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Mashup Score: 1A novel nabelschnur protein regulates segregation of the kinetoplast DNA in Trypanosoma brucei - 4 hour(s) ago
The kinetoplast DNA (kDNA), a distinctive arrangement of mitochondrial DNA found in trypanosomatid protists, comprises a concatenated network of minicircles and maxicircles that undergo division and segregation once during each cell cycle. Despite the identification and characterization of numerous proteins involved in kDNA maintenance and replication, its segregation and the formation of the nabelschnur remain poorly understood on a molecular level. This enigmatic filamentous structure, transiently appearing in Trypanosoma brucei, connects the daughter kDNA networks prior to their complete segregation. Here, we characterize TbNAB70, a high mobility group box-like protein localized exclusively to the nabelschnur and the kDNA disc. Our findings demonstrate that TbNAB70 is critical for the segregation, but not replication, of kDNA, a so far unprecedented phenotype. Furthermore, structural predictions suggest that this protein holds the capacity to bind to kDNA illuminating the exact mole
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Mashup Score: 4MED1 IDR acetylation reorganizes the transcription preinitiation complex, rewires 3D chromatin interactions and reprograms gene expression - 4 hour(s) ago
With our current appreciation of the complexity of eukaryotic transcription, whose dysregulation drives diseases including cancer, it is becoming apparent that identification of key events coordinating multiple aspects of transcriptional regulation is of special importance. To elucidate how assembly of RNA polymerase II (Pol II) with Mediator complex preinitiation complexes (PICs) and formation of transcription-permissive 3D chromatin organization are coordinated, we studied MED1, a representative subunit of the Mediator complex that acts to establish functional preinitiation complexes (PICs) that forms biomolecular condensates through an intrinsically disordered region (IDR) to facilitate transcription, and is implicated in the function of estrogen receptor α (hereafter ER) in ER-positive breast cancer (ER+ BC) cells. We found that MED1 is acetylated at 6 lysines in its IDR and, further, that MCF7 ER+ BC cells in which endogenous MED1 is replaced by an ectopic 6KR (non-acetylatable) m
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Mashup Score: 3A Protein Language Model for Exploring Viral Fitness Landscapes - 4 hour(s) ago
Successively emerging SARS-CoV-2 variants lead to repeated epidemic surges through escalated spreading potential (i.e., fitness). Modeling genotype-fitness relationship enables us to pinpoint the mutations boosting viral fitness and flag high-risk variants immediately after their detection. Here, we introduce CoVFit, a protein language model able to predict the fitness of variants based solely on their spike protein sequences. CoVFit was trained with genotype-fitness data derived from viral genome surveillance and functional mutation data related to immune evasion. When limited to only data available before the emergence of XBB, CoVFit successfully predicted the higher fitness of the XBB lineage. Fully-trained CoVFit identified 549 fitness elevation events throughout SARS-CoV-2 evolution until late 2023. Furthermore, a CoVFit-based simulation was able to predict the higher fitness of JN.1 subvariants before their detection. Our study provides both insight into the SARS-CoV-2 fitness la
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Mashup Score: 0Sustainable and Ecofriendly Nanoparticle Synthesis Using Microbial Strains Isolated From Heavy Metal Rich Industrial Effluent - 4 hour(s) ago
Heavy metals present in industrial effluent that are discharged into the environment can leach into water resources and adversely affect human health and ecosystems. Bacteria have evolved defensive mechanisms to counteract heavy metal toxicity. In this study, the concentrations of Cobalt (Co), Copper (Cu), Iron (Fe), Manganese (Mn) and Zinc (Zn) in titanium industry effluent were found to surpass the permissible limits set by three authentic standards for drinking water. Notably, the concentration of manganese exceeded the permissible limit by a staggering factor of 500 times followed by Co, Fe, Zn and Cu. Eight morphologically different bacteria and fungi were isolated from this effluent. The cell free supernatants of six out of these eight cultures produced heavy metal nanoparticles at room temperature over a period of upto 7 days. The presence of nanoparticles was verified by visible colour changes, UV-Vis spectroscopy and FT-IR analysis. The maximum absorption of the Fe, Co, Cu, Zn
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Mashup Score: 0
In 2018–2019, Thailand experienced a nationwide spread of chikungunya virus (CHIKV), with approximately 15,000 confirmed cases of disease reported. Here, we investigated the evolutionary and molecular history of the East/Central/South African (ECSA) genotype to determine the origins of the 2018–2019 CHIKV outbreak in Thailand. This was done using newly sequenced clinical samples from travellers returning to Sweden from Thailand in late 2018 and early 2019 and previously published genome sequences. Our phylogeographic analysis showed that before the outbreak in Thailand, the Indian Ocean lineage (IOL) found within the ESCA, had evolved and circulated in East Africa, South Asia, and Southeast Asia for about 15 years. In the first half of 2017, an introduction occurred into Thailand from another South Asian country, most likely Bangladesh, which subsequently developed into a large outbreak in Thailand with export to neighbouring countries. Based on comparative phylogenetic analyses of the
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Mashup Score: 0
Abstract There is a critical gap in knowledge about how Gram-negative bacterial pathogens, using survival strategies developed for other niches, cause lethal bacteremia. Facultative anaerobic species of the Enterobacterales order are the most common cause of Gram-negative bacteremia, including Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, and Enterobacter hormaechei. Bacteremia often leads to sepsis, a life-threatening organ dysfunction resulting from an unregulated immune response to infection. Despite a lack of specialization for this host environment, Gram-negative pathogens cause nearly half of bacteremia cases annually. Based on our existing Tn-Seq fitness factor data from a murine model of bacteremia combined with comparative genomics of the five Enterobacterales species above, we prioritized 18 conserved fitness genes or operons for further characterization. Each mutant in each species was used to cochallenge C57BL/6 mice via tail vein injec
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Mashup Score: 1Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations - 4 hour(s) ago
The microbiota in individual habitats differ both in relative composition and absolute abundance. While sequencing approaches determine only the relative abundances of taxa and genes, experimental techniques for absolute abundance determination are rarely applied to large-scale microbiome studies. Here, we developed a machine learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applied to large-scale datasets (n = 34,539), we demonstrate that microbial load is the major determinant of gut microbiome variation and associated with numerous host factors. We found that for several diseases, the altered microbial load, not the disease itself, was the main driver of the gut microbiome changes. Adjusting for this effect substantially reduced the significance of more than half of the disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance
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Mashup Score: 0Natural history of eukaryotic DNA viruses with double jelly-roll major capsid proteins - 4 hour(s) ago
The phylum Preplasmiviricota (kingdom Bamfordvirae, realm Varidnaviria) is a broad assemblage of diverse viruses with comparatively short double-stranded DNA genomes (<50 kbp) that produce icosahedral capsids built from double jelly-roll major capsid proteins. Preplasmiviricots infect hosts from all cellular domains, testifying to their ancient origin and, in particular, are associated with six of the seven supergroups of eukaryotes. Preplasmiviricots comprise four major groups of viruses, namely, polintons, polinton-like viruses (PLVs), virophages, and adenovirids. We employed protein structure modeling and analysis to show that protein-primed DNA polymerases (pPolBs) of polintons, virophages, and cytoplasmic linear plasmids encompass an N-terminal domain homologous to the terminal proteins (TPs) of prokaryotic PRD1-like tectivirids and eukaryotic adenovirids that are involved in protein-primed replication initiation, followed by a viral ovarian tumor-like cysteine deubiquitinylase (v
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Mashup Score: 0Identification of unique and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries - 4 hour(s) ago
In vitro screening of large libraries of compounds with automated High-throughput screening is expensive, time consuming and requires dedicated infrastructures. Conversely, the screening of DNA-encoded chemical libraries can be rapidly performed with basic equipment available in most laboratories. In this study we identified novel inhibitors of SARS-CoV-2 main protease (Mpro) through the affinity screening of the commercially available ″DELopen″ library, containing 4.2 billion compounds. The identified inhibitors were peptidomimetics compounds containing a C-terminal electrophilic group able to covalently bind to Mpro reactive Cys145 (confirmed by x-ray crystallography). Compound SLL11 had IC50 = 30nM and was found to be well optimized, proving that the rapid exploration of large chemical spaces, enabled by DECL technology, allows the direct identification of potent inhibitors avoiding several rounds of iterative medicinal chemistry. Compound MP6, a close analogue of SLL11, showed anti
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Mashup Score: 0Genome-Wide Transcription Response of Staphylococcus epidermidis to Heat Shock and Medically Relevant Glucose Levels - 4 hour(s) ago
Skin serves as both barrier and interface between body and environment. Skin microbes are intermediaries evolved to respond, transduce, or act in response to changing environmental or physiological conditions. Here, we quantify genome-wide changes in gene expression levels for one abundant skin commensal, Staphylococcus epidermidis, in response to an internal physiological signal, glucose levels, and an external environmental signal, temperature. We find 85 of 2354 genes change up to ~34-fold in response to medically relevant changes in glucose concentration (0 mM to 17 mM; adj P value less than 0.05). We observed carbon catabolite repression in response to a range of glucose spikes, as well as upregulation of genes involved in glucose utilization in response to persistent glucose. We observed 366 differentially expressed genes in response to a physiologically relevant change in temperature (37C to 45C; adj P value less than 0.05) and an S. epidermidis heat-shock response that mostly r
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A novel nabelschnur protein regulates segregation of the kinetoplast DNA in Trypanosoma brucei https://t.co/XMoB1c91EG #bioRxiv