acute kidney injury (AKI) remains unexplored. Here, we report that Smad7 protects against AKI by rescuing the G1 cell ...cycle arrest of tubular epithelial cells (TECs) in ischemia/reperfusion-induced AKI in mice in which Smad7 gene is disrupted or restored locally into the kidney. In Smad7 gene knockout (KO) mice, more severe renal impairment including higher levels of serum creatinine and massive tubular necrosis was developed at 48 h after AKI. In contrast, restored renal Smad7 gene locally into the kidney of Smad7 KO mice protected against AKI by promoting TEC proliferation identified by PCNA+ and BrdU+ cells. Mechanistic studies revealed that worsen AKI in Smad7 KO mice was associated with a marked activation of TGF-β/Smad3-p21/p27 signaling and a loss of CDK2/cyclin E activities, thereby impairing TEC regeneration at the G1 cell cycle arrest. In contrast, restored Smad7 locally into the kidneys of Smad7 KO mice protected TECs from the G1 cell cycle arrest and promoted TEC G1/S transition via a CDK2/cyclin E-dependent mechanism. In conclusion, Smad7 plays a protective role in AKI. Blockade of TGF-β/Smad3-p21/p27-induced G1 cell cycle arrest may be a key mechanism by which Smad7 treatment inhibits AKI. Thus, Smad7 may be a novel therapeutic agent for AKI.
Aims
As a natural antimicrobial agent, Melaleuca alternifolia oil (MAO) is generally recognized to be safe and effective in the inhibition of phytopathogenic fungi. Due to lack of comprehensive ...studies on MAO for controlling postharvest Aspergillus, we investigated the preservative mechanism of MAO and its components against Aspergillus ochraceus in postharvest grapes to evaluate their potential effectiveness as fruit preservatives.
Methods and Results
In our study, the compositions in MAO were analysed by gas chromatography–mass spectrometry. The inhibitory effects of MAO and its main constituents against A. ochraceus were compared by scanning electron microscopy and transmission electron microscopy observation, and metabolic analysis. Two components of MAO, α‐terpineol and terpene‐4‐alcohol, showed higher antifungal effects than MAO, of which α‐terpineol caused the worst leakage of cytoplasm and most serious hyphae distortions and spore disruptions. The downregulation of metabolic pathways of A. ochraceus was strongest with α‐terpineol. The best inhibitory efficacy against A. ochraceus in grapes also occurred with α‐terpineol. 3‐Carene showed little inhibitory effect.
Conclusions
These results demonstrate that not all components in MAO possess antimicrobial effects, and α‐terpineol is the main contributor of MAO's A. ochraceus inhibition effect.
Significance and Impact of the Study
α‐Terpineol may be used as an alternative natural preservative for the postharvest storage of grapes and other fruits.
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