The results of an amplitude analysis of the charmless three-body decay B+→π+π+π−, in which CP-violation effects are taken into account, are reported. The analysis is based on a data sample ...corresponding to an integrated luminosity of 3 fb−1 of pp collisions recorded with the LHCb detector. The most challenging aspect of the analysis is the description of the behavior of the π+π− S-wave contribution, which is achieved by using three complementary approaches based on the isobar model, the K-matrix formalism, and a quasi-model-independent procedure. Additional resonant contributions for all three methods are described using a common isobar model, and include the ρ(770)0, ω(782) and ρ(1450)0 resonances in the π+π− P-wave, the f2(1270) resonance in the π+π− D-wave, and the ρ3(1690)0 resonance in the π+π− F-wave. Significant CP-violation effects are observed in both S- and D-waves, as well as in the interference between the S- and P-waves. The results from all three approaches agree and provide new insight into the dynamics and the origin of CP-violation effects in B+→π+π+π− decays.
Omicron and its subvariants have rendered most authorized monoclonal antibody-based treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ineffective, highlighting the need for ...biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective antibodies target variable epitopes. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to known non-neutralizing antibodies that target highly conserved epitopes in the viral spike protein. These inhibitors, called receptor-blocking conserved non-neutralizing antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron. Neutralization potency is lost when the linker joining the binding and inhibitory ReconnAb components is severed. In addition, a bi-functional ReconnAb, made by linking ACE2 to a bi-specific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron and BA.2. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad-spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases.
Previous research has shown beneficial cognitive changes following exercise training in older adults. However, the work on the potential moderating effects of Apoliprotein E (APOE) ε4 carrier status ...has been mixed, and the role of exercise intensity remains largely unexplored. The present study sought to examine the influence of APOE ε4 status and exercise intensity on measures of cognitive performance in a group of older adults. Cross-sectional comparisons between a group of younger inactive adults (n = 44, age = 28.86 ± 0.473 SD, 60.5% female) and a group of older inactive adults (n = 142, age = 67.8 ± 5.4, 62.7% female) were made on baseline measurements of APOE ε4 status, VO2peak, and cognitive performance in the domain of executive functioning. The older adults also participated in a randomized controlled exercise trial, exercising three times per week for 16-weeks in either a low-intensity continuous training (LICT) group or a moderate-intensity continuous training plus interval training (MICT+IT) group at the Center for Health and Neuroscience, Genes, and Environment (CUChange) Exercise Laboratory. Follow-up measurements of VO2peak and cognitive performance were collected on the older adults after the exercise intervention. Cross-sectional comparisons between the older and younger adults demonstrated significant impairments among older adults in Stroop effect on error and time, Category Switch mixing effects, and Keep Track task. This impairment was not moderated by APOE ε4 carrier status. Improvements from pre- to post-exercise intervention were observed in both exercise groups in Stroop effect on error (F (1, 256) = 9.381, p < 0.01, η2 = 0.031) and Category Switch switching effect reaction time (F(1, 274) = 4.442, p < 0.05, η2 = 0.020), with no difference between exercise groups. The moderating effects of APOE ε4 carrier status were mixed. Exercise did not improve the Stroop effect on error among ε4 carriers assigned to MICT+IT when improvements were seen in all other groups. Further research is needed to examine the mechanisms of action by which exercise impacts cognitive task performance, and possible moderators such as genetic variability and exercise intensity.
•Therapeutic or protective effects against cognitive changes are often associated with increased physical activity.•The possible role of APOE ε4 carrier status with physical activity and cognitive changes is mixed.•This study used controlled aerobic exercise conditions to investigate these relationships.•Results were mixed, particularly among APOE ε4 carriers, with some differences between exercise conditions.
Effective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems ...biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from ∼500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans.
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•Understanding inter-individual variation of immune cells and immunoglobulin levels•Season and gender influence B cell subpopulation abundance•Identification of genetic loci that might regulate B cell levels in blood•Cell count QTLs overlap with risk SNPs for (auto)immune/inflammatory disease
As part of the Human Functional Genomics Project, this study by Aguirre-Gamboa et al. maps the contribution of genetics and non-heritable factors onto immune-cell counts and immunoglobulin levels. They find that season and gender influence the abundance of most of B cell subpopulations.
Background. Because adolescents and adults act as a primary source of pertussis infection for infants, vaccination of mothers immediately postpartum is a potential strategy to reduce transmission ...(cocoon strategy). For this to be effective, high levels of antibodies must be achieved rapidly after vaccination. We sought to determine whether the antibody response to tetanus-diphtheria-acellular pertussis vaccine (Tdap) is sufficiently rapid to support the cocoon strategy. Methods. Two sequential studies were performed. The first was a nonrandomized, open study of a 5-pertussis-component Tdap vaccine (tetanus toxoid, diphtheria toxoid, pertussis toxoid PT, filamentous hemagglutinin FHA, fimbriae types 2 and 3 FIM, and pertactin PRN) given to women of childbearing age; the second was a randomized, open study of Tdap or no vaccine in postpartum women. Serum levels of immunoglobin (Ig) G and IgA against pertussis antigens, serum levels of IgG against diphtheria and tetanus, and breast milk levels of IgA against pertussis antigens were measured at various times after vaccination. Results. In both studies, the antibody response was relatively rapid, with serum IgG and IgA levels beginning to increase noticeably by days 5—7 and approaching peak levels by day 14. Greater than 68% and 84.4% of IgG and IgA responders, respectively, achieved ≥90% of their maximum titer by day 14. The diphtheria and tetanus antibody kinetics followed a similar time course. Breast milk levels of IgA against PT, FHA, and FIM were first detectable at day 7, peaked by day 10, and then slowly decreased through day 28. Antibodies against PRN showed a similar response, although the peak occurred at day 14. There were no significant antibody responses in the control group. Conclusions. Although the antibody response to a dose of Tdap in healthy nonpregnant women of childbearing age and postpartum women occurs by day 14 and is suggestive of an anamnestic immune response, it may not be sufficiently rapid to protect infants in the first weeks of life.
Expression quantitative trait loci (eQTL) studies are used to interpret the function of disease-associated genetic risk factors. To date, most eQTL analyses have been conducted in bulk tissues, such ...as whole blood and tissue biopsies, which are likely to mask the cell type-context of the eQTL regulatory effects. Although this context can be investigated by generating transcriptional profiles from purified cell subpopulations, current methods to do this are labor-intensive and expensive. We introduce a new method, Decon2, as a framework for estimating cell proportions using expression profiles from bulk blood samples (Decon-cell) followed by deconvolution of cell type eQTLs (Decon-eQTL).
The estimated cell proportions from Decon-cell agree with experimental measurements across cohorts (R ≥ 0.77). Using Decon-cell, we could predict the proportions of 34 circulating cell types for 3194 samples from a population-based cohort. Next, we identified 16,362 whole-blood eQTLs and deconvoluted cell type interaction (CTi) eQTLs using the predicted cell proportions from Decon-cell. CTi eQTLs show excellent allelic directional concordance with eQTL (≥ 96-100%) and chromatin mark QTL (≥87-92%) studies that used either purified cell subpopulations or single-cell RNA-seq, outperforming the conventional interaction effect.
Decon2 provides a method to detect cell type interaction effects from bulk blood eQTLs that is useful for pinpointing the most relevant cell type for a given complex disease. Decon2 is available as an R package and Java application (https://github.com/molgenis/systemsgenetics/tree/master/Decon2) and as a web tool (www.molgenis.org/deconvolution).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
► Cocaine-cue extinction increased and decreased, respectively, total GluA1 in vmPFC and BLA. ► Cocaine-cue extinction increased GluA1-pSer845 in vmPFC and NAc. ► Lever responding positively ...correlated with total GluA1 in NAc. ► The BLA and vmPFC appear to be loci for cocaine-cue extinction learning. ► Understanding extinction mechanisms may improve exposure therapy in cocaine addicts.
Brain regional analyses of total GluA1 and GluA1-pSer845 were used to delineate plasticity of the AMPA receptor in conjunction with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a 2-s light cue and later underwent a single 2h extinction session for which cocaine was withheld but response-contingent cues were presented. Control groups received yoked-saline sessions or received cocaine self-administration training without undergoing extinction training. Extinction-related increases and decreases, respectively, in total GluA1 were observed in the ventromedial prefrontal cortex (vmPFC) and basolateral amygdala (BLA). Phosphorylation of GluA1 at Ser845 was increased in the vmPFC and nucleus accumbens (NAc). Though total GluA1 did not change in NAc, there was a positive association between the number of responses during extinction training and the magnitude of total GluA1 in NAc. No significant changes were evident in the dorsal hippocampus. We conclude that the BLA and vmPFC, in particular, appear to be loci for the inhibition of learned behavior induced via extinction training, but each site may have different signaling functions for cocaine-cue extinction learning.
Spirit's Mössbauer (MB) instrument determined the Fe mineralogy and oxidation state of 71 rocks and 43 soils during its exploration of the Gusev plains and the Columbia Hills (West Spur, Husband ...Hill, Haskin Ridge, northern Inner Basin, and Home Plate) on Mars. The plains are predominantly float rocks and soil derived from olivine basalts. Outcrops at West Spur and on Husband Hill have experienced pervasive aqueous alteration as indicated by the presence of goethite. Olivine‐rich outcrops in a possible mafic/ultramafic horizon are present on Haskin Ridge. Relatively unaltered basalt and olivine basalt float rocks occur at isolated locations throughout the Columbia Hills. Basalt and olivine basalt outcrops are found at and near Home Plate, a putative hydrovolcanic structure. At least three pyroxene compositions are indicated by MB data. MB spectra of outcrops Barnhill and Torquas resemble palagonitic material and thus possible supergene aqueous alteration. Deposits of Fe3+‐sulfate soil, located at Paso Robles, Arad, and Tyrone, are likely products of acid sulfate fumarolic and/or hydrothermal activity, possibly in connection with Home Plate volcanism. Hematite‐rich outcrops between Home Plate and Tyrone (e.g., Montalva) may also be products of this aqueous activity. Low water‐to‐rock ratios (isochemical alteration) are implied during palagonite, goethite, and hematite formation because bulk chemical compositions are basaltic (SO3‐free basis). High water‐to‐rock ratios (leaching) under acid sulfate conditions are implied for the high‐SiO2 rock and soil in Eastern Valley and the float rock FuzzySmith, which has possible pyrite/marcasite as a hydrothermal alteration product.
The present study assesses training characteristics, scholastic achievements, and traditional career accomplishments of ethnically underrepresented in medicine (UIM) plastic and reconstructive ...surgery (PRS) faculty relative to non-UIM PRS faculty.
A cross-sectional analysis of core PRS faculty appointed to accredited United States residency training programs (n = 99) was performed.
Of the 949 US PRS faculty, a total of 51 (5.4%) were identified as UIM. Compared with non-UIM faculty, there were few differences when evaluating medical education, residency training, pursuit of advanced degrees, and attainment of subspecialty fellowship training. UIM faculty were more likely than non-UIM faculty to have graduated from a medical school outside the United States (25% versus 13%,
= 0.014). In addition, UIM faculty did not differ from non-UIM counterparts in traditional career accomplishments, including promotion to full professor, obtaining NIH funding, serving as program director, receiving an endowed professorship, appointment to a peer-reviewed editorial board, scholarly contributions (H-index and number of publications), and appointment to chief/chair of their division/department.
The historical lack of ethnic diversity that comprise US academic PRS faculty persists. This study reveals that those UIM faculty who are able to obtain faculty appointments are equally successful in achieving scholastic success and traditional career accomplishments as their non-UIM counterparts. As we strive toward increasing representation of UIM physicians in academic plastic surgery, the field will benefit from efforts that promote a pipeline for underrepresented groups who traditionally face barriers to entry.
Branching fraction and effective lifetime measurements of the rare decay B_{s}^{0}→μ^{+}μ^{-} and searches for the decays B^{0}→μ^{+}μ^{-} and B_{s}^{0}→μ^{+}μ^{-}γ are reported using proton-proton ...collision data collected with the LHCb detector at center-of-mass energies of 7, 8, and 13 TeV, corresponding to a luminosity of 9 fb^{-1}. The branching fraction B(B_{s}^{0}→μ^{+}μ^{-})=(3.09_{-0.43-0.11}^{+0.46+0.15})×10^{-9} and the effective lifetime τ(B_{s}^{0}→μ^{+}μ^{-})=2.07±0.29±0.03 ps are measured, where the first uncertainty is statistical and the second systematic. No significant signal for B^{0}→μ^{+}μ^{-} and B_{s}^{0}→μ^{+}μ^{-}γ decays is found and upper limits B(B^{0}→μ^{+}μ^{-})<2.6×10^{-10} and B(B_{s}^{0}→μ^{+}μ^{-}γ)<2.0×10^{-9} at the 95% C.L. are determined, where the latter is limited to the range m_{μμ}>4.9 GeV/c^{2}. The results are in agreement with the standard model expectations.
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