Bachmannputnam8184

Post-surgical cardiac adhesions represent a significant problem during routine cardiothoracic procedures. This fibrous tissue can impair heart function and inhibit surgical access in reoperation procedures. Here, we propose a hydrogel barrier composed of oxime crosslinked poly(ethylene glycol) (PEG) with the inclusion of a catechol (Cat) group to improve retention on the heart for pericardial adhesion prevention. This three component system is comprised of aldehyde (Ald), aminooxy (AO), and Cat functionalized PEG mixed to form the final gel (Ald-AO-Cat). Ald-AO-Cat has favorable mechanical properties, degradation kinetics, and minimal swelling, as well as superior tissue retention compared to an initial Ald-AO gel formulation. We show that the material is cytocompatible, resists cell adhesion, and led to a reduction in the severity of adhesions in an in vivo rat model. We further show feasibility in a pilot porcine study. The Ald-AO-Cat hydrogel barrier may therefore serve as a promising solution for preventing post-surgical cardiac adhesions.A regioselective carbosilylation of alkenes has emerged as a powerful strategy to access molecules with functionalized silylated alkanes, by incorporating silyl and carbon groups across an alkene double bond. However, to the best of our knowledge, organic fluorides have never been used in this protocol. Here we disclose the catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides mediated by tBuOK. The main feature of this transformation is the selective activation of the C-F bond of an organic fluoride by the silyl boronate without undergoing potential side-reactions involving C-O, C-Cl, heteroaryl-CH, and even CF3 groups. Various silylated alkanes with tertiary or quaternary carbon centers that have aromatic, hetero-aromatic, and/or aliphatic groups at the β-position are synthesized in a single step from substituted or non-substituted aryl alkenes. An intramolecular variant of this carbosilylation is also achieved via the reaction of a fluoroarene with a ω-alkenyl side chain and a silyl boronate.In addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection.Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10-24, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10-8, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10-16, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10-8, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10-9, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors.α-Synuclein aggregation is a key driver of neurodegeneration in Parkinson's disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein toxic assemblies with high affinity is a long-pursued objective. Here, we exploit the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of α-helical peptides that bind to these α-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into a high anti-aggregation potency and the ability to abrogate oligomer-induced cell damage. Using a structure-guided search we identify a human peptide expressed in the brain and the gastrointestinal tract with analogous binding, anti-aggregation, and detoxifying properties. The chemical entities we describe here may represent a therapeutic avenue for the synucleinopathies and are promising tools to assist diagnosis by discriminating between native and toxic α-synuclein species.Risk factors for increased risk of death from COVID-19 have been identified, but less is known on characteristics that make communities resilient or vulnerable to the mortality impacts of the pandemic. We applied a two-stage Bayesian spatial model to quantify inequalities in excess mortality in people aged 40 years and older at the community level during the first wave of the pandemic in England, March-May 2020 compared with 2015-2019. Here we show that communities with an increased risk of excess mortality had a high density of care homes, and/or high proportion of residents on income support, living in overcrowded homes and/or with a non-white ethnicity. We found no association between population density or air pollution and excess mortality. Effective and timely public health and healthcare measures that target the communities at greatest risk are urgently needed to avoid further widening of inequalities in mortality patterns as the pandemic progresses.Children's behavioral problems have been associated with their family environments. Here, we investigate whether specific features of brain structures could relate to this link. Using structural magnetic resonance imaging of 8756 children aged 9-11 from the Adolescent Brain Cognitive Developmental study, we show that high family conflict and low parental monitoring scores are associated with children's behavioral problems, as well as with smaller cortical areas of the orbitofrontal cortex, anterior cingulate cortex, and middle temporal gyrus. A longitudinal analysis indicates that psychiatric problems scores are associated with increased family conflict and decreased parental monitoring 1 year later, and mediate associations between the reduced cortical areas and family conflict, and parental monitoring scores. These results emphasize the relationships between the brain structure of children, their family environments, and their behavioral problems.Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs-/- mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs-/- mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.Primary small cell carcinoma of the esophagus (PSCCE) is a lethal neuroendocrine carcinoma. Previous studies proposed a genetic similarity between PSCCE and esophageal squamous cell carcinoma (ESCC) but provided little evidence for differences in clinical course and neuroendocrine differentiation. We perform whole-exome sequencing, RNA sequencing and immunohistochemistry profiling on 46 PSCCE cases. Integrated analyses enable the discovery of multiple mechanisms of RB1 disruption in 98% (45/46) of cases. The transcriptomic landscape of PSCCE closely resembles small cell lung cancer (SCLC) but differs from ESCC or esophageal adenocarcinoma (EAC). Distinct gene expression patterns regulated by ASCL1 and NEUROD1 define two molecular subtypes, PSCCE-A and PSCCE-N, which are highly similar to SCLC subtypes. A T cell excluded phenotype is widely observed in PSCCE. In conclusion, PSCCE has genomic alterations, transcriptome features and molecular subtyping highly similar to SCLC but distinct from ESCC or EAC. These observations are relevant to oncogenesis mechanisms and therapeutic vulnerability.Contemporary asymmetric catalysis faces huge challenges when prochiral substrates bear electronically and sterically unbiased substituents and when substrates show low reactivities. One of the inherent limitations of chiral catalysts and ligands is their incapability in recognizing prochiral substrates bearing similar groups. This has rendered many enantiopure substances bearing several similar substituents inaccessible. Here we report the rationale, scope, and applications of the strategy of kinetic resolution of auxiliary adjacent alcohols (KRA*) that can be used to solve the above troubles. Using this method, a large variety of optically enriched tertiary alcohols, epoxides, esters, ketones, hydroxy ketones, epoxy ketones, β-ketoesters, and tetrasubstituted methane analogs with two, three, and four spatially and electronically similar groups can be readily obtained (totally 96 examples). At the current stage, the strategy serves as the optimal solution that can complement the inability caused by direct asymmetric catalysis in getting chiral molecules with challenging fully substituted stereocenters.De novo lipogenesis (DNL) is disrupted in a wide range of human disease. Thus, quantification of DNL may provide insight into mechanisms and guide interventions if it can be performed rapidly and noninvasively. DNL flux is commonly measured by 2H incorporation into fatty acids following deuterated water (2H2O) administration. However, the sensitivity of this approach is limited by the natural abundance of 13C, which masks detection of 2H by mass spectrometry. Here we report that high-resolution Orbitrap gas-chromatography mass-spectrometry resolves 2H and 13C fatty acid mass isotopomers, allowing DNL to be quantified using lower 2H2O doses and shorter experimental periods than previously possible. Serial measurements over 24-hrs in mice detects the nocturnal activation of DNL and matches a 3H-water method in mice with genetic activation of DNL. Most importantly, DNL is detected in overnight-fasted humans in less than an hour and is responsive to feeding during a 4-h study. Thus, 2H specific MS provides the ability to study DNL in settings that are currently impractical.