Measurement of the Higgs boson production rate in association with top quarks in final states with electrons, muons, and hadronically decaying tau leptons at s√=13TeV

The rate for Higgs (H) bosons production in association with either one (tH) or two (tt¯H) top quarks is measured in final states containing multiple electrons, muons, or tau leptons decaying to hadrons and a neutrino, using proton–proton collisions recorded at a center-of-mass energy of 13TeV by the CMS experiment. The analyzed data correspond to an integrated luminosity of 137fb−1. The analysis is aimed at events that contain H→WW, H→ττ, or H→ZZ decays and each of the top quark(s) decays either to lepton+jets or all-jet channels. Sensitivity to signal is maximized by including ten signatures in the analysis, depending on the lepton multiplicity. The separation among tH, tt¯H, and the backgrounds is enhanced through machine-learning techniques and matrix-element methods. The measured production rates for the tt¯H and tH signals correspond to 0.92±0.19(stat)+0.17−0.13(syst) and 5.7±2.7(stat)±3.0(syst) of their respective standard model (SM) expectations. The corresponding observed (expected) significance amounts to 4.7 (5.2) standard deviations for tt¯H, and to 1.4 (0.3) for tH production. Assuming that the Higgs boson coupling to the tau lepton is equal in strength to its expectation in the SM, the coupling yt of the Higgs boson to the top quark divided by its SM expectation, κt=yt/ySMt, is constrained to be within −0.9<κt<−0.7 or 0.7<κt<1.1, at 95% confidence level. This result is the most sensitive measurement of the tt¯H production rate to date.SCOAP

Erector spinae plane block for cancer pain – A scoping review of current evidence

Cancer patients experience pain secondary to the disease process or due to treatment. Refractory cancer pain can present a clinical challenge for pain physicians, which significantly affects patients' quality of life and increases disability. Erector spinae plane (ESP) blocks have rapidly been used in both acute and chronic pain practice. However, the use of ESP block for cancer pain management remains unclear. Thus, we conducted this scoping review to perform a comprehensive overview of current evidence on ESP block for cancer pain management. We searched the PubMed and Google Scholar databases for relevant articles published between January 2016 and March 2023 using the keywords “erector spinae plane block,” “ESP block,” and “cancer pain”. After excluding duplicate and irrelevant articles, we included a total of 26 studies, which were case reports, case series, cohort studies, and randomized control trials. Both neurolytic and non-neurolytic ESP blocks were used for cancer pain. The ESP blocks were performed in all patients with severe pain (Visual Analog Score or Numerical Rating Scale >7) and the majority of cases had some degree of pain relief. None of the studies has reported any serious complications related to procedure or drug used. There was heterogeneity in the type of drug, volume, and concentration used for ESP block. A definitive conclusion regarding the efficacy and safety of ESP block in cancer pain management was not possible. The current literature suggests that the ESP block can be helpful in cancer pain management. However, caution must be exercised not to overestimate the safety of either neurolytic or non-neurolytic ESP block as 88% (n = 23) of included studies were either case reports or case series. Randomized controlled clinical trials are warranted to establish the efficacy and safety of ESP block in cancer pain management.

Effect of various factors on functional properties of MtSerB2 and its phosphatase domain (PSPD) respectively.

<p>(<b>A</b>) Relative change in hydrolysis of l-phosphoserine with increasing pH. Hydrolysis at pH 7.5 was taken as 100%. (<b>B</b>) Changes in the enzyme activity of MtSerB2 on increasing the temperature. Data are shown in percentages with enzyme activity observed for MtSerB2 at 37°C taken as 100%. (<b>C</b>) Effect of divalent cations on enzymatic hydrolysis of l-phosphoserine by MtSerB2. Relative activity was measured at concentrations of different divalent cations and that with Mg²⁺ was considered as 100%. Inset shows inhibition by Calcium Chloride. (<b>D</b>) Effect of varying the temperature on the phosphatase activity of PSPD. (<b>E</b>) Optimal pH for maximum substrate hydrolysis.</p

Fluorescent microscopy experiments involving THP-1 cells shows alteration in cell microtubules in the presence of MtSerB2.

<p>Exogenous addition of purified MtSerB2 protein to THP-1 cells induces microtubule rearrangements. Cells were stained for α-tubulin (<i>red</i>) and images were taken at 60× magnification. Arrows indicate the presence of enriched tubulin at the cell surface. Controls (vehicle) contained enzyme buffer only. Additional controls involve the D341N catalytic site mutant which induced very less/negligible tubulin rearrangement and this is attributed to the residual activity possessed by the mutant.</p

Characterization of <i>M. tuberculosis</i> SerB2, an Essential HAD-Family Phosphatase, Reveals Novel Properties

<div><p><i>M. tuberculosis</i> harbors an essential phosphoserine phosphatase (MtSerB2, Rv3042c) that contains two small- molecule binding ACT-domains (Pfam 01842) at the N-terminus followed by the phosphoserine phosphatase (PSP) domain. We found that exogenously added MtSerB2 elicits microtubule rearrangements in THP-1 cells. Mutational analysis demonstrates that phosphatase activity is co-related to the elicited rearrangements, while addition of the ACT-domains alone elicits no rearrangements. The enzyme is dimeric, exhibits divalent metal- ion dependency, and is more specific for l- phosphoserine unlike other classical PSPases. Binding of a variety of amino acids to the ACT-domains influences MtSerB2 activity by either acting as activators/inhibitors/have no effects. Additionally, reduced activity of the PSP domain can be enhanced by equimolar addition of the ACT domains. Further, we identified that G18 and G108 of the respective ACT-domains are necessary for ligand-binding and their mutations to G18A and G108A abolish the binding of ligands like l- serine. A specific transition to higher order oligomers is observed upon the addition of l- serine at ∼0.8 molar ratio as supported by Isothermal calorimetry and Size exclusion chromatography experiments. Mutational analysis shows that the transition is dependent on binding of l- serine to the ACT-domains. Furthermore, the higher-order oligomeric form of MtSerB2 is inactive, suggesting that its formation is a mechanism for feedback control of enzyme activity. Inhibition studies involving over eight inhibitors, MtSerB2, and the PSP domain respectively, suggests that targeting the ACT-domains can be an effective strategy for the development of inhibitors.</p></div

Native PAGE.

<p>The appropriate fractions from the size-exclusion chromatography experiments were evaluated using Native PAGE. Clearly MtSerB2 and the D341N active-site mutant shifted to a tetrameric association in the presence of ∼0.8 molar ratio of l-serine. On the other hand, the G18A and G108A ACT-domain mutants exhibit no such transition.</p

Size exclusion chromatography experiments involving MtSerB2, its mutants and l-serine.

<p>(<b>A</b>) <b>Wildtype SerB2</b> (<b>B</b>) <b>D341N</b> (<b>C</b>) <b>G18A</b> (D) <b>G108A</b>. Chromatogram in the absence of l-serine is in <i>black</i>, whereas the chromatogram in the presence of of l-serine, and MtSerB2 and its mutants, are shown in grey. Wild-type MtSerB2 and D341N show a shift to the tetrameric/higher order oligomeric forms in the presence of ∼0.8 molar ratio of l-serine.</p

Substrate specificity of MtSerB2.

<p>Relative change in the hydrolysis of different substrates. l- PS depicts l-phosphoserine, l- PT depicts l-phosphothreonine, l- PTy depicts l-phosphotyrosine, G-6-P depicts Glucose-6-phosphate and ATP is adenosine triphosphate. The experiment was performed in triplicate and the values represent the average. Inset shows a close-up of the active site and the docked moiety is indicated in stick representation. l-phosphotyrosine is occluded from the active site due to steric hindrance while l-phosphoserine fits well in the active site.</p