We report on a search for elementary particles with charges much smaller than the electron charge using a data sample of proton-proton collisions provided by the CERN Large Hadron Collider in 2018, ...corresponding to an integrated luminosity of 37.5 fb−1 at a center-of-mass energy of 13 TeV. A prototype scintillator-based detector is deployed to conduct the first search at a hadron collider sensitive to particles with charges ≤ 0.1 e . The existence of new particles with masses between 20 and 4700 MeV is excluded at 95% confidence level for charges between 0.006 e and 0.3 e , depending on their mass. New sensitivity is achieved for masses larger than 700 MeV.
Plant diseases induced by fungi are among the most important limiting factors during pre- and post-harvest food production. For decades, synthetic chemical fungicides have been used to control these ...diseases, however, increase on worldwide regulatory policies and the demand to reduce their application, have led to searching for new ecofriendly alternatives such as the biostimulants. The commercial application of yeasts as biocontrol agents, has shown low efficacy compared to synthetic fungicides, mostly due to the limited knowledge of the molecular mechanisms of yeast-induced responses. To date, only two genome-wide transcriptomic analyses have characterized the mode of action of biocontrols using the plant model
, missing, in our point of view, all its molecular and genomic potential. Here we describe that compounds released by the biocontrol yeast
(HoFs) can protect
and
plants against the broad host-range necrotrophic fungi
and
. We show that HoFs have a long-lasting, dose-dependent local, and systemic effect against
. Additionally, we performed a genome-wide transcriptomic analysis to identify genes differentially expressed after application of HoFs in
. Our work provides novel and valuable information that can help researchers to improve HoFs efficacy in order for it to become an ecofriendly alternative to synthetic fungicides.
Intervening in depression and/or low perceived social support within 28 days after myocardial infarction (MI) in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial did not ...increase event-free survival. The purpose of the present investigation was to conduct post hoc analyses on sex and ethnic minority subgroups to assess whether any treatment subgroup is at reduced or increased risk of greater morbidity/mortality.
The 2481 patients with MI (973 white men, 424 minority men, 674 white women, 410 minority women) who had major or minor depression and/or low perceived social support were randomly allocated to usual medical care or cognitive behavior therapy. Total mortality or recurrent nonfatal MI (ENRICHD primary endpoint) and cardiac mortality or recurrent nonfatal MI (secondary endpoint) were analyzed as composite endpoints by group for time to first event using Cox proportional hazards regression.
There was a trend in the direction of treatment efficacy for white men for the primary endpoint (hazard ratio HR, 0.80; 95% confidence interval, 0.61-1.05; p =.10) and a significant (p <.006, Bonferroni corrected) effect for the secondary endpoint (HR, 0.63; 95% CI, 0.46-0.87; p =.004). In contrast, the HRs for each of the other three subgroups were nonsignificant. The magnitude of differences in treatment effects between white men and the other subgroups remained significant for the secondary endpoint (p =.04) after adjustment for age, education, living alone, antidepressant use, comorbidity score, cardiac catheterization, ejection fraction, history of hypertension, and major depression.
White men, but not other subgroups, may have benefited from the ENRICHD intervention, suggesting that future studies need to attend to issues of treatment design and delivery that may have prevented benefit among sex and ethnic subgroups other than white men.
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced ...by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.
A growing number of investigators are studying ketamine effects in healthy human subjects, but concerns remain about its safety as a research tool. Therefore, it is timely to revisit the safety of ...subanesthetic doses of ketamine in experimental psychopharmacology studies.
To report on the safety of laboratory studies with subanesthetic doses of ketamine in healthy humans using an existing dataset.
Medically healthy subjects with no personal or familial Axis I psychotic spectrum disorders were administered subanesthetic doses of ketamine by intravenous infusion in a series of clinical investigations from 1989 to 2005. The safety of ketamine administration was monitored in these subjects.
Four hundred and fifty subjects received at least one dose of active ketamine. Eight hundred and thirty three active ketamine and 621 placebo infusions were administered. Ten adverse mental status events were documented in nine subjects/infusions that were deemed related to ketamine administration (2% of subjects, 1.45% of infusions). All but one adverse reaction resolved by the end of the test session. The side effects in the remaining individual were no longer clinically significant within 4 days of the test session. No residual sequelae were observed.
Ketamine administration at subanesthetic doses appears to present an acceptable level of risk for carefully screened populations of healthy human subjects in the context of clinical research programs that intensively monitor subjects throughout their study participation.
Phosphoinositide 3-kinase gamma (PI3Kγ) has profound roles downstream of G-protein–coupled receptors in inflammation, cardiac function, and tumor progression. To gain insight into how the enzyme’s ...activity is shaped by association with its p101 adaptor subunit, lipid membranes, and Gβγ heterodimers, we mapped these regulatory interactions using hydrogen–deuterium exchange mass spectrometry. We identify residues in both the p110γ and p101 subunits that contribute critical interactions with Gβγ heterodimers, leading to PI3Kγ activation. Mutating Gβγ-interaction sites of either p110γ or p101 ablates G-protein–coupled receptor-mediated signaling to p110γ/p101 in cells and severely affects chemotaxis and cell transformation induced by PI3Kγ overexpression. Hydrogen–deuterium exchange mass spectrometry shows that association with the p101 regulatory subunit causes substantial protection of the RBD-C2 linker as well as the helical domain of p110γ. Lipid interaction massively exposes that same helical site, which is then stabilized by Gβγ. Membrane-elicited conformational change of the helical domain could help prepare the enzyme for Gβγ binding. Our studies and others identify the helical domain of the class I PI3Ks as a hub for diverse regulatory interactions that include the p101, p87 (also known as p84), and p85 adaptor subunits; Rab5 and Gβγ heterodimers; and the β-adrenergic receptor kinase.
Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and ...how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors. Here, we develop
umor
nterstitial
luid
edium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling us to study PDAC metabolism ex vivo under physiological nutrient conditions. We show that PDAC cells cultured in TIFM adopt a cellular state closer to that of PDAC cells present in tumors compared to standard culture models. Further, using the TIFM model, we found arginine biosynthesis is active in PDAC and allows PDAC cells to maintain levels of this amino acid despite microenvironmental arginine depletion. We also show that myeloid derived arginase activity is largely responsible for the low levels of arginine in PDAC tumors. Altogether, these data indicate that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity to in vivo systems and enable the discovery of novel cancer metabolic phenotypes.
We report results from a reanalysis of data from the Cryogenic Dark Matter Search (CDMS II) experiment at the Soudan Underground Laboratory. Data taken between October 2006 and September 2008 using ...eight germanium detectors are reanalyzed with a lowered, 2 keV recoil-energy threshold, to give increased sensitivity to interactions from weakly interacting massive particles (WIMPs) with masses below ∼10 GeV/c(2). This analysis provides stronger constraints than previous CDMS II results for WIMP masses below 9 GeV/c(2) and excludes parameter space associated with possible low-mass WIMP signals from the DAMA/LIBRA and CoGeNT experiments.
The CDMS low ionization threshold experiment (CDMSlite) uses cryogenic germanium detectors operated at a relatively high bias voltage to amplify the phonon signal in the search for weakly interacting ...massive particles (WIMPs). Results are presented from the second CDMSlite run with an exposure of 70 kg day, which reached an energy threshold for electron recoils as low as 56 eV. A fiducialization cut reduces backgrounds below those previously reported by CDMSlite. New parameter space for the WIMP-nucleon spin-independent cross section is excluded for WIMP masses between 1.6 and 5.5 GeV/c^{2}.
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