Direct O mediated oxidation of a Ni(II)NO structural model complex for the active site of nickel acireductone dioxygenase (Ni-ARD): characterization, biomimetic reactivity, and enzymatic implications.

A new biomimetic model complex of the active site of acireductone dioxygenase (ARD) was synthesized and crystallographically characterized (ii1). 1 displays carbon-carbon oxidative cleavage activity in the presence of O towards the substrate 2-hydroxyacetophenone. This reactivity was monitored UV-Visible and NMR spectroscopy.

Affinity gaps among B cells in germinal centers drive the selection of MPER precursors.

Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs.

Vaccination induces broadly neutralizing antibody precursors to HIV gp41.

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display.

mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models.

Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition.

mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies.

Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody-induced epitope masking, driving further B cell receptor (BCR) modification in GC-experienced B cells after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors to the V3-glycan-targeted bnAb BG18 and that B cells primed by N332-GT5 were effectively boosted by either of two novel protein immunogens designed to have minimum cross-reactivity with the off-target V1-binding responses.

Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses.

Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model.

Blood-based assessment of oxidative stress, inflammation, endocrine and metabolic adaptations in eventing horses accounting for plasma volume shift after exercise.

Background: After submaximal exercise, blood values of eventing horses show physiological reactions.

Objectives: This prospective longitudinal study investigated blood parameters in 20 elite eventing horses before and after two-four-star cross-country rides.

Methods: Using a mixed model adjusting for plasma volume shift, we assessed exercise-dependent parameters and compared blood values with reference ranges for healthy horses at rest.

Antibody production relies on the tRNA inosine wobble modification to meet biased codon demand.

Antibodies are produced at high rates to provide immunoprotection, which puts pressure on the B cell translational machinery. Here, we identified a pattern of codon usage conserved across antibody genes. One feature thereof is the hyperutilization of codons that lack genome-encoded Watson-Crick transfer RNAs (tRNAs), instead relying on the posttranscriptional tRNA modification inosine (I34), which expands the decoding capacity of specific tRNAs through wobbling.

Percutaneous Left Atrial Appendage Occlusion-Current Evidence and Future Directions.

Over the past two decades, percutaneous left atrial appendage occlusion (LAAO) has proven to be a viable alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF), in particular in those patients who are at increased risk for stroke and bleeding complications. This systematic review provides a comprehensive evaluation of anatomical features, patient selection, procedural planning and execution, complications, medical treatment following the procedure, and contemporary outcome data.

A Delphi Study to Determine International and National Equestrian Expert Opinions on Domains and Sub-Domains Essential to Managing Sporthorse Health and Welfare in the Olympic Disciplines.

The public is increasingly questioning equestrianism's social license to operate. While the focus historically centered on horseracing, increased scrutiny is now being placed on how dressage, showjumping, and eventing are addressing equine management and welfare concerns. Nominated equestrian federation and equestrian organization experts ( = 104) directly involved in international and/or national-level horse sports took part in a four-stage, iterative Delphi to obtain consensus on what factors should be considered essential to manage sporthorse health and welfare.

Blood-Based Markers for Skeletal and Cardiac Muscle Function in Eventing Horses before and after Cross-Country Rides and How They Are Influenced by Plasma Volume Shift.

Horses competing in cross-country tests are subjected to high physical demands. Within the scope of this prospective longitudinal study, blood values of 20 elite eventing horses were examined before and after two- to four-star cross-country rides. The aim was to find out whether blood-based markers for skeletal muscle and cardiac muscle function change after cross-country exercise.

Specific inhibition of an anticancer target, polo-like kinase 1, by allosterically dismantling its mechanism of substrate recognition.

Polo-like kinase 1 (Plk1) is considered an attractive target for anticancer therapy. Over the years, studies on the noncatalytic polo-box domain (PBD) of Plk1 have raised the expectation of generating highly specific protein-protein interaction inhibitors. However, the molecular nature of the canonical PBD-dependent interaction, which requires extensive water network-mediated interactions with its phospholigands, has hampered efforts to identify small molecules suitable for Plk1 PBD drug discovery.

Architectural basis for cylindrical self-assembly governing Plk4-mediated centriole duplication in human cells.

Proper organization of intracellular assemblies is fundamental for efficient promotion of biochemical processes and optimal assembly functionality. Although advances in imaging technologies have shed light on how the centrosome is organized, how its constituent proteins are coherently architected to elicit downstream events remains poorly understood. Using multidisciplinary approaches, we showed that two long coiled-coil proteins, Cep63 and Cep152, form a heterotetrameric building block that undergoes a stepwise formation into higher molecular weight complexes, ultimately generating a cylindrical architecture around a centriole.

The Lysyl Oxidase G473A Polymorphism Exacerbates Oral Cancer Development in Humans and Mice.

Oral cancer is primarily squamous-cell carcinoma with a 5-year survival rate of approximately 50%. Lysyl oxidase (LOX) participates in collagen and elastin maturation. The propeptide of LOX is released as an 18 kDa protein (LOX-PP) in the extracellular environment by procollagen C-proteinases and has tumor-inhibitory properties.

Multilineage Differentiation Potential of Equine Adipose-Derived Stromal/Stem Cells from Different Sources.

The investigation of multipotent stem/stromal cells (MSCs) in vitro represents an important basis for translational studies in large animal models. The study's aim was to examine and compare clinically relevant in vitro properties of equine MSCs, which were isolated from abdominal (abd), retrobulbar (rb) and subcutaneous (sc) adipose tissue by collagenase digestion (ASCs-) and an explant technique (ASCs-). Firstly, we examined proliferation and trilineage differentiation and, secondly, the cardiomyogenic differentiation potential using activin A, bone morphogenetic protein-4 and Dickkopf-1.

Study design and baseline to evaluate water service provision among peri-urban communities in Kasai Oriental, Democratic Republic of the Congo.

We present a study design and baseline results to establish the impact of interventions on peri-urban water access, security and quality in Kasai Oriental province of the Democratic Republic of the Congo. In standard development practice, program performance is tracked via monitoring and evaluation frameworks of varying sophistication and rigor. Monitoring and evaluation, while usually occurring nearly concurrently with program delivery, may or may not measure parameters that can identify performance with respect to the project's overall goals.

Structural Optimization and Anticancer Activity of Polo-like Kinase 1 (Plk1) Polo-Box Domain (PBD) Inhibitors and Their Prodrugs.

Polo-like kinase 1 (Plk1), a mitotic kinase whose activity is widely upregulated in various human cancers, is considered an attractive target for anticancer drug discovery. Aside from the kinase domain, the C-terminal noncatalytic polo-box domain (PBD), which mediates the interaction with the enzyme's binding targets or substrates, has emerged as an alternative target for developing a new class of inhibitors. Various reported small molecule PBD inhibitors exhibit poor cellular efficacy and/or selectivity.

Analytical Performance Evaluation of the New GEM Premier™ 5000 in Comparison to the Epoc Blood Gas Analyzer in Horses.

Different blood gas analyzers are used in equine practice. Every machine needs to be validated, as they have not been designed for use in horses. The aim of this study was to compare the newly marketed GEM5000 machine to the formerly validated epoc machine for blood gas analysis in horses.

Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice.

Eliciting broadly neutralizing antibodies (bnAbs) is the core of HIV vaccine design. bnAbs specific to the V2-apex region of the HIV envelope acquire breadth and potency with modest somatic hypermutation, making them attractive vaccination targets. To evaluate Apex germline-targeting (ApexGT) vaccine candidates, we engineered knockin (KI) mouse models expressing the germline B cell receptor (BCR) of the bnAb PCT64.

Antibodies from primary humoral responses modulate the recruitment of naive B cells during secondary responses.

Vaccines generate high-affinity antibodies by recruiting antigen-specific B cells to germinal centers (GCs), but the mechanisms governing the recruitment to GCs on secondary challenges remain unclear. Here, using preclinical SARS-CoV and HIV mouse models, we demonstrated that the antibodies elicited during primary humoral responses shaped the naive B cell recruitment to GCs during secondary exposures. The antibodies from primary responses could either enhance or, conversely, restrict the GC participation of naive B cells: broad-binding, low-affinity, and low-titer antibodies enhanced recruitment, whereas, by contrast, the high titers of high-affinity, mono-epitope-specific antibodies attenuated cognate naive B cell recruitment.

Surveys of community garden affiliates and soils in Houston, Texas.

Although urban community food gardens have the capacity to strengthen and support neighborhoods in need, the benefits of such operations must be considered in tandem with the potential risks associated with urban environmental contamination. Therefore, research is needed to characterize existing community gardens in urban areas. In the present study, a survey of Houston, TX, community gardeners (N = 20) was conducted to better understand their risk-based knowledge and perceptions, current gardening practices, and willingness to implement risk mitigation measures.