bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular evolution of protein sequences and codon usage in monkeypox viruses
Authors: Shan Ke-jia , Wu Changcheng , Tang Xiaolu , Lu Roujian , Tan Wenjie , Lu Jian 
Published: December 2022

ABSTRACTThe monkeypox virus (mpox virus, MPXV) epidemic in 2022 poses a significant public health risk. However, the evolutionary principles of MPXV are largely unknown. Here, we examined the evolutionary patterns of protein sequences and codon usage in MPXV. We first showed the signal of positive selection inOPG027specifically in Clade I. We then discovered accelerated protein sequence evolution over time in 2022 outbreak-causing variants. We also found strong epistasis between amino acid substitutions located in different genes. Codon adaptation index (CAI) analysis revealed that MPXV tended to use more unpreferred codons than human genes and that the CAI decreased with time and diverged between clades, with Clade I > IIa and IIb-A > IIb-B. Although the decrease in fatality rate in the three groups matched the CAI pattern, it is unclear whether this is a coincidence or if the deoptimization of codon usage in MPXV induced a decrease in fatality. This study sheds new light on the processes influencing the evolution of MPXV in human populations.
Superinfection plays an important role in the acquisition of complexPlasmodium falciparuminfections among femaleAnophelesmosquitoes
Authors: Bérubé Sophie , Freedman Betsy , Menya Diana , Kipkoech Joseph , Abel Lucy , Lapp Zena , Taylor Steve M. , O’Meara Wendy Prudhomme , Obala Andrew A. , Wesolowski Amy 
Published: December 2022

AbstractStudies of human malaria infections with multiple, genetically distinct parasites have illuminated mechanisms of malaria transmission. However, few studies have used the genetic diversity in mosquito infections to understand how transmission is sustained. We identified likely human sources of mosquito infections from a longitudinal cohort in Western Kenya based on genetic similarity between parasites and the timing of infections. We found that several human infections were required to reconstitute each mosquito infection and that multiple parasite clones were likely transmitted from infected humans to mosquitoes in each bite, suggesting that superinfection and co-transmission occur simultaneously and are important mechanisms of transmission. We further investigated this using an individual human and mosquito simulation model and found that co-transmission alone was unlikely to reproduce the high complexity of mosquito infections. We concluded that the superinfection of mosquitoes likely plays an important, but under studied, role in sustaining moderate to high malaria transmission.
Amplification and extraction free quantitative detection of viral nucleic acids and single-base mismatches using magnetic signal amplification circuit
Authors: Rösch Enja Laureen , Sack Rebecca , Chowdhury Mohammad Suman , Wolgast Florian , Schilling Meinhard , Viereck Thilo , Lak Aidin 
Published: December 2022

ABSTRACTEstablished nucleic acid detection assays require extraction and purification before sequence amplification and/or enzymatic reactions, hampering their widespread applications in point-of-care (POC) formats. Magnetic immunoassays based on magnetic particle spectroscopy and magnetic nanoparticles (MNPs) are isothermal, extraction- and purification-free, and can be quantitative and benchtop, making them suitable for POC settings. Here, we demonstrate a Magnetic signal Amplification Circuit (MAC) that combines specificity of toehold-mediated DNA strand displacement with magnetic response of MNPs to a clustering/declustering process. Our MAC assays require neither amplification nor extraction of target nucleic acids, and reveal four times better sensitivity than that of a magnetic circuit without signal amplification. Using MAC, we detect a highly specific 43 nucleotides sequence of SARS-CoV-2 virus. The MAC enables sensing both DNA and RNA targets with varying lengths and resolving single-base mismatches. Our MAC can be a powerful tool for translating research of nucleic acids detection to the clinic.
Structural insights into human ABCC4 mediated transport of platelet agonist and inhibitor
Authors: Chen Yu , Wang Liang , Hou Wen-Tao , Zha Zhi-Hui , Xu Kang , Zhou Cong-Zhao , Li Qiong , Chen Yuxing 
Published: December 2022

AbstractThe activation and accumulation of human platelets contributes to hemostasis and thrombosis, the imbalance of which would cause cardiovascular diseases, an increasing threat to the global health. Human ABC transporter ABCC4 that pumps out the platelet agonist and anti-platelet drug such as aspirin, might become a promising target for preventing cardiovascular diseases. Here we solve the structures of human ABCC4 in the apo and two complexed forms, all of which adopt a typical architecture of type-IV ABC transporters in an inward-facing conformation. Structure of ABCC4 complexed with U46619, an analog of the unstable TXA2, provides the first structural evidence that the platelet agonist TXA2is also exported via ABCC4. The dipyridamole-complexed structure reveals the inhibitory mechanism of dipyridamole against ABCC4. Structural comparisons enabled us to identify a transmembrane pocket in ABCC4 that provides a defined space for the rational design of specific anti-platelet drugs.
Genetic diversity, virulence, antimicrobial resistance genes, and antimicrobial susceptibility of group BStreptococcus(GBS) linked to mass mortalities of cultured Nile tilapia in Brazil
Authors: Assane Inácio Mateus , de Oliveira Neto Rubens Ricardo , de Abreu Reis Ferreira Daniel , do Vale Oliveira André , Hashimoto Diogo Teruo , Pilarski Fabiana 
Published: December 2022

AbstractStreptococcus agalactiae, group BStreptococcus(GBS), is the main bacterial pathogen of cultured Nile tilapia in many countries and causes extensive deaths in all stages of the farming cycle throughout the year. This study investigated the genetic diversity, virulence, presence of antibiotic resistance genes and antimicrobial susceptibility of 72 GBS linked to mass mortalities of cultured Nile tilapia in Brazil. Isolate identity was confirmed by morphological, biochemical and molecular analyses. Capsular serotype, multi-locus sequence typing (MLST) allelic profiles and putative pathogenic factors were identified by polymerase chain reaction (PCR), gel electrophoresis, sequencing and molecular analyses of different genes. The presence of antimicrobial resistance genes and antimicrobial susceptibility to florfenicol (FFC), oxytetracycline (OTC), thiamphenicol (TAP) and their combination were evaluated by PCR, followed by gel electrophoresis, and broth microdilution antimicrobial susceptibility testing, respectively. All clinical isolates studied were confirmed to be GBS, one from serotype III (IA2022) and 71 from serotype Ib, suggesting that serotype Ib was the most prevalent strain between 2011 and 2016 in the south and southern and southeastern regions of Brazil. Eight different allelic profiles were identified for the first time, beingadhP-52,pheS-2,atr-31,glnA-4,sdhA-2,tkt-19 the most predominant. Between one (glcK) and three (adhPandglnA) alleles were present at each locus. All strains, except IA2022, showed a partial gene deletion event on theglcKgene. The surface proteinRiband hypervirulent GBS adhesinBibAwere detected in all strains, except for 18P, which was negative forrib. On the other hand, α and β antigens of the C protein were only detected in IA2022. All antimicrobials showed high minimum inhibitory concentration (MIC ≥ 16 µg/mL) values against several strains with negative results for resistance genes. Despite indifference and antagonism being the most predominant activities in all combinations evaluated, the record of synergism, including in a strain with a resistance gene and phenotypic resistance, suggests that combination therapy can have therapeutic efficacy when well planned. The combination involving OTC and TAP or FFC is a likely candidate for improving the treatment of streptococcosis using combination therapy, even for strains showing phenotypic and genotypic resistance to OTC. This study provides pertinent data on pathogenic GBS genetic diversity, virulence, the presence of antibiotic resistance genes and antimicrobial susceptibility, which may be useful in the development of effective vaccines and therapeutic strategies for the prevention and control of streptococcosis in aquaculture farms.
Morphology of the Ovaries, Uterine Tubes and Uterus ofPteronotus gymnonotus(Chiroptera: Mormoopidae)
Authors: Costa Erich Fernando Espinelo , de Morais Danielle Barbosa 
Published: December 2022

ABSTRACTThe present study aimed to characterize the ovarian, tubal and uterine morphology in the insectivorous batPteronotus gymnonotus, in specimens collected in the state of Rio Grande do Norte, Brazil. After euthanasia, these organs were histologically processed for inclusion in historesin for morphological and morphometric analysis under light microscopy. The morphological characterization of the ovaries was based on the development of the oocyte and follicle growth, while the uterine tubes were characterized in terms of their anatomy and division of their parts into: infundibulum, ampulla and isthmus, where the height of the tubal epithelium and muscle layer thickness. The analysis of the uterus was based on the formation and thickness of its three layers: endometrium, myometrium and perimetrium. Morphometric analyzes were performed by capturing images of histological slides at different magnifications. The variables were submitted to descriptive analysis, with data expressed as mean and standard deviation. It was observed that the ovaries are bilateral and oval, presenting a squamous to simple cubic epithelium, forming the germinal epithelium, certain stratification regarding the location of the ovarian follicles, where most of the primordial follicles are arranged in the peripheral region of the ovary, however being it is possible to identify many follicles in various stages of maturation in the central region; the uterus is bicornuate and the layers of the uterus and uterine tubes observed follow the same pattern of other eutherian mammals. This information is important to allow comparisons between species, aiming at knowledge about reproductive morphology in mammals, especially those belonging to the order Chiroptera. Therefore, this research is essential to subsidize conservation measures that protect their natural populations, in an effort to maintain the ecological balance.
Integrating spatial transcriptomics data across different conditions, technologies, and developmental stages
Authors: Zhou Xiang , Dong Kangning , Zhang Shihua 
Published: December 2022

AbstractWith the rapid generation of spatial transcriptomics (ST) data, integrative analysis of multiple ST datasets from different conditions, technologies, and developmental stages is becoming increasingly important. However, identifying shared and specific spatial domains across ST datasets of multiple slices remains challenging. To this end, we develop a graph attention neural network STAligner for integrating and aligning ST datasets, enabling spatially-aware data integration, simultaneous spatial domain identification, and downstream comparative analysis. We apply STAligner to the integrative analysis of ST datasets of the human cortex slices from different samples, the mouse olfactory bulb slices generated by two profiling technologies, the mouse hippocampus tissue slices under normal and Alzheimer’s disease conditions, and the spatiotemporal atlases of mouse organogenesis. STAligner efficiently captures the shared tissue structures across different slices, the disease-related substructures, and the dynamical changes during mouse embryonic development. Additionally, the shared spatial domain and nearest neighbor pairs identified by STAligner can be further considered as corresponding pairs to guide the three-dimensional reconstruction of consecutive slices, achieving more accurate local structure-guided registration results than the existing method.
Visualization of mitochondrial cristae and mtDNA evolvement and interactions with super-resolution microscopy
Authors: Ren Wei , Ge Xichuan , Li Meiqi , Li Shiyi , Shan Chunyan , Gao Baoxiang , Xi Peng 
Published: December 2022

AbstractMitochondrial cristae host the respiratory chain complexes composed of mitochondrial DNA (mtDNA)-encoded and nuclear-encoded proteins and are responsible for ATP production. Movement of mtDNA located in the matrix is limited due to blockade by the cristae; yet, the dynamic interaction between the inner membrane and mtDNA remains unknown due to the insufficient spatiotemporal resolution of conventional microscopy and the lack of appropriatein vivoprobes targeted to the mitochondrial inner membrane. Here, we developed a novel fluorescence probe to visualize the inner membrane using low-power stimulated emission depletion (STED) microscopy. Dual-color imaging of the inner membrane and mtDNA demonstrated that mtDNA is more likely to spread at mitochondrial tips or branch points under an overall even distribution. Interestingly, exploration of forming this distribution propensity uncovered that the mitochondrial dynamics are closely related to the location of mtDNA, and further insight found that fusion always occurs near mtDNA in order to minimize the pressure for cristae remodeling. In healthy cells, mitochondrial dynamics based on cristae remodeling promotes the even distribution of mtDNA, on the contrary, when cristae structure fails in apoptosis and ferroptosis, leading to mtDNA distribution disorder. Observation of active changes during apoptosis further captured the dynamic process of inner membrane herniation and mtDNA leakage along with cristae remodeling. Under ferroptosis, the mitochondria shrank into ellipsoids and mtDNA converged at the center of mitochondria. The rich dynamics between the cristae and mtDNA, revealed at unprecedented spatiotemporal resolution, show the motive and outgrowth of mtDNA distribution.
Structural basis for the ligand promiscuity of the neofunctionalized, carotenoid-binding fasciclin domain protein AstaP
Authors: Kornilov Fedor D. , Slonimskiy Yury B. , Lunegova Daria A. , Egorkin Nikita A. , Savitskaya Anna G. , Kleymenov Sergey Yu. , Maksimov Eugene G. , Goncharuk Sergey A. , Mineev Konstantin S. , Sluchanko Nikolai N. 
Published: December 2022

ABSTRACTFasciclins (FAS1) are ancient adhesion protein domains found across different phyla from bacteria to humans, with no common small ligand binding function reported. A unique FAS1-containing astaxanthin-binding protein (AstaP) from green algae can efficiently bind an unusually broad repertoire of carotenoids (astaxanthin, zeaxanthin, canthaxanthin, β-carotene), but the underlying mechanism is largely unknown. Here we dissect the structural basis for the ligand binding promiscuity of AstaP-orange1 (AstaPo1) by determining its solution NMR structure in complex with its natural ligand, astaxanthin (AXT), and validate this structure by SAXS, calorimetry, optical spectroscopy and mutagenesis data. While the unstructured tails of AstaPo1 are not essential for carotenoid binding, they enhance protein solubility. The a1-a2 helices of the AstaPo1 FAS1 domain embrace the carotenoid polyene like a jaw, organizing a conserved hydrophobic tunnel, too short to prevent the AXT β-ionone rings from protruding on both sides of the tunnel, thereby not imposing specificity restrictions. The only specific protein-AXT interactions involve H-bonds between the oxygenated groups on AXT and a peripheral Gln56 residue. Remarkably, mapping of this and other AXT-contacting AstaPo1 residues revealed their different conservation in AstaP orthologs with the tentative carotenoid-binding function and in FAS1 proteins in general, supporting neofunctionalization of AstaPs within green algae. Correspondingly, a cyanobacterial homolog with a similar domain structure cannot bind carotenoids due to subtle differences in residues decorating the tunnel. These structure-activity relationships inform the sequence-based prediction of the carotenoid-binding FAS1 members.SIGNIFICANCEA water-soluble astaxanthin-binding protein (AstaP) is a photoprotective protein in green algae helping them to tolerate stress conditions. While belonging to a ubiquitous protein family sharing an ancient structural domain, fasciclin, involved in cell adhesion, AstaP possesses an outstanding ability to bind carotenoid pigments of a different type, which are potent antioxidants. To understand the molecular basis for such carotenoid-binding promiscuity of AstaP, here we determined its spatial structure – the first structure of a carotenoid-protein complex solved by nuclear magnetic resonance spectroscopy. Together with biochemical and sequence conservation analyses, our data illustrate a remarkable case of neofunctionalization of the ancient protein domain and pave the way for its bioengineering and practical use as antioxidant transporter for biomedical applications.
ESCRT recruitment to mRNA-encoded SARS-CoV-2 spike induces virus-like particles and enhanced antibody responses
Authors: Hoffmann Magnus A. G. , Yang Zhi , Huey-Tubman Kathryn E. , Cohen Alexander A. , Gnanapragasam Priyanthi N. P. , Nakatomi Leesa M. , Storm Kaya N. , Moon Woohyun J. , Lin Paulo J.C. , Bjorkman Pamela J. 
Published: December 2022

SummaryPrime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely-arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8+ T-cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared to conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for three months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses.
Sodium channel slow inactivation normalizes firing in axons with uneven conductance distributions
Authors: Zang Yunliang , Marder Eve , Marom Shimon 
Published: December 2022

SummaryThe Na+channels that are important for action potentials show rapid inactivation, a state in which they do not conduct, although the membrane potential remains depolarized1,2. Rapid inactivation is a determinant of millisecond scale phenomena, such as spike shape and refractory period. Na+channels also inactivate orders of magnitude more slowly, and therefore have impacts on excitability over much longer time scales than those of a single spike or a single inter-spike interval3-9. Here, we focus on the contribution of slow inactivation to the resilience of axonal excitability10,11when ion channels are unevenly distributed across the axonal membrane. We study models in which the voltage-gated Na+and K+channels are unevenly distributed along axons with different variances, capturing the heterogeneity that biological axons display12. In the absence of slow inactivation many conductance distributions result in spontaneous tonic activity. Faithful axonal propagation is achieved with the introduction of Na+channel slow inactivation. This “normalization” effect depends on relations between the kinetics of slow inactivation and the firing frequency. Consequently, neurons with characteristically different firing frequencies will need to implement different sets of channel properties to achieve resilience. The results of this study demonstrate the importance of the intrinsic biophysical properties of ion channels in normalizing axonal function.HighlightsVariation in ion channel density in axons may compromise axonal spike propagation.Slow inactivation of Na+channels modulates their availability.Na+channel slow inactivation increases the reliability of spike propagation.Normalization by slow inactivation can compensate for uneven channel distributions.
Tissue protective role of Ganetespib in SARS-CoV-2-infected Syrian golden hamsters
Authors: Teixeira Alves Luiz Gustavo , Baumgardt Morris , Hoppe Judith , Firsching Theresa C. , Adler Julia M. , Mastrobuoni Guido , Grobe Jenny , Hönzke Katja , Kempa Stefan , Gruber Achim D. , Hocke Andreas C. , Trimpert Jakob , Wyler Emanuel , Landthaler Markus 
Published: December 2022

AbstractThe emergence of new SARS-CoV-2 variants, capable of escaping the humoral immunity acquired by the available vaccines, together with waning immunity and vaccine hesitancy, challenges the efficacy of the vaccination strategy in fighting COVID-19. Improved therapeutic strategies are therefore urgently needed to better intervene particularly in severe cases of the disease. They should aim at controlling the hyper-inflammatory state generated upon infection, at reducing lung tissue pathology and endothelial damages, along with viral replication. Previous research has pointed a possible role for the chaperone HSP90 in SARS-CoV-2 replication and COVID-19 pathogenesis. Pharmacological intervention through HSP90 inhibitors was shown to be beneficial in the treatment of inflammatory diseases, infections and reducing replication of diverse viruses. In this study, we analyzed the effects of the potent HSP90 inhibitor Ganetespibin vitroon alveolar epithelial cells and alveolar macrophages to characterize its effects on cell activation and viral replication. Additionally, to evaluate its efficacy in controlling systemic inflammation and the viral burden after infectionin vivo, a Syrian hamster model was used.In vitro, Ganetespib reduced viral replication on AECs in a dose-dependent manner and lowered significantly the expression of pro-inflammatory genes, in both AECs and alveolar macrophages.In vivo, administration of Ganetespib led to an overall improvement of the clinical condition of infected animals, with decreased systemic inflammation, reduced edema formation and lung tissue pathology. Altogether, we show that Ganetespib could be a potential medicine to treat moderate and severe cases of COVID-19.