Short bZIP homologue of sulfur regulator Met4 from Ogataea parapolymorpha does not depend on DNA-binding cofactors for activating genes in sulfur starvation

The acquisition of sulfur from environment and its assimilation is essential for fungal growth and activities. Here, we describe novel features of the regulatory network of sulfur metabolism in Ogataea parapolymorpha, a thermotolerant methylotrophic yeast with high resistance to harsh environmental conditions. A short bZIP protein (OpMet4p) of O. parapolymorpha, displaying the combined structural characteristics of yeast and filamentous fungal Met4 homologues, plays a key role as a master regulator of cell homeostasis during sulfur limitation, but also its function is required for the tolerance of various stresses. Domain swapping analysis, combined with deletion analysis of the regulatory domains and genes encoding OpCbf1p, OpMet28p, and OpMet32p, indicated that OpMet4p does not require the interaction with these DNA-binding cofactors to induce the expression of sulfur genes, unlike the Saccharomyces cerevisiae Met4p. ChIP analysis confirmed the notion that OpMet4p, which contains a canonical bZIP domain, can bind the target DNA in the absence of cofactors, similar to homologues in other filamentous fungi. Collectively, the identified unique features of the O. parapolymorpha regulatory network, as the first report on the sulfur regulation by a short yeast Met4 homologue, provide insights into conservation and divergence of the sulfur regulatory networks among diverse ascomycetous fungi.     

Integrating comprehensive functional annotations to boost power and accuracy in gene-based association analysis

Gene-based association tests aggregate genotypes across multiple variants for each gene, providing an interpretable gene-level analysis framework for genome-wide association studies (GWAS). Early gene-based test applications often focused on rare coding variants; a more recent wave of gene-based methods, e.g. TWAS, use eQTLs to interrogate regulatory associations. Regulatory variants are expected to be particularly valuable for gene-based analysis, since most GWAS associations to date are non-coding. However, identifying causal genes from regulatory associations remains challenging and contentious. Here, we present a statistical framework and computational tool to integrate heterogeneous annotations with GWAS summary statistics for gene-based analysis, applied with comprehensive coding and tissue-specific regulatory annotations. We compare power and accuracy identifying causal genes across single-annotation, omnibus, and annotation-agnostic gene-based tests in simulation studies and an analysis of 128 traits from the UK Biobank, and find that incorporating heterogeneous annotations in gene-based association analysis increases power and performance identifying causal genes.     

Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

Alzheimer's disease (AD) is an age‐related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD‐504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLP^APT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient‐derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau‐interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLP^APT mice.     

Review: Helicobacter pylori infection in children

Helicobacter pylori infection in children and adolescents differs in comparison to adults with respect to epidemiology, host responses, and disease manifestations. Furthermore, treatment options are limited in this population and antibiotic resistance rates continue to increase. Therefore, ongoing research is vital to understand disease pathogenesis and provide optimal management of children with infection. This review summarizes relevant publications from April 2019 to March 2020. Similar to adults, recent studies show a decreasing prevalence of infection in the pediatric population. Studies of pathogenesis investigated serum immune responses and the potential inverse association of infection and allergy. Several studies investigated the effect of H pylori and related inflammation on the gut microbiome. The recommendation of endoscopy‐based testing to identify the cause of symptoms and not just H pylori, reserving noninvasive UBT or stool antigen tests for post‐eradication follow‐up, was supported by the current literature.     

Structural and sequence comparisons of bacterial enoyl-CoA isomerase and enoyl-CoA hydratase

Crystal structures of enoyl-coenzyme A (CoA) isomerase from Bosea sp. PAMC 26642 (BoECI) and enoyl-CoA hydratase from Hymenobacter sp. PAMC 26628 (HyECH) were determined at 2.35 and 2.70 Å resolution, respectively. BoECI and HyECH are members of the crotonase superfamily and are enzymes known to be involved in fatty acid degradation. Structurally, these enzymes are highly similar except for the orientation of their C-terminal helix domain. Analytical ultracentrifugation was performed to determine the oligomerization states of BoECI and HyECH revealing they exist as trimers in solution. However, their putative ligand-binding sites and active site residue compositions are dissimilar. Comparative sequence and structural analysis revealed that the active site of BoECI had one glutamate residue (Glu135), this site is occupied by an aspartate in some ECIs, and the active sites of HyECH had two highly conserved glutamate residues (Glu118 and Glu138). Moreover, HyECH possesses a salt bridge interaction between Glu98 and Arg152 near the active site. This interaction may allow the catalytic Glu118 residue to have a specific conformation for the ECH enzyme reaction. This salt bridge interaction is highly conserved in known bacterial ECH structures and ECI enzymes do not have this type of interaction. Collectively, our comparative sequential and structural studies have provided useful information to distinguish and classify two similar bacterial crotonase superfamily enzymes.     

Sequence analysis of the first B5 subgenogroup strain of enterovirus 71 isolated in Korea

Journal of Microbiology - Enterovirus A71 (EV71), the main etiological agent of handfoot- mouth disease (HFMD), circulates in many areas of the world and has caused large epidemics since 1997,...     

Peroxiredoxin 2 deficiency reduces white adipogenesis due to the excessive ROS generation

Reactive oxygen species (ROS) act as signaling molecules to regulate various cell functions. Numerous studies have demonstrated ROS to be essential for the differentiation of adipocytes. Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant enzymes in mammalian cells. Prx2 is present in the cytoplasm and cell membranes and demonstrates ROS scavenging activity. We focused on Prx2 involvement in regulating adipogenesis and lipid accumulation and demonstrated that Prx2 expression was upregulated during adipocyte differentiation. In addition, the silencing of Prx2 (shPrx2) inhibited adipogenesis by modulating adipogenic gene expression, and cell death was enhanced via increased ROS production in shPrx2‐3T3‐L1 cells. These results demonstrate that shPrx2 triggers adipocyte cell death and weakens adipocyte function via ROS production. Taken together, our data suggest the participation of Prx2 in adipocyte function and differentiation. Our results also imply that the downregulation of Prx2 activity could help prevent obesity. Overall, findings support the development of ROS‐based therapeutic solutions for the treatment of obesity and obesity‐related metabolic disorders.     

Heterogeneity–diversity relationships in sessile organisms: a unified framework

The hypothesis that environmental heterogeneity promotes species richness by increasing opportunities for niche partitioning is a fundamental paradigm in ecology. However, recent studies suggest that heterogeneity–diversity relationships (HDR) are more complex than expected from this niche‐based perspective, and often show a decrease in richness at high levels of heterogeneity. These findings have motivated ecologists to propose new mechanisms that may explain such deviations. Here we provide an overview of currently recognised mechanisms affecting the shape of HDRs and present a conceptual model that integrates all previously proposed mechanisms within a unified framework. We also translate the proposed framework into an explicit community dynamic model and use the model as a tool for generating testable predictions concerning how landscape properties interact with species traits in determining the shape of HDRs. Our main finding is that, despite the enormous complexity of such interactions, the predicted HDRs are rather simple, ranging from positive to unimodal patterns in a highly consistent and predictable manner.