bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of potential biomarker candidates of drug-induced vascular injury (DIVI) in rats using gene expression and histopathology data
Authors: Liu Anika , Munoz-Muriedas Jordi , Bender Andreas , Dalmas Deidre A. 
Published: August 2022

AbstractDrug-induced vascular injury (DIVI) observed in non-clinical species often leads to significant delays or termination of compounds in drug development due to the lack of translatable biomarkers and unknown relevance to humans. This study focused on the identification of potential biomarker candidates of drug-induced vascular injury, or more specifically mesenteric medial arterial necrosis (MAN), in rats. To do so, an adapted bioinformatic filtering pipeline was applied to previously generated gene expression data obtained from laser capture microdissected endothelial and vascular smooth muscle cells and corresponding histopathological annotations from mesenteric arteries following treatment of rats with known vascular toxicants, non-vasotoxic vasoactive comparator compounds, and corresponding vehicle. A novel gene panel including 33 genes with consistent, specific, and dose-responsive dysregulation across multiple treatments inducing MAN was identified. The degree to which these reflect injury progression was characterized and changes were identified in samples from animals where injury was anticipated but not yet histologically observed. The most predictive candidates (AUC > 0.9) with the strongest changes (logFC > 1.7) in MAN encode secreted proteins (Tnc, Vcan, Timp1andFn1)which are strongly interlinked with each other and other potential candidate biomarkers encoding cell surface proteins. Although further validation is required for biomarker qualification, the adapted bioinformatic approach utilized in this study provides informed data-driven starting points for further DIVI biomarker discovery and development in rats, as well as potential mechanistic insight into MAN pathogenesis.
Rewiring cattle movements to limit infection spread
Authors: Morel-Journel Thibaut , Ezanno Pauline , Vergu Elisabeta 
Published: August 2022

AbstractThe cattle tracing databases set up over the past decades in Europe have become major resources for representing demographic processes of livestock and assessing potential risk of infections spreading by trade. The herds registered in these databases are nodes of a network of commercial movements, which can be altered to lower the risk of disease transmission. In this study, we develop an algorithm aimed at reducing the number of infected animals and herds, by rewiring specific movements responsible for trade flows from high- to low-prevalence herds. The algorithm is coupled with a generic computational model describing infection spread within and between herds, based on data extracted from the French cattle movement tracing database (BDNI). This model is used to simulate a wide array of infections, with either a recent outbreak (epidemic) or an outbreak that occurred five years earlier (endemic), on which the performances of the rewiring algorithm are explored. Results highlight the effectiveness of rewiring in containing infections to a limited number of herds for all scenarios, but especially if the outbreak is recent and if the estimation of disease prevalence is frequent. Further analysis reveal that the key parameters of the algorithm affecting infection outcome vary with the infection parameters. Allowing any animal movement from high to low-prevalence herds reduces the effectiveness of the algorithm in epidemic settings, while frequent and fine-grained prevalence assessments improve the impact of the algorithm in endemic settings. According to our results, our approach focusing on a few commercial movements is expected to lead to substantial improvements in the control of a targeted disease, although changes in the network structure should be monitored for potential vulnerabilities to other diseases. Due to its generality, the developed rewiring algorithm could be applied to any network of controlled individual movements liable to spread disease.
SARS-CoV-2 Omicron BA.2.75 variant may be much more infective than preexisting variants
Authors: Sugano Aki , Takaoka Yutaka , Kataguchi Haruyuki , Kumaoka Minoru , Ohta Mika , Kimura Shigemi , Araki Masatake , Morinaga Yoshitomo , Yamamoto Yoshihiro 
Published: August 2022

ABSTRACTObjectivesIn our previous research, we developed a mathematical model via molecular simulation analysis to predict the infectivity of seven SARS-CoV-2 variants. In this report, we aimed to predict the relative risk of the recent new variants of SARS-CoV-2 as based on our previous research.MethodsWe subjected Omicron BA.4/5 and BA.2.75 variants of SARS-CoV-2 to the analysis to determine the absolute evolutionary distance of the spike protein gene (S gene) of the variants from the Wuhan variant so as to appreciate the changes in the spike protein. We performed the molecular docking simulation analyses of the spike proteins with human angiotensin-converting enzyme 2 (ACE2) to understand the docking affinities of these variants. We then compared the evolutionary distances and the docking affinities of these variants with those of the seven variants that we had analyzed in our previous research.ResultsThe evolutionary distances of the S gene in BA.4/5 and BA.2.75 from the Wuhan variant were longer than those of the other variants. BA.2.75 had the highest docking affinity of the spike protein with ACE2 (ratio per Wuhan variant).ConclusionThe important results from this analysis are the following: BA.2.75 has both the highest docking affinity and the longest evolutionary distance of the S gene. These results suggest that BA.2.75 infection can spread farther than can infections of preexisting variants.
Paradoxical tumor suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer
Authors: Itakura Hiroaki , Hata Tsuyoshi , Okuzaki Daisuke , Takeda Koki , Iso Kenji , Qian Yamin , Morimoto Yoshihiro , Adachi Tomohiro , Hirose Haruka , Yokoyama Yuhki , Ogino Takayuki , Miyoshi Norikatsu , Takahashi Hidekazu , Uemura Mamoru , Mizushima Tsunekazu , Hinoi Takao , Mori Masaki , Doki Yuichiro , Eguchi Hidetoshi , Yamamoto Hirofumi 
Published: August 2022

SummarySomatic cell reprogramming using the microRNAs miR200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene-like behavior in multiple myeloma and T-cell lymphoma, decreased in tumor samples but increased in microRNA-treated normal mucosa. Immunohistochemistry identified downregulation of c-MAF as an early tumorigenesis event in CRC, with low c-MAF expression associated with poor prognosis. Of note, c-MAF expression and p53 protein levels were inversely correlated in CRC samples. c-MAF knockout led to enhanced tumor formation in azoxymethane/dextran sodium sulfate–treated mice, with activation of cancer-promoting genes. c-MAF may play a tumor-suppressive role in CRC development.
Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study
Authors: Millar Peter R , Gordon Brian A , Luckett Patrick H , Benzinger Tammie LS , Cruchaga Carlos , Fagan Anne M , Hassenstab Jason J , Perrin Richard J , Schindler Suzanne E , Allegri Ricardo F , Day Gregory S , Farlow Martin R , Mori Hiroshi , Nübling Georg ,   the Dominantly Inherited Alzheimer Network, Bateman Randall J , Morris John C , Ances Beau M 
Published: August 2022

AbstractBackgroundEstimates of “brain-predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD), but has not been well explored in preclinical AD. Prior studies have typically modeled BAG with structural magnetic resonance imaging (MRI), but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored.MethodsWe trained three models to predict age from FC, volumetric (Vol), or multimodal MRI (Vol+FC) in 390 control participants (18-89 years old). In independent samples of 144 older adult controls, 154 preclinical AD participants, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid, tau, and neurodegeneration, as well as a global cognitive composite.ResultsAll models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG and Vol+FC-BAG were marginally reduced in preclinical AD participants compared to controls. In CI participants only, elevated Vol-BAG and Vol+FC-BAG were associated with more advanced AD pathology and lower cognitive performance.ConclusionsBoth FC-BAG and Vol-BAG are elevated in CI participants. However, FC and volumetric MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to preclinical AD pathology, while Vol-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model captures these modality-specific patterns, and further, improves sensitivity to healthy age differences.FundingThis work was supported by the National Institutes of Health (P01-AG026276, P01-AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer’s Association (SG-20-690363-DIAN).
Cooperative host-microbe metabolism of a plant toxin in bees
Authors: Motta Erick V. S. , Gage Alejandra , Smith Thomas E. , Blake Kristin J. , Kwong Waldan K. , Riddington Ian M. , Moran Nancy A. 
Published: August 2022

AbstractDuring pollination, bees are exposed to a myriad of xenobiotics, including plant metabolites, which may exert a wide range of effects on their health. Although bees encode enzymes that help in the metabolism of xenobiotics, they still have reduced detoxification gene diversity when compared to other insects, and may rely on other components of their physiology, such as the microbiota, to degrade potentially toxic molecules. In this study, we show that amygdalin, a cyanogenic glycoside found in honey bee-pollinated almond trees, can be metabolized by both bees and members of the gut microbiota. In microbiota-deprived bees, amygdalin is degraded into prunasin, leading to prunasin accumulation in the midgut and hindgut. In microbiota-colonized bees, on the other hand, amygdalin is degraded even further, and prunasin does not accumulate in the gut, suggesting that the microbiota contribute to the full degradation of amygdalin into hydrogen cyanide.In vitroexperiments demonstrated that amygdalin degradation by bee gut bacteria is strain-specific and not characteristic of a particular genus or species. We found strains ofBifidobacterium,BombilactobacillusandGilliamellathat can degrade amygdalin, and the degradation mechanism appears to vary since only some strains produce prunasin as an intermediate. Finally, we investigated the basis of degradation inBifidobacteriumwkB204, a strain that fully degrades amygdalin. We found overexpression and secretion of several carbohydrate-degrading enzymes, including one in glycoside hydrolase family 3 (GH3). We expressed this GH3 inEscherichia coliand detected prunasin as a byproduct when cell lysates were cultured with amygdalin, supporting its contribution to amygdalin degradation. These findings demonstrate that both host and microbiota can act together to metabolize dietary plant metabolites. How amygdalin degradation into hydrogen cyanide affects bee health remains to be elucidated.
SAMHD1 controls nucleoside-based cancer therapeutics, deoxyguanosine toxicity, and inflammation
Authors: Moore Michael D. , Johnson Errin , Jacklin Chloe , Johnson Steven , Green Owen , James William 
Published: August 2022

ABSTRACTSAMHD1 is a key regulator of dNTP metabolism, being activated by dGTP and converting dNTPs into their respective nucleosides. As a result, it plays a significant role in several distinct diseases. Not only is SAMHD1 a restriction factor for HIV-1 replication, which requires dNTPs for replication, but it is also required for genome stability, is mutated in multiple cancers, and loss of function mutations cause Acardi-Goutières Syndrome, an early-onset inherited encephalopathy. In this paper we knock out the SAMHD1 gene in pluripotent stem cells, and show that it also affects nucleoside analogue sensitivity of dividing cells and deoxyguanosine toxicity in a cell cycle-independent manner. Comparing wild type and gene-edited macrophages, we also show that deoxyguanosine toxicity is associated with pro-inflammatory cell death, modifications in uric acid production and the formation of monosodium urate crystals within the macrophages. These novel features of the SAMHD1−/− phenotype provide unique insights into the aetiology of Acardi-Goutières Syndrome, and have implications for certain chemotherapeutic agents.
TMEM100, a Lung-Specific Endothelium Gene
Authors: Liu Bin , Yi Dan , Yu Zhiyun , Pan Jiakai , Ramirez Karina , Li Shuai , Wang Ting , Glembotski Christopher C. , Fallon Michael B. , Oh S. Paul , Gu Mingxia , Kalucka Joanna , Dai Zhiyu 
Published: August 2022

AbstractThe heterogeneity of endothelium across different organs was recently explored using single-cell RNA-sequencing analysis. Compared to other organs, the lung exhibits a distinct structure composed of a thin layer of capillary for efficient gas exchange. In this study, we demonstrate that Tmem100 is a lung-specific endothelium gene.
Identification and characterization of repressive domains in Drosophila transcription factors
Authors: Klaus Loni , de Almeida Bernardo P. , Vlasova Anna , Nemčko Filip , Schleiffer Alexander , Bergauer Katharina , Rath Martina , Stark Alexander 
Published: August 2022

AbstractAll multicellular life relies on differential gene expression, determined by regulatory DNA elements and DNA-binding transcription factors that mediate activation and repression via cofactor recruitment. While activators have been extensively characterized, repressors are less well studied and their repressive domains (RDs) are typically unknown, as are the RDs’ properties and the co-repressors (CoRs) they recruit. Here, we develop the high-throughput next-generation-sequencing-based method Repressive-Domain (RD)-seq to systematically identify RDs in complex libraries. Screening more than 200,000 fragments covering the coding sequences of all transcription-related proteins in Drosophila melanogaster, we identify 195 RDs in known repressors and in proteins not previously associated with repression. Many RDs contain recurrent short peptide motifs that are required for RD function, as demonstrated by motif mutagenesis, and are conserved between fly and human. Moreover, we show that RDs which contain one of five distinct repressive motifs interact with and depend on different CoRs, including Groucho, CtBP, Sin3A or Smrter. Overall, our work constitutes an invaluable resource and advances our understanding of repressors, their sequences, and the functional impact of sequence-altering mutations.
Microcirculatory dysfunction associates with neurovascular uncoupling in peri-ischemic brain regions after ischemic stroke
Authors: Staehr Christian , Giblin John T. , Gutiérrez-Jiménez Eugenio , Guldbrandsen Halvor , Tang Jianbo , Sandow Shaun L. , Boas David A. , Matchkov Vladimir V. 
Published: August 2022

BackgroundDespite recanalization after ischemic stroke, neurovascular coupling, i.e., the local hyperaemic response to neuronal activity, is impaired in peri-ischemic brain regions. Reduced neurovascular coupling may contribute to neurological deterioration over time. The mechanism underlying dysfunctional neurovascular coupling following stroke is largely unknown.MethodsMice implanted with chronic cranial windows were trained for awake head-fixation prior to experiments. One hour occlusion of the anterior middle cerebral artery branch was induced using single vessel photothrombosis. Cerebral perfusion and neurovascular coupling were assessed by optical coherence tomography and laser speckle contrast imaging. Capillaries and pericytes were studied in perfusion-fixed tissue by labelling lectin and platelet-derived growth factor receptor β.ResultsArterial occlusion induced on average 11 spreading depressions over one hour associated with substantially reduced blood flow in the peri-ischemic cortex. Approximately half of the capillaries in the peri-ischemic area were no longer perfused 3 and 24 hours after reperfusion, which was associated with constriction of an equivalent proportion of peri-ischemic capillary pericytes. The capillaries in the peri-ischemic cortex that remained perfused showed increased prevalence of dynamic flow stalling. Whisker stimulation led to reduced neurovascular coupling responses in the sensory cortex corresponding to the peri-ischemic region 3 and 24 hours after reperfusion.ConclusionArterial occlusion led to constriction of pericytes in the peri-ischemic cortex associated with long-lasting microcirculatory failure. This reduced capillary capacity may, at least in part, underlie impaired neurovascular coupling in peri-ischemic brain regions after stroke and reperfusion.
NEUROTRANSMITTER TRANSPORTER/RECEPTOR CO-EXPRESSION SHARES ORGANIZATIONAL TRAITS WITH BRAIN STRUCTURE AND FUNCTION
Authors: Hänisch Benjamin , Hansen Justine Y. , Bernhardt Boris C. , Eickhoff Simon B. , Dukart Juergen , Misic Bratislav , Valk Sofie L. 
Published: August 2022

AbstractThe relationship between brain areas based on neurotransmitter receptor and transporter molecule expression patterns may provide a link between brain structure and its function. Here, we studied the organization of the receptome, a measure of regional neurotransmitter receptor/transporter molecule (NTRM) similarity, derived from in vivo PET imaging studies of 19 different receptors and transporters. Nonlinear dimensionality reduction revealed three main spatial gradients of receptor similarity in the cortex. The first gradient differentiated the somato-motor network from the remaining cortex. The second gradient spanned between temporo-occipital and frontal anchors, differentiating visual and limbic networks from attention and control networks, and the third receptome gradient was anchored between the occipital and temporal cortices. In subcortical structures, the receptome delineated a striato-thalamic axis, separating functional communities. Moreover, we observed similar organizational principles underlying receptome differentiation in cortex and subcortex, indicating a link between subcortical and cortical NTRM patterning. Overall, we found that the cortical receptome shared key organizational traits with brain structure and function. Node-level correspondence of receptor similarity to functional, microstructural, and diffusion MRI-based measures decreased along a primary-to-transmodal gradient. Compared to primary and paralimbic regions, we observed higher receptomic diversification in unimodal and heteromodal regions, possibly supporting functional flexibility. In sum, we show how receptor similarity may form an additional organizational layer of human brain architecture, bridging brain structure and function.
A stress-responsive p38 signaling axis in choanoflagellates
Authors: Rutaganira Florentine U.N. , Coyle Maxwell C. , Scopton Alex P. , Dar Arvin C. , King Nicole 
Published: August 2022

AbstractAnimal kinases regulate cellular responses to environmental stimuli, including cell differentiation, migration, survival, and response to stress, but the ancestry of these functions is poorly understood. Choanoflagellates, the closest living relatives of animals, encode homologs of diverse animal kinases and have emerged as model organisms for reconstructing animal origins. However, efforts to study kinase signaling in choanoflagellates have been constrained by the limitations of currently available genetic tools. Here we demonstrate that small molecule approaches provide a complementary and scalable approach for studying kinase function in choanoflagellates. To study the physiological roles of choanoflagellate kinases, we established two high-throughput platforms to screen the model choanoflagellateSalpingoeca rosettawith a curated library of human kinase inhibitors. We identified 95 diverse kinase inhibitors that disruptS. rosettacell proliferation. By exploring structure-activity relationships of one inhibitor, sorafenib, we identified a p38 kinase as a regulator of heat and oxidative stress inS. rosetta. This finding indicates a conserved p38 function between choanoflagellates, animals, and fungi. Moreover, this study demonstrates that existing kinase inhibitors can serve as powerful tools to examine the ancestral roles of kinases that regulate modern animal development.
Unraveling the genetic architecture of the adaptive potential of Arabidopsis thaliana to face the bacterial pathogen Pseudomonas syringae in the context of global change
Authors: Bartoli Claudia , Rigal Mylène , Mayjonade Baptiste , Roux Fabrice 
Published: August 2022

ABSTRACTPhytopathogens are a continuous threat for global food production and security. Emergence or re-emergence of plant pathogens is highly dependent on the environmental conditions affecting pathogen spread and survival. Under climate change, a geographic expansion of pathogen distribution poleward has been observed, potentially resulting in disease outbreaks on crops and wild plants. Therefore, estimating the adaptive potential of plants to novel epidemics and describing its underlying genetic architecture, is a primary need to propose agricultural management strategies reducing pathogen outbreaks and to breed novel plant cultivars adapted to pathogens that might spread in novel habitats under climate change. To address this challenge, we inoculated Pseudomonas syringae strains isolated from Arabidopsis thaliana populations located in south-west of France on the highly genetically polymorphic TOU-A A. thaliana population located east-central France. While no adaptive potential was identified in response to most P. syringae strains, the TOU-A population displays a variable disease response to the P. syringae strain JACO-CL belonging to the phylogroup 7 (PG7). This strain carried a reduced T3SS characteristic of the PG7 as well as flexible genomic traits and potential novel effectors. GWA mapping on 192 TOU-A accessions inoculated with JACO-CL revealed a polygenic architecture. The main QTL region encompasses two R genes and the AT5G18310 gene encoding for ubiquitin hydrolase, a target of the AvrRpt2 P. syringae effector. Altogether, our results pave the way for a better understanding of the genetic and molecular basis of the adaptive potential in an ecologically relevant A. thaliana – P. syringae pathosystem.