Miracle-dz/UniFAR-FTUs huggingface dataset:
Homeobox Transcription Factors Are Required for Fungal Development and the Suppression of Host Defense Mechanisms in the Colletotrichum scovillei-Pepper Pathosystem

The ascomycete phytopathogenic fungus, Colletotrichum scovillei, causes serious yield loss on peppers. However, little is known about molecular mechanisms involved in the development of anthracnose caused by this fungus. ABSTRACT Colletotrichum scovillei, an ascomycete phytopathogenic fungus, is the main causal agent of serious yield losses of economic crops worldwide. The fungus causes anthracnose disease on several fruits, including peppers. However, little is known regarding the underlying molecular mechanisms involved in the development of anthracnose caused by this fungus. In an initial step toward understanding the development of anthracnose on pepper fruits, we retrieved 624 transcription factors (TFs) from the whole genome of C. scovillei and comparatively analyzed the entire repertoire of TFs among phytopathogenic fungi. Evolution and proliferation of members of the homeobox-like superfamily, including homeobox (HOX) TFs that regulate the development of eukaryotic organisms, were demonstrated in the genus Colletotrichum. C. scovillei was found to contain 10 HOX TF genes (CsHOX1 to CsHOX10), which were functionally characterized using deletion mutants of each CsHOX gene. Notably, CsHOX1 was identified as a pathogenicity factor required for the suppression of host defense mechanisms, which represents a new role for HOX TFs in pathogenic fungi. CsHOX2 and CsHOX7 were found to play essential roles in conidiation and appressorium development, respectively, in a stage-specific manner in C. scovillei. Our study provides a molecular basis for understanding the mechanisms associated with the development of anthracnose on fruits caused by C. scovillei, which will aid in the development of novel approaches for disease management. IMPORTANCE The ascomycete phytopathogenic fungus, Colletotrichum scovillei, causes serious yield loss on peppers. However, little is known about molecular mechanisms involved in the development of anthracnose caused by this fungus. We analyzed whole-genome sequences of C. scovillei and isolated 624 putative TFs, revealing the existence of 10 homeobox (HOX) transcription factor (TF) genes. We found that CsHOX1 is a pathogenicity factor required for the suppression of host defense mechanism, which represents a new role for HOX TFs in pathogenic fungi. We also found that CsHOX2 and CsHOX7 play essential roles in conidiation and appressorium development, respectively, in a stage-specific manner in C. scovillei. Our study contributes to understanding the mechanisms associated with the development of anthracnose on fruits caused by C. scovillei, which will aid for initiating novel approaches for disease management.
Insights from Clonal Expansion and HIV Persistence in Perinatal Infections

The latent HIV reservoir forms early in the course of infection and is maintained for life despite effective antiretroviral treatment (ART), including early treatment. Perinatal HIV infection presents a unique opportunity to limit seeding of the reservoir through early ART. However, a greater understanding of the persistence of the integrated proviruses is needed for targeting the residual proviruses that form barriers to cure. A study was performed by Bale and Katusiime et al. (M. J. Bale, M. G. ABSTRACT The latent HIV reservoir forms early in the course of infection and is maintained for life despite effective antiretroviral treatment (ART), including early treatment. Perinatal HIV infection presents a unique opportunity to limit seeding of the reservoir through early ART. However, a greater understanding of the persistence of the integrated proviruses is needed for targeting the residual proviruses that form barriers to cure. A study was performed by Bale and Katusiime et al. (M. J. Bale, M. G. Katusiime, D. Wells, X. Wu, et al., mBio 12:e00568-21, 2021, https://doi.org/10.1128/mBio.00568-21) using in-depth integration site analysis in 11 children before ART and after up to nine years of ART. They have identified early development of long-lived proviruses, although the replication competence is unknown. A small fraction of cells bearing integrated proviruses clonally expand early during infection and persist. Integration in the oncogenes STAT5B and BACH2 were also found; these findings confirm the early development of clonal proliferation in perinatal HIV infection despite early effective ART, with a propensity for oncogenes.
Ground-dwelling spider families and forest structure variables for monitoring ecologically sustainable logging operations

Summary Approximately 80% of neotropical forests are subject to unsustainable economic practices, such as logging. Spiders are a megadiverse taxonomic group with a particularly great diversity in forest ecosystems and could help indicate the sustainability of logging operations. At six sites at 400–700 m altitude in the piedmont forest of north-western Argentina, spiders collected using pitfall traps and forest structure and spider assemblage structure variables were quantified in order to examine the association between them and to identify indicator spider families. Logging changes forest structure and seems to generate an unsuitable habitat for spiders associated with mature forests. The family taxonomic level is a good surrogate for spider morphospecies. The Mysmenidae, Nemesiidae, Theridiidae, Pholcidae, Hahniidae and Tetragnathidae families were associated with upper canopy cover of 20% or more and with more than two dead fallen trees per 0.1 ha and >15 live trees per 0.1 ha, found in unlogged forests. Bearing in mind that the piedmont forest of north-western Argentina is being logged in the absence of sustainability criteria, we suggest including spiders in monitoring schemes to complement the information obtained from more readily used groups, such as charismatic vertebrates.
Natural disasters in Italy: do we invest enough in risk prevention and mitigation?

Abstract Italy is exposed to a number of major natural risks. In the period 1944–2012, earthquakes, landslides and floods have resulted in huge losses with an economic cost (widely underestimated) of 3.5 billion Euros per year. Risk prevention and mitigation (RPM) should represent, therefore, a national priority and would require an adequate scale of financing. The Italian Government has earmarked financial resources for RPM through a multitude of laws. Based on an analysis of this legislation, this paper surveys the main measures financed by the Government to prevent and mitigate the seismic and hydrogeological risks in recent years. Besides, it compares RPM Government financing to the available estimates of the RPM financial need. It concludes that RPM Government financing, although increasing, still represents a small share of the RPM financial need, with, however, discrepancies across Regions.
Progressive Discrete Domains for Implicit Surface Reconstruction

Many global implicit surface reconstruction algorithms formulate the problem as a volumetric energy minimization, trading data fitting for geometric regularization. As a result, the output surfaces may be located arbitrarily far away from the input samples. This is amplified when considering i) strong regularization terms, ii) sparsely distributed samples or iii) missing data. This breaks the strong assumption commonly used by popular octree‐based and triangulation‐based approaches that the output surface should be located near the input samples. As these approaches refine during a pre‐process, their cells near the input samples, the implicit solver deals with a domain discretization not fully adapted to the final isosurface. We relax this assumption and propose a progressive coarse‐to‐fine approach that jointly refines the implicit function and its representation domain, through iterating solver, optimization and refinement steps applied to a 3D Delaunay triangulation. There are several advantages to this approach: the discretized domain is adapted near the isosurface and optimized to improve both the solver conditioning and the quality of the output surface mesh contoured via marching tetrahedra.
Constitutive signaling by the C-terminal fragment of polycystin-1 is mediated by a tethered peptide agonist

Mutation of the PKD1 gene, encoding polycystin-1 (PC1), is the primary cause of autosomal dominant polycystic kidney disease. PC1 is an 11-transmembrane domain protein that binds and modulates the activity of multiple heterotrimeric G protein families and is thought to function as a non-canonical G protein-coupled receptor (GPCR). PC1 shares a conserved GPCR autoproteolysis inducing [GAIN] domain with the adhesion family of GPCRs, that promotes an auto-catalytic, cis-cleavage at the GPCR proteolysis site (GPS) located proximal to the first transmembrane domain. GPS cleavage divides these receptors into two associated ‘subunits’, the extracellular N-terminal (NTF) and transmembrane C-terminal (CTF) fragments. For the adhesion GPCRs, removal of the NTF leads to activation of G protein signaling as a result of the exposure and subsequent intramolecular binding of the extracellular N-terminal stalk of the CTF, i.e., the tethered cryptic ligand or tethered agonist model. Here, we test the hypothesis that PC1-mediated signaling is regulated by an adhesion GPCR-like, tethered agonist mechanism. Using cell-based reporter assays and mutagenesis of PC1 expression constructs, we show that the CTF form of PC1 requires the stalk for signaling activation and synthetic peptides derived from the PC1 stalk sequence can re-activate signaling by a ‘stalk-less’ CTF. In addition, we demonstrate that ADPKD-associated missense mutations within the PC1 stalk affect signaling and can inhibit GPS cleavage. These results provide a foundation for beginning to understand the molecular mechanism of G protein regulation by PC1 and suggest that a tethered agonist-mediated mechanism can contribute to PKD pathogenesis. SIGNIFICANCE STATEMENT Mutations of the PKD1 gene, encoding polycystin-1, are the predominant cause of autosomal dominant polycystic kidney disease (ADPKD), a systemic disease that is the 4th leading cause of kidney failure. Polycystin-1 functions as an atypical GPCR capable of binding or activating heterotrimeric G proteins, which is essential for preventing renal cystogenesis. However, little is known regarding its regulation. Polycystin-1 shares structural features with the Adhesion family of GPCRs. In this work, we combined mutagenesis and cellular signaling assays which demonstrated that constitutive activation of signaling by polycystin-1 involves an Adhesion GPCR-like molecular mechanism. This study provides new knowledge regarding the structure-function relationships of polycystin-1 which will stimulate additional areas of investigation and reveal novel avenues of therapeutic intervention for ADPKD.
Role of miR-181c in Diet-induced obesity through regulation of lipid synthesis in liver

We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene (mt-COX1), and influence obesity-induced cardiac dysfunction through mitochondrial pathway. Liver plays a pivotal role during obesity. Therefore, we hypothesized that miR-181c plays an important role in pathophysiological complications associated with obesity. We used miR-181c/d-/- mice to study the miR-181c role in lipogenesis in hepatocytes during diet-induced obesity (DIO). Indirect calorimetric measurements were made during the 26 weeks high fat diet (HFD) exposure. qPCR was performed to examine the gene expression involved in lipid synthesis. Here, we show that miR-181c/d-/- mice are not protected against all metabolic consequences of HFD exposure. After 26 weeks of the HFD, miR-181c/d-/- mice had a significantly higher body fat (%) compared to WT. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. HFD-fed miR-181c/d-/- mice had higher serum and liver triglyceride levels compared to HFD-fed WT mice. qPCR data demonstrated that several genes which are regulated by isocitrate dehydrogenase 1 (IDH1) were upregulated in miR-181c/d-/- liver compared to WT liver. Furthermore, an AAV-8 was used to deliver miR-181c, in vivo, to validate the potential role of miR-181c in the liver. miR-181c delivery attenuate the lipogenesis by downregulating the same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.
Cannabidiol activates neuronal Kv7 channels

Cannabidiol (CBD), a chemical found in the Cannabis sativa plant, is a clinically effective antiepileptic drug whose mechanism of action is unknown. Using a fluorescence-based thallium flux assay, we performed a large-scale screen and found enhancement of flux through heterologously-expressed human Kv7.2/7.3 channels by CBD. Using patch clamp recordings, we found that CBD at low concentrations activates Kv7.2/7.3 channels at subthreshold voltages, with 100 nM CBD producing a doubling of current at -50 mV. CBD shifted the voltage-dependence of channels in the hyperpolarizing direction, producing a shift in the midpoint of activation by ∼-14 mV at 300 nM. CBD also effectively enhanced native M-current in both mouse superior cervical ganglion neurons and rat hippocampal neurons. The potent enhancement of Kv2/7.3 channels by CBD seems likely to contribute to its effectiveness as an antiepileptic drug by reducing neuronal hyperexcitability.
Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5α in mitophagy

The protein TRIM5α has multiple roles in anti-retroviral defense, but the mechanisms underlying TRIM5α action are unclear. Here, we used an APEX2-based proteomics approach to identify TRIM5α-interacting proteins. Analysis of the TRIM5α interactome found proteins participating in a wide variety of cellular functions including regulating antiviral signaling pathways. We used this data set to uncover a novel role for TRIM5α in mitophagy, an autophagy-based mode of mitochondrial quality control that is compromised in multiple human diseases. Mitochondrial damage triggered the relocalization of TRIM5α to ER-mitochondria contact sites where TRIM5α colocalized with markers of autophagy initiation and autophagosome biogenesis. Furthermore, we found that TRIM5α knockout attenuated both Parkin-dependent and Parkin-independent mitophagy by preventing the recruitment of autophagy regulators FIP200 and ATG13 to unhealthy mitochondria. Finally, TRIM5α knockout cells showed reduced mitochondrial function under basal conditions and were more susceptible to uncontrolled immune activation and cell death in response to mitochondrial damage than were wild type cells. Taken together, our studies have identified a homeostatic role for a protein previously recognized exclusively for its antiviral actions.
Free for all, or free-for-all? A content analysis of Australian university open access policies

Recent research demonstrates that Australia lags in providing open access to research outputs. In Australia, while the two major research funding bodies require open access of outputs from projects they fund, these bodies only fund a small proportion of research conducted. The major source of research and experimental development funding in Australian higher education is general university, or institutional, funding, and such funds are not subject to national funder open access policies. Thus, institutional policies and other institutional supports for open access are important in understanding Australia’s OA position. The purpose of this paper is, therefore, to understand the characteristics of Australian institutional open access policies and to explore the extent they represent a coherent and unified approach to delivering and promoting open access in Australia. Open access policies were located using a systematic web search approach and then their contents were analysed. Only half of Australian universities were found to have an open access policy. There was a wide variation in language used, expressed intent of the policy and expectations of researchers. Few policies mention monitoring or compliance and only three mention consequences for non-compliance. While it is understandable that institutions develop their own policies, when language is used which does not reflect national and international understandings, when requirements are not clear and with consequences, policies are unlikely to contribute to understanding of open access, to uptake of the policy, or to ease of transferring understanding and practices between institutions. A more unified approach to open access is recommended.
Computational metabolomics illuminates the lineage-specific diversification of resin glycoside acylsugars in the morning glory (Convolvulaceae) family

Acylsugars are a class of plant defense compounds produced across many distantly related families. Members of the horticulturally important morning glory (Convolvulaceae) family produce a diverse sub-class of acylsugars called resin glycosides (RGs), which comprise oligosaccharide cores, hydroxyacyl chain(s), and decorating aliphatic and aromatic acyl chains. While many RG structures are characterized, the extent of structural diversity of this class in different genera and species is not known. In this study, we asked whether there has been lineage-specific diversification of RG structures in different Convolvulaceae species that may suggest diversification of the underlying biosynthetic pathways. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed from root and leaf extracts of 26 species sampled in a phylogeny-guided manner. LC-MS/MS revealed thousands of peaks with signature RG fragmentation patterns with one species producing over 300 signals, mirroring the diversity in Solanaceae-type acylsugars. A novel RG from Dichondra argentea was characterized using Nuclear Magnetic Resonance spectroscopy, supporting previous observations of RGs with open hydroxyacyl chains instead of closed macrolactone ring structures. Substantial lineage-specific differentiation in utilization of sugars, hydroxyacyl chains, and decorating acyl chains was discovered, especially among Ipomoea and Convolvulus – the two largest genera in Convolvulaceae. Adopting a computational, knowledge-based strategy, we further developed a high-recall workflow that successfully explained ~72% of the MS/MS fragments, predicted the structural components of 11/13 previously characterized RGs, and partially annotated ~45% of the RGs. Overall, this study improves our understanding of phytochemical diversity and lays a foundation for characterizing the evolutionary mechanisms underlying RG diversification.
Mutations that adapt SARS-CoV-2 to mustelid hosts do not increase fitness in the human airway

SARS-CoV-2 has a broad mammalian species tropism infecting humans, cats, dogs and farmed mink. Since the start of the 2019 pandemic several reverse zoonotic outbreaks of SARS-CoV-2 have occurred in mink, one of which reinfected humans and caused a cluster of infections in Denmark. Here we investigate the molecular basis of mink and ferret adaptation and demonstrate the spike mutations Y453F, F486L, and N501T all specifically adapt SARS-CoV-2 to use mustelid ACE2. Furthermore, we risk assess these mutations and conclude mink-adapted viruses are unlikely to pose an increased threat to humans, as Y453F attenuates the virus replication in human cells and all 3 mink-adaptations have minimal antigenic impact. Finally, we show that certain SARS-CoV-2 variants emerging from circulation in humans may naturally have a greater propensity to infect mustelid hosts and therefore these species should continue to be surveyed for reverse zoonotic infections.
Role of Copper on Mitochondrial Function and Metabolism

Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.
Diagnostic Value of Serum Pepsinogen Levels for Screening Gastric Cancer and Atrophic Gastritis in Asymptomatic Individuals: A Cross-Sectional Study

Background Pepsinogens (PGs) can be used for gastric cancer (GC) screening, but the cutoff levels vary among studies, and PG levels are influenced by numerous factors. The aim of this article is to examine the diagnostic value of PG levels and Helicobacter pylori (Hp) status for GC and atrophic gastritis screening in asymptomatic individuals undergoing health checkup in China. Patients and Methods This was a multicenter cross-sectional study of subjects who underwent health checkup from 10/2016 to 10/2018 at nine International Healthcare Centers in China. All participants underwent gastroscopy and pathological examination, serum PG, 13C-urea breath test, and/or Hp serological current infection marker rapid test, all on the same day. PG-related parameters were analyzed in different Hp subgroups and regions. Results The patients were grouped as non-atrophic (NAG, n = 1,590), mild to moderate atrophic (MAG, n = 273), severe atrophic (SAG, n = 49), and GC (n = 10). The serum PG levels in these groups decreased with increasing pathological severity. In the same pathological groups, PGI and PGII levels were higher in the Hp-positive subgroup, while PGR (PGI/PGII ratio) was lower (P < 0.05). The best cutoff values for atrophy diagnosis were PGI ≤73.1 ng/ml and PGR ≤9.8, for severe atrophy were PGI ≤63.9 ng/ml and PGR ≤9.09, and for GC was PGR ≤4.7 (all P < 0.05 and area under the curve >0.7). The cutoff points varied with Hp status and China regions. Conclusion Serum PG levels might be used for the screening of gastric atrophic gastritis lesions. The results suggest that different cutoff values should possibly be used in different Hp status groups and geographical regions, but it will have to be validated in future studies. Future studies should also examine the value of PG levels for GC detection.