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Found 37443 matches. Displaying 191-200
Braunscheidel KM, Voren G, Fowler CD, Lu Q, Kuryatov A, Cameron MD, Ibañez-Ta...
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SR9883 is a novel small-molecule enhancer of α4β2*nicotinic acetylcholine rec... (opens in new window)

FRONTIERS IN MOLECULAR NEUROSCIENCE 2024 SEP 5; 17(?):? Article 1459098
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Background Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents.Methods 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) was used as a starting point for medical chemistry efforts to develop novel small molecule enhancers of alpha 4 beta 2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of alpha 4/alpha 4 and alpha 4/alpha 5 subunits.Results The NS9283 derivative SR9883 enhanced the effect of nicotine on alpha 4 beta 2* nAChR stoichiometries containing low-affinity agonist binding sites, with EC50 values from 0.2-0.4 mu M. SR9883 had no effect on alpha 3 beta 2* or alpha 3 beta 4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg-1) and oral (10-20 mg kg-1) administration and penetrated into the brain. When administered alone, SR9883 (5-10 mg kg-1) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg-1) decreased responding for intravenous nicotine infusions (0.03 mg kg-1 per infusion) but had no effect on responding for food rewards in rats.Conclusions These data suggest that SR9883 is useful for investigating behavioral processes regulated by certain alpha 4 beta 2* nAChR stoichiometries. SR9883 and related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.
Potapov V, Krudup S, Maguire S, Unlu I, Guan SX, Buss JA, Smail BA, van Eeuwe...
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Discrete measurements of RNA polymerase and reverse transcriptase fidelity re... (opens in new window)

RNA 2024 SEP; 30(9):1246-1258
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Direct methods for determining the fidelity of DNA polymerases are robust, with relatively little sample manipulation before sequencing. In contrast, methods for measuring RNA polymerase and reverse transcriptase fidelities are complicated by additional preparation steps that introduce ambiguity and error. Here, we describe a sequencing method, termed Roll-Seq, for simultaneously determining the individual fidelities of RNA polymerases and reverse transcriptases (RT) using Pacific Biosciences single molecule real-time sequencing. By using reverse transcriptases with high rolling-circle activity, Roll-Seq generates long concatemeric cDNA from a circular RNA template. To discern the origin of a mutation, errors are recorded and determined to occur within a single concatemer (reverse transcriptase error) or all concatemers (RNA polymerase error) over the cDNA strand. We used Roll-Seq to measure the fidelities of T7 RNA polymerases, a Group II intron-encoded RT (Induro), and two LINE RTs (Fasciolopsis buski R2-RT and human LINE-1). Substitution rates for Induro and R2-RT are the same for cDNA and second-strand synthesis while LINE-1 has 2.5-fold lower fidelity when performing second-strand synthesis. Deletion and insertion rates increase for all RTs during second-strand synthesis. In addition, we find that a structured RNA template impacts fidelity for both RNA polymerase and RT. The accuracy and precision of Roll-Seq enable this method to be applied as a complementary analysis to structural and mechanistic characterization of RNA polymerases and reverse transcriptases or as a screening method for RNAP and RT fidelity.
Hayrapetyan A, Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, ...
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Search for bottom-type vectorlike quark pair production in dileptonic and ful... (opens in new window)

PHYSICAL REVIEW D 2024 SEP 17; 110(5):? Article 052004
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A search is described for the production of a pair of bottom-type vectorlike quarks (B VLQs) with mass greater than 1000 GeV. Each B VLQ decays into a b quark and a Higgs boson, a b quark and a Z boson, or a t quark and a W boson. This analysis considers both fully hadronic final states and those containing a charged lepton pair from a Z boson decay. The products of the H -> bb boson decay and of the hadronic Z or W boson decays can be resolved as two distinct jets or merged into a single jet, so the final states are classified by the number of reconstructed jets. The analysis uses data corresponding to an integrated luminosity of 138 fb(-1) collected in proton-proton collisions at root s = 13 TeV with the CMS detector at the LHC from 2016 to 2018. No excess over the expected background is observed. Lower limits are set on the B VLQ mass at the 95% confidence level. These depend on the B VLQ branching fractions and are 1570 and 1540 GeV for 100% B -> bH and 100% B -> bZ, respectively. In most cases, the mass limits obtained exceed previous limits by at least 100 GeV.
Le Pen J, Paniccia G, Kinast V, Moncada-Velez M, Ashbrook AW, Bauer M, Hoffma...
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A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier... (opens in new window)

PLOS BIOLOGY 2024 SEP; 22(9):? Article e3002767
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Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently. Interferons (IFNs) have a role in the regulation of virus-host interactions. This study uses genome-wide CRISPR knockout screen data to identify 28 genes that impact SARS-CoV-2 infection, including PLSCR1, which restricts spike-mediated SARS-CoV-2 entry independently of its IFN-related role.
El Kettani A, Ouair H, Marnissi F, El Bakkouri J, Chevalier R, Lorenzo L, Kho...
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Case Report of Two Independent Moroccan Families with Syndromic Epidermodyspl... (opens in new window)

VIRUSES-BASEL 2024 SEP; 16(9):? Article 1415
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Epidermodysplasia verruciformis (EV) is a rare genodermatosis caused by beta-human papillomaviruses (HPV) in immunodeficient patients. EV is characterized by flat warts and pityriasis-like lesions and might be isolated or syndromic, associated with some other infectious manifestations. We report here three patients from two independent families, with syndromic EV for both of them. By whole exome sequencing, we found that the patients carry new homozygous variants in STK4, both leading to a premature stop codon. STK4 deficiency causes a combined immunodeficiency characterized by a broad infectious susceptibility to bacteria, viruses, and fungi. Auto-immune manifestations were also reported. Deep immunophenotyping revealed multiple cytopenia in the three affected patients, in particular deep CD4(+) T cells deficiency. We report here the fourth and the fifth cases of the syndromic EV due to STK4 deficiency.
Short B
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Grammotoxin increases its toxic behavior (opens in new window)

JOURNAL OF GENERAL PHYSIOLOGY 2024 SEP 25; 156(10):? Article e202413665
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This JGP study reveals that in addition to voltage-gated Ca2+ and K+ channels, omega-grammotoxin-SIA also inhibits voltage-gated Na+ channel currents.
Hayrapetyan A, Tumasyan A, Adam W, Andrejkovic JW, Arnold B, Bergauer H, Berg...
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Performance of CMS muon reconstruction from proton-proton to heavy ion collis... (opens in new window)

JOURNAL OF INSTRUMENTATION 2024 SEP; 19(9):? Article P09012
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The performance of muon tracking, identification, triggering, momentum resolution, and momentum scale has been studied with the CMS detector at the LHC using data collected at root s(NN) = 5.02 TeV in proton-proton (pp) and lead-lead (PbPb) collisions in 2017 and 2018, respectively, and at root s(NN) = 8.16 TeV in proton-lead (pPb) collisions in 2016. Muon efficiencies, momentum resolutions, and momentum scales are compared by focusing on how the muon reconstruction performance varies from relatively small occupancy pp collisions to the larger occupancies of pPb collisions and, finally, to the highest track multiplicity PbPb collisions. We find the efficiencies of muon tracking, identification, and triggering to be above 90% throughout most of the track multiplicity range. The momentum resolution and scale are unaffected by the detector occupancy. The excellent muon reconstruction of the CMS detector enables precision studies across all available collision systems.
Karaaslan BG, Rosain J, Bustamante J, Kiykim A
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Interferon Gamma in Sickness Predisposing to Mycobacterial Infectious ... (opens in new window)

BALKAN MEDICAL JOURNAL 2024 SEP; 41(5):326-332
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In recent decades, the prevalence of inborn errors of immunity has increased, necessitating the development of more effective treatment and care options for these highly morbid conditions. Due to these "experiments of nature," the complicated nature of the immune system is being revealed. Based on the functional and molecular tests, targeted therapies are now being developed which offer a more effective approach and reduce damage. This study aimed to investigate a key cytokine of the cellular immune response, interferon-gamma (IFN-gamma), gamma ), which is linked to Mendelian susceptibility to Mycobacterial disease, and its potential as a therapeutic option for IFN-gamma gamma deficiency.
Lopes J, de Lencastre H, Conceiçao T
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Genomic analysis of Enterococcus faecium from non-clinical settings: a... (opens in new window)

FRONTIERS IN MICROBIOLOGY 2024 SEP 11; 15(?):? Article 1466990
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Introduction Enterococci are commensals of the gastrointestinal tract of humans and animals that evolved into opportunistic pathogens with high antimicrobial resistance and virulence. Multidrug-resistant Enterococcus is a major cause of hospital-acquired infections worldwide. For this reason, the characterization of non-clinical reservoirs of Enterococci and their epidemiological link to resistant hospital isolates is crucial for controlling their spread. Methods A total of 295 samples collected from livestock (pigs and cows, n = 135) and environment (public buses, passengers hands, and urban environments, n = 160) were screened for Enterococcus spp. E. faecium antimicrobial resistance profiles, virulence potential, and clonal population were further characterized. Results Enterococci were detected in 90.5% (n = 267) of the samples, with a higher prevalence in livestock (100%) than the environment (82.5%, p < 0.0001), but none of the isolates exhibited vancomycin resistance. E. faecalis was the most prevalent species (51.7%), predominantly found in livestock (62.2%), while E. faecium was more common in the environment. Of the 59 E. faecium isolates, 78% showed resistance to >= 3 antibiotic classes and contained associated resistance genes, namely tetracyclines (tetM and tetL), beta-lactams (mutations in pbp5), and high-level resistance to aminoglycosides (ant(6)-Ia and aac(6 ')-aph(2 '')). A wide array of virulence factors was detected among E. faecium, associated with adherence, biofilm formation, and adaptation to host response, while hospital-associated virulence markers, such as IS16, were less frequent, probably due to the non-clinical nature of the isolates. Clonal population analysis revealed a diverse E. faecium population. Although no direct epidemiological link could be traced between our isolates and specific clinical isolates, infection-associated genetic backgrounds were identified in non-clinical isolates: one isolate from pigs belonged to CC17 (ST32), while four isolates belonged to CC94, including one recovered from pigs (ST296), one from cows (ST2206), one from the urban environment (ST1205), and other from buses (ST800). Discussion This study underscores a high prevalence of clinically relevant Enterococcus species among healthy livestock and the environment. Despite the absence of vancomycin resistance and limited hospital infection-associated clonal lineages, the presence of E. faecium with significant virulence potential and resistance to critical antibiotics in human and veterinary medicine highlights the need for continuing surveillance of non-clinical reservoirs.
Mc Larney BE, Sonay AY, Apfelbaum E, Mostafa N, Monette S, Goerzen D, Aguirre...
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A pan-cancer dye for solid-tumour screening, resection and wound monitoring v... (opens in new window)

NATURE BIOMEDICAL ENGINEERING 2024 SEP; 8(9):?
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The efficacy of fluorescence-guided surgery in facilitating the real-time delineation of tumours depends on the optical contrast of tumour tissue over healthy tissue. Here we show that CJ215-a commercially available, renally cleared carbocyanine dye sensitive to apoptosis, and with an absorption and emission spectra suitable for near-infrared fluorescence imaging (wavelengths of 650-900 nm) and shortwave infrared (SWIR) fluorescence imaging (900-1,700 nm)-can facilitate fluorescence-guided tumour screening, tumour resection and the assessment of wound healing. In tumour models of either murine or human-derived breast, prostate and colon cancers and of fibrosarcoma, and in a model of intraperitoneal carcinomatosis, imaging of CJ215 with ambient light allowed for the delineation of nearly all tumours within 24 h after intravenous injection of the dye, which was minimally taken up by healthy organs. At later timepoints, CJ215 provided tumour-to-muscle contrast ratios up to 100 and tumour-to-liver contrast ratios up to 18. SWIR fluorescence imaging with the dye also allowed for quantifiable non-contact wound monitoring through commercial bandages. CJ215 may be compatible with existing and emerging clinical solutions. A commercial near-infrared dye that is sensitive to apoptosis and that provides high tumour-to-muscle and tumour-to-liver contrast ratios facilitates fluorescence-guided tumour screening, tumour resection and the assessment of wound healing.