FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation.

A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2).

A Novel Confocal Scanning Protein-Protein Interaction Assay (PPI-CONA) Reveals Exceptional Selectivity and Specificity of CC0651, a Small Molecule Binding Enhancer of the Weak Interaction between the E2 Ubiquitin-Conjugating Enzyme CDC34A and Ubiquitin.

Protein-protein interactions (PPIs) are some of the most challenging target classes in drug discovery. Highly sensitive detection techniques are required for the identification of chemical modulators of PPIs. Here, we introduce PPI confocal nanoscanning (PPI-CONA), a miniaturized, microbead based high-resolution fluorescence imaging assay.

Protecting Great Barrier Reef resilience through effective management of crown-of-thorns starfish outbreaks.

Resilience-based management is essential to protect ecosystems in the Anthropocene. Unlike large-scale climate threats to Great Barrier Reef (GBR) corals, outbreaks of coral-eating crown-of-thorns starfish (COTS; Acanthaster cf. solaris) can be directly managed through targeted culling.

Validation of the prevalence to incidence conversion method for healthcare associated infections in long-term care facilities.

Introduction: Residents of long-term care facilities (LTCFs) are a population at high risk of developing severe healthcare associated infections (HAIs). In the assessment of HAIs in acute-care hospitals, selection bias can occur due to cases being over-represented: patients developing HAIs usually have longer lengths of stays compared to controls, and therefore have an increased probability of being sampled in PPS, leading to an overestimation of HAI prevalence. Our hypothesis was that in LTCFs, the opposite may occur: residents developing HAIs either may have a greater chance of being transferred to acute-care facilities or of dying, and therefore could be under-represented in PPS, leading to an underestimation of HAI prevalence.

Physical, biological and anthropogenic drivers of spatial patterns of coral reef fish assemblages at regional and local scales.

Species abundance, diversity and community assemblage structure are determined by multiple physical, habitat and management drivers that operate across multiple spatial scales. Here we used a multi-scale coral reef monitoring dataset to examine regional and local differences in the abundance, species richness and composition of fish assemblages in no-take marine reserve (NTMR) and fished zones at four island groups in the Great Barrier Reef Marine Park, Australia. We applied boosted regression trees to quantify the influence of 20 potential drivers on the coral reef fish assemblages.

Interactive Effect of Cultivars, Crop Years and Rootstocks on the Biochemical Traits of (L.) Batsch Fruits.

Peach fruit is one of the most economically widespread temperate fruits, whose productivity, and nutritional and sensory qualities are determined by interactions among several environmental and genetic factors, rootstocks, agronomic practices and pedo-climatic conditions. In recent years, climate change has prompted peach breeding programs to use specific rootstocks that are well adapted to unusual soil and climate characteristics, thus improving the plant's adaptability and fruit quality. The aim of this work was to assess the biochemical and nutraceutical profile of two different peach cultivars, considering their growth on different rootstocks over three crop years.

Viral Hepatitis and Human Papillomavirus Vaccination During HIV Pre-Exposure Prophylaxis: Factors Associated With Missed Vaccination.

Background: We evaluated factors associated with lack of triple vaccination (hepatitis A virus [HAV], hepatitis B virus [HBV], and human papillomavirus [HPV]) among men who have sex with men using pre-exposure prophylaxis (PrEP).

Setting: PrEP users at the San Raffaele Scientific Institute, Italy, with ≥1 follow-up visit (May 2017-2022).

Methods: Participants were considered protected if (1) before PrEP access: positive serology (IgG-HAV+, hepatitis B surface antigen >10 mUI/mL) or vaccination history was recorded and (2) after starting PrEP: ≥1 dose of each vaccination was administered.

Should we expect weight changes in people with HIV and a reported weight gain only by switching antiretroviral therapy?

Weight gain following the initiation or the switch of antiretroviral therapy (ART) is well documented and mainly associated with some of the most recent drugs, such as integrase strand transfer inhibitors and tenofovir alafenamide. However, limited data have been published on weight trends in ART-experienced people living with HIV (PLWH) with a long exposure to HIV infection and antiretroviral drugs. In our study, we assessed changes in weight after switching ART among PLWH who reported weight gain under a previous regimen.

Characteristics of HIV pre-exposure prophylaxis users at first PrEP counselling visit: the CSL-PrEP cohort.

Objectives: Pre-exposure prophylaxis (PrEP) is effective for HIV prevention and is mostly used by men who have sex with men (MSM). The aim of this study was to describe the characteristics of a cohort of PrEP users at first PrEP counselling visits (baseline, BL).

Design: Cross-sectional study of a cohort of MSM receiving PrEP (Centro San Luigi, CSL-PrEP Cohort).

Discovery and Structural Characterization of Small Molecule Binders of the Human CTLH E3 Ligase Subunit GID4.

Targeted protein degradation (TPD) strategies exploit bivalent small molecules to bridge substrate proteins to an E3 ubiquitin ligase to induce substrate degradation. Few E3s have been explored as degradation effectors due to a dearth of E3-binding small molecules. We show that genetically induced recruitment to the GID4 subunit of the CTLH E3 complex induces protein degradation.

Succession in the caecal microbiota of developing broilers colonised by extended-spectrum β-lactamase-producing Escherichia coli.

Background: Broilers are among the most common and dense poultry production systems, where antimicrobials have been used extensively to promote animal health and performance. The continuous usage of antimicrobials has contributed to the appearance of resistant bacteria, such as extended-spectrum β-lactamase-producing Escherichia coli (ESBL-Ec). Here, we studied the ESBL-Ec prevalence and successional dynamics of the caecal microbiota of developing broilers in a commercial flock during their production life cycle (0-35 days).

Theistic evolution and evolutionary ethics: Henry Fairfield Osborn and Huxley's legacy.

Scholars have often considered evolutionary social theories a product of Positivist scientism and the naturalization of ethics. Yet the theistic foundations of many evolutionary theories proposed between the nineteenth and the twentieth centuries bolstered the belief that following natural laws was morally desirable, if not vital, to guaranteeing social and moral progress. In the early twentieth century, American paleontologist and leading evolutionist Henry Fairfield Osborn represented one of the most authoritative advocates of this interpretation of natural normativity.

Identification and optimization of molecular glue compounds that inhibit a noncovalent E2 enzyme-ubiquitin complex.

Pharmacological control of the ubiquitin-proteasome system (UPS) is of intense interest in drug discovery. Here, we report the development of chemical inhibitors of the ubiquitin-conjugating (E2) enzyme CDC34A (also known as UBE2R1), which donates activated ubiquitin to the cullin-RING ligase (CRL) family of ubiquitin ligase (E3) enzymes. A FRET-based interaction assay was used to screen for novel compounds that stabilize the noncovalent complex between CDC34A and ubiquitin, and thereby inhibit the CDC34A catalytic cycle.

Bipartite binding of the N terminus of Skp2 to cyclin A.

Skp2 and cyclin A are cell-cycle regulators that control the activity of CDK2. Cyclin A acts as an activator and substrate recruitment factor of CDK2, while Skp2 mediates the ubiquitination and subsequent destruction of the CDK inhibitor protein p27. The N terminus of Skp2 can interact directly with cyclin A but is not required for p27 ubiquitination.

Competitive Exclusion Prevents Colonization and Compartmentalization Reduces Transmission of ESBL-Producing in Broilers.

Extended spectrum beta-lactamase (ESBL)-producing bacteria are resistant to extended-spectrum cephalosporins and are common in broilers. Interventions are needed to reduce the prevalence of ESBL-producing bacteria in the broiler production pyramid. This study investigated two different interventions.

A substrate binding model for the KEOPS tRNA modifying complex.

The KEOPS complex, which is conserved across archaea and eukaryotes, is composed of four core subunits; Pcc1, Kae1, Bud32 and Cgi121. KEOPS is crucial for the fitness of all organisms examined. In humans, pathogenic mutations in KEOPS genes lead to Galloway-Mowat syndrome, an autosomal-recessive disease causing childhood lethality.

Biophysical and anthropogenic influences on the status of Tonga's coral reefs and reef fish fishery.

Despite increasing threats to Tonga's coral reefs from stressors that are both local (e.g. overfishing and pollution) and global (e.

Substrate stabilisation and small structures in coral restoration: State of knowledge, and considerations for management and implementation.

Coral reef ecosystems are under increasing pressure from local and regional stressors and a changing climate. Current management focuses on reducing stressors to allow for natural recovery, but in many areas where coral reefs are damaged, natural recovery can be restricted, delayed or interrupted because of unstable, unconsolidated coral fragments, or rubble. Rubble fields are a natural component of coral reefs, but repeated or high-magnitude disturbances can prevent natural cementation and consolidation processes, so that coral recruits fail to survive.

Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients.

While the antibody response to SARS-CoV-2 has been extensively studied in blood, relatively little is known about the antibody response in saliva and its relationship to systemic antibody levels. Here, we profiled by enzyme-linked immunosorbent assays (ELISAs) IgG, IgA and IgM responses to the SARS-CoV-2 spike protein (full length trimer) and its receptor-binding domain (RBD) in serum and saliva of acute and convalescent patients with laboratory-diagnosed COVID-19 ranging from 3-115 days post-symptom onset (PSO), compared to negative controls. Anti-SARS-CoV-2 antibody responses were readily detected in serum and saliva, with peak IgG levels attained by 16-30 days PSO.

Functional characterization of a PROTAC directed against BRAF mutant V600E.

The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated.