bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presence of ventriculoperitoneal and lumbar shunts stimulate long lasting non-inflammatory changes in the cerebrospinal fluid distinct from the response to bacterial infection
Authors: Cuff Simone M. , Merola Joseph P. , Eberl Matthias , Gray William P. 
Published: October 2022

AbstractVentriculoperitoneal (VP) shunts are effective at relieving hydrocephalus but are prone to malfunction. There are two hypotheses as to how shunts may malfunction independently of mechanical failure or blockage by debris from initial placement. The first is that the presence of a foreign object results in cells migrating into and colonising the shunt. The second is that the shunts contain either small numbers of live bacteria or residual bacterial products from manufacture or handling, triggering an inflammatory response that attracts cells to the site which go on to cause malfunctions. The presence of bacteria can be difficult to definitively rule in or out, given that they are capable of forming biofilms which poses challenges for isolation and microbiological culture. In this study, we measured 91 soluble immunological molecules and 91 soluble neurological molecules in CSF of patients with VP shunts and compared them to both patients without shunts and those with bacterial infection to determine whether there is an ongoing inflammatory response to shunting. We find that shunts elicit a soluble signature of neural wound healing and cell migration proteins that is distinct from the inflammatory signature of patients with neurological infection. This appears to represent a long-term response, persisting for at least 5 years in one patient.
Personalized Mood Prediction from Patterns of Behavior Collected with Smartphones
Authors: Balliu Brunilda , Douglas Chris , Seok Darsol , Shenhav Liat , Wu Yue , Chatzopoulou Doxa , Kaiser William , Chen Victor , Kim Jennifer , Deverasetty Sandeep , Arnaudova Inna , Gibbons Robert , Congdon Eliza , Craske Michelle G. , Freimer Nelson , Halperin Eran , Sankararaman Sriram , Flint Jonathan 
Published: October 2022

AbstractOver the last ten years, there has been considerable progress in using digital behavioral phenotypes, captured passively and continuously from smartphones and wearable devices, to infer depressive mood. However, most digital phenotype studies suffer from poor replicability, often fail to detect clinically relevant events, and use measures of depression that are not validated or suitable for collecting large and longitudinal data. Here, we report high-quality longitudinal validated assessments of depressive mood from computerized adaptive testing paired with continuous digital assessments of behavior from smartphone sensors for up to 40 weeks on 183 individuals experiencing mild to severe symptoms of depression. We apply a combination of cubic spline interpolation and idiographic models to generate individualized predictions of future mood from the digital behavioral phenotypes, achieving high prediction accuracy of depression severity up to three weeks in advance (R2:2 80%) and a 65.7% reduction in the prediction error over a baseline model which predicts future mood based on past depression severity alone. Finally, our study verified the feasibility of obtaining high-quality longitudinal assessments of mood from a clinical population and predicting symptom severity weeks in advance using passively collected digital behavioral data. Our results indicate the possibility of expanding the repertoire of patient-specific behavioral measures to enable future psychiatric research.
Spleen stiffness can predict liver decompensation and survival in patients with cirrhosis
Authors: Karagiannakis Dimitrios S , Voulgaris Theodoros , Markakis George , Lakiotaki Dimitra , Michailidou Elisavet , Cholongitas Evangelos , Papatheodoridis George 
Published: October 2022

AbstractBackground/AimLiver stiffness measurement (LSM) has been predicting liver decompensation and survival in cirrhotics. The aim of our study was to investigate if spleen stiffness measurement (SSM) by 2D-Shear Wave Elastography could predict better the probability of decompensation and mortality, compared to LSM and other parameters.MethodsConsecutive cirrhotic patients were recruited between 1/2017-12/2021. LSM and SSM were performed at baseline and epidemiological, clinical and laboratory data were collected. Clinical events were recorded every 3 months.ResultsTotally, 177 patients were followed for a mean period of 31±18 months. In Cox regression analysis, only SSM was independently associated with the probability of decompensation (HR: 1.063, 95% CI: 1.009-1.120; p=0.021), offering an AUROC of 0.710 (p=0.003) for predicting 1-year liver decompensation (NPV: 81.1% for the cut-off point of 37 kPa). The occurrence of death/liver transplantation was independently associated only with higher SSM (HR: 1.043; 95% CI:1.003-1.084; p=0.034). The AUROC of SSM for predicting 1-year death/liver transplantation was 0.72 (p=0.006), (NPV: 95% for the cut-off of 38.8 kPa). The performance of SSM to predict the 1-year death/liver transplantation increased in high-risk patients (CTP: B/C plus MELD >10 plus LSM >20 kPa) giving an AUROC of 0.80 (p<0.001). Only 1/26 high-risk patients with SSM <38.8 kPa died during the first year of follow-up (NPV: 96.4%).ConclusionsSSM was the only factor independently associated with the probability of decompensation and occurrence of death, showing better diagnostic accuracy for the prediction of 1-year decompensation or death compared to LSM and MELD score.
Use of artificial intelligence on retinal images to accurately predict the risk of cardiovascular event (CVD-AI)
Authors: Vaghefi Ehsan , Squirrell David , Yang Song , An Songyang , Marshall John 
Published: October 2022

AbstractPurposeTo create and evaluate the accuracy of an artificial intelligence platform capable of using only retinal fundus images to predict both an individual’s overall 10 year Cardiovascular Disease (CVD) risk and the relative contribution of the component risk factors that comprise this risk (CVD-AI).MethodsThe UK Biobank and the US-based AREDS 1 datasets were obtained and used for this study. The UK Biobank data was used for training, validation and testing, while the AREDS 1 dataset was used as an external testing dataset. Overall, we used 110,272 fundus images from 55,118 patient visits. A series of models were trained to predict the risk of CVD against available labels in the UK Biobank dataset.ResultsIn both the UK Biobank testing dataset and the external validation dataset (AREDS 1), the 10-year CV risk scores generated by CVD-AI were significantly higher for patients who had suffered an actual CVD event when compared to patients who did not experience a CVD event. In the UK Biobank dataset the median 10-year CVD risk for those individuals who experienced a CVD was higher than those who did not (4.9% [ICR 2.9-8%] v 2.3% [IQR 4.3-1.3%] P<0.01.]. Similar results were observed in the AREDS 1 dataset The median 10-year CVD risk for those individuals who experienced a CVD event was higher than those who did not (6.2% [ICR 3.2%-12.9%] v 2.2% [IQR 3.9-1.3%] P<0.01ConclusionRetinal photography is inexpensive and as fully automated, inexpensive camera systems are now widely available, minimal training is required to acquire them. As such, AI enabled retinal image-based CVD risk algorithms like CVD-AI will make cardiovascular health screening more affordable and accessible. CVD-AI’s unique ability to assess the relative contribution of the components that comprise an individual’s overall risk could inform personalized treatment decisions based on the specific needs of an individual, thereby increasing the likelihood of positive health outcomes.
Essential role of the amino-terminal region of Drosha for the Microprocessor function
Authors: Prabhakar Amit , Hu Song , Tang Jin , Ghatpande Prajakta , Lagna Giorgio , Jiang Xuan , Hata Akiko 
Published: October 2022

SummaryThe ribonuclease (RNase) III enzyme Drosha enables processing of microRNA (miRNA) primary transcripts (pri-miRNAs) and control of ribosomal protein (RP) biogenesis by the Microprocessor. The extensively studied carboxyl-terminal half of Drosha is sufficient to crop pri-miRNAs in vitro, but the function of the evolutionarily conserved Drosha amino-terminal region (NTR) is unknown, despite it harboring mutations linked to a hereditary vascular disorder. Here, we provide evidence that, when replacing the endogenous Drosha, a mutant missing the NTR (ΔN-Drosha) fails to associate with endogenous pri-miRNAs and to support the expression of all miRNAs, except the miR-183 cluster. Surprisingly, Argonaute2 (Ago2) associates with and cleaves pri-miR-183 in ΔN-Drosha cells and in Drosha-depleted cells. ΔN-Drosha is also unable to inhibit RP biogenesis upon serum starvation. Thus, Drosha NTR is essential for pri-miRNA processing and RP biogenesis in vivo, and Ago2 can process the miR-183 cluster in the absence of Drosha.
Alterations in platelet proteome signature and impaired platelet integrin αIIbβ3activation in patients with COVID-19
Authors: Goudswaard Lucy J. , Williams Christopher M. , Khalil Jawad , Burley Kate L. , Hamilton Fergus , Arnold David , Milne Alice , Lewis Phil A. , Heesom Kate J. , Mundell Stuart J. , Davidson Andrew D. , Poole Alastair W. , Hers Ingeborg 
Published: October 2022

AbstractBackgroundPatients with coronavirus disease-19 (COVID-19) are at increased risk of thrombosis, which is associated with altered platelet function and coagulopathy, contributing to excess mortality.ObjectivesWe aimed to characterise the mechanism of altered platelet function in COVID-19 patients.MethodsThe platelet proteome, platelet functional responses and platelet-neutrophil aggregates were compared between patients hospitalised with COVID-19 and healthy control subjects using Tandem Mass Tag (TMT) proteomic analysis, Western blotting and flow cytometry.ResultsCOVID-19 patients showed a different profile of platelet protein expression (858 altered out of 5773 quantified). Levels of COVID-19 plasma markers were enhanced in COVID-19 platelets. Gene ontology (GO) pathway analysis demonstrated that levels of granule secretory proteins were raised, whereas some platelet activation proteins, such as the thrombopoietin receptor and PKCα, were lowered. Basally, COVID-19 platelets showed enhanced phosphatidylserine (PS) exposure, with unaltered integrin αIIbβ3activation and P-selectin expression. Agonist-stimulated integrin αIIbβ3activation and PS exposure, but not P-selectin expression, were significantly decreased in COVID-19 patients. COVID-19 patients had high levels of platelet-neutrophil aggregates, even under basal conditions, compared to controls. This interaction was disrupted by blocking P-selectin, demonstrating that platelet P-selectin is critical for the interaction.ConclusionsOverall, our data suggests the presence of two platelet populations in patients with COVID-19: one with circulating platelets with an altered proteome and reduced functional responses and another with P-selectin expressing neutrophil-associated platelets. Platelet driven thromboinflammation may therefore be one of the key factors enhancing the risk of thrombosis in COVID-19 patients.Essentials-COVID-19 patient platelet function and platelet proteins were compared with healthy controls-Proteomic analysis of platelets indicated that COVID-19 decreased platelet activation proteins-Agonist induced PS exposure and integrin αIIbβ3activation were impaired in COVID-19-COVID-19 led to maximal levels of P-selectin dependent platelet-neutrophil aggregates
Restoration of functional PAX6 in aniridia patient iPSC-derived ocular tissue models using repurposed nonsense suppression drugs
Authors: Lima Cunha Dulce , Eintracht Jonathan , Harding Philippa , Zhou Jo Huiqing , Moosajee Mariya 
Published: October 2022

AbstractAniridia is a rare, pan-ocular disease causing severe sight loss, with only symptomatic intervention offered to patients. Approximately 40% of aniridia patients present with heterozygous nonsense variants inPAX6, resulting in haploinsufficiency. Translational readthrough inducing compounds (TRIDs) have the ability to weaken the recognition of in-frame premature stop codons (PTCs), permitting full-length protein to be translated. We have established induced pluripotent stem cell (iPSC)-derived 3D optic cups and 2D limbal epithelial stem cell (LESC) models from an aniridia patient with a prevalentPAX6nonsense mutation. Bothin vitromodels show reduced PAX6 protein levels, mimicking the disease. Repurposed TRIDs amlexanox and 2,6-diaminopurine (DAP), and positive control compounds ataluren and G418 were tested for their efficiency. Amlexanox was identified as the most promising TRID, increasing full-length PAX6 levels in both models, and rescuing the disease phenotype through normalization of VSX2 and cell proliferation in the optic cups and reduction of ABCG2 protein andSOX10expression in LESC. This study highlights the significance of patient iPSC-derived cells as a new model system for aniridia and proposes amlexanox as a new putative treatment for nonsense-mediated aniridia.
Genetic analysis of a phenotypic loss in the mechanosensory entrainment of a circalunar clock
Authors: Briševac Dušica , Prakash Celine , Kaiser Tobias S. 
Published: October 2022

ABSTRACTGenetic variants underlying traits that become either non-adaptive or selectively neutral are expected to have altered evolutionary trajectories. Uncovering genetic signatures associated with phenotypic loss presents the opportunity to discover the molecular basis for the phenotype in populations where it persists. Here we study circalunar clocks in populations of marine midgeClunio marinus. The circalunar clock synchronizes development to the lunar phase, and it is set by moonlight and tidal cycles of mechanical agitation. Two out of ten studied populations have lost their sensitivity to mechanical agitation while preserving sensitivity to moonlight. Intriguingly, the F1 offspring of the two insensitive populations regained the sensitivity to mechanical entrainment, implying a genetically independent loss of the phenotype. By combining quantitative trait locus mapping and genome-wide screens, we explored the genetics of this phenotypic loss. QTL analysis suggested an oligogenic origin with one prevalent additive locus in one of the strains. In addition, it confirmed a distinct genetic architecture in the two insensitive populations. Genomic screens further uncovered several candidate genes underlying QTL regions. The strongest signal under the most prominent QTL contains a duplicatedSTAT1gene, which has a well-established role in development, andCG022363, an ortholog of theDrosophila melanogaster CG32100gene, which plays a role in gravitaxis. Our results support the notion that adaptive phenotypes have a complex genetic basis with mutations occurring at several loci. By dissecting the most prevalent signals, we started to reveal the molecular machinery responsible for the entrainment of the circalunar clock.
MR1-restricted T cell clonotypes are associated with ‘resistance’ toM.tuberculosisinfection
Authors: Cross Deborah L. , Layton Erik D. , Yu Krystle K.Q. , Smith Malisa T. , Aguilar Melissa S. , Li Shamin , Mayanja-Kizza Harriet , Stein Catherine M. , Boom W. Henry , Hawn Thomas R. , Bradley Philip , Newell Evan , Seshadri Chetan 
Published: October 2022

ABSTRACTT cells are required for a protective immune response against the human adapted pathogenMycobacterium tuberculosis(M.tb). We recently described a cohort of Ugandan household contacts of tuberculosis cases that appear to ‘resist’ M.tb infection (RSTRs) and showed that these individuals harbor IFN-γ independent T cell responses to M.tb-specific peptide antigens. However, T cells also recognize non-protein antigens via antigen presenting systems that are independent of genetic background, leading to their designation as donor-unrestricted T (DURT) cells. We used combinatorial tetramer staining and multi-parameter flow cytometry to comprehensively characterize the association between DURTs and ‘resistance’ to M.tb infection. We did not observe a difference in peripheral blood frequencies of invariant natural killer T (iNKT) cells, germline encoded mycolyl-reactive (GEM) T cells, or γδ T cells between RSTRs and matched controls with latent M.tb infection (LTBIs). However, we did observe a 1.65-fold increase in frequency of circulating MR1-restricted T (MR1T) cells among RSTRs in comparison with LTBI (p=0.03). Multi-modal single cell RNA-sequencing of 18,251 MR1T cells sorted from a subset of donors revealed 5150 clonotypes that expressed a common transcriptional program, the majority of which were private. Deep sequencing of the TCR-α repertoire revealed several DURT clonotypes that were expanded among RSTRs, including at least two MR1T clonotypes. Taken together, our data reveal unexpected donor-specific diversity in the TCR repertoire of human MR1T cells as well as associations between MR1 clonotypes and ‘resistance’ to M.tb infection.
PAR-4/LKB1 regulates intestinal cell number by restricting endoderm specification to the E lineage
Authors: Demouchy Flora , Nicolle Ophélie , Michaux Grégoire , Pacquelet Anne 
Published: October 2022

AbstractThe master kinase PAR-4/LKB1 appears as a major regulator of intestinal physiology. It is in particular mutated in the Peutz-Jeghers syndrome, an inherited disorder in which patients develop benign intestine polyps. Moreover, ectopic activation of PAR-4/LKB1 is sufficient to induce the polarized accumulation of apical and basolateral surface proteins and the formation of apical microvilli-like structures in intestinal epithelial cancer cell lines. InC. elegans, PAR-4 was shown to be required for the differentiation of intestinal cells. Here, we further examine the role of PAR-4 during intestinal development. We find that it is not required for the establishment of enterocyte polarity and plays only a minor role in brush border formation. By contrast,par-4mutants display severe deformations of the intestinal lumen as well as supernumerary intestinal cells, thereby revealing a novel function of PAR-4 in preventing intestinal hyperplasia. Importantly, we find that the ability of PAR-4 to control intestinal cell number does not involve the regulation of cell proliferation but is rather due to its ability to restrict the expression of intestinal cell fate factors to the E blastomere lineage. We therefore propose that PAR-4 is required to regulateC. elegansintestine specification.
Structural journey of an insecticidal pore-forming protein targeting western corn rootworm
Authors: Marini G. , Poland B. , Leininger C. , Lukoyanova N. , Spielbauer D. , Barry J. , Altier D. , Lum A. , Scolaro E. , Pérez Ortega C. , Yalpani N. , Sandahl G. , Mabry T. , Klever J. , Nowatzki T. , Zhao J-Z. , Sethi A. , Kassa A. , Crane V. , Lu A. , Nelson M.E. , Eswar N. , Topf M. , Saibil H.R. 
Published: October 2022

AbstractBroad adoption of transgenic crops has revolutionized agriculture. However, resistance to insecticidal proteins by agricultural pests poses a continuous challenge to maintaining crop productivity and new proteins are urgently needed to replace existing transgenic traits. We identified an insecticidal membrane attack complex/perforin (MACPF) protein, Mpf2Ba1, with strong activity against western corn rootworm larvae and a novel site of action. By integrating X-ray crystallography, cryo-EM, and modelling, we determined monomeric, pre-pore and pore structures, revealing changes between structural states at atomic resolution. We discovered a monomer inhibition mechanism, a molecular “switch” associated with pre-pore activation/oligomerization upon gut fluid incubation and solved the highest resolution MACPF pore structure to-date. Our findings provide a mechanistic basis for Mpf2Ba1 effectiveness as an insecticidal protein with potential for biotechnology development.One-Sentence SummaryThe molecular mechanism of an insecticidal protein is revealed through 3D structures of the three main pore formation states
Model-driven approach for the production of butyrate from CO2/H2by a novel co-culture ofC. autoethanogenumandC. beijerinckii
Authors: Benito-Vaquerizo Sara , Nouse Niels , Schaap Peter J. , Hugenholtz Jeroen , Brul Stanley , Lopez-Contreras Ana , Martins dos Santos Vitor A. P. , Suarez-Diez Maria 
Published: October 2022

ABSTRACTOne-carbon (C1) compounds are promising feedstocks for sustainable production of commodity chemicals. CO2is a particularly advantageous C1-feedstock since it is an unwanted industrial off-gas that can be converted to valuable products while reducing its atmospheric levels. Acetogens are known microorganisms that can grow on CO2/H2and syngas converting these substrates into ethanol and acetate. Co-cultivation of acetogens with microbes that can further process such products can expand the variety of products to, for example, medium chain fatty acids (MCFA) and longer chain alcohols. Solventogens are microorganisms known to produce MCFA and alcohols via the acetone, butanol and ethanol (ABE) fermentation in which acetate is a key metabolite. Thus, co-cultivation of a solventogen and acetogen in a consortium provides a potential platform to produce valuable chemicals from CO2.In this study, metabolic modelling was implemented to design a new co-culture of an acetogen and a solventogen to produce butyrate from CO2/H2mixtures. The model-driven approach suggested the ability of the studied solventogenic species to grow on lactate/glycerol with acetate as co-substrate. This ability was confirmed experimentally by cultivation ofClostridium beijerinckiion these substrates in serum bottles and subsequently in pH-controlled bioreactors.Community modelling also suggested that a novel microbial consortium consisting of the acetogenClostridium autoethanogenum,and the solventogenC. beijerinckiiwould be feasible and stable. On the basis of this prediction, a co-culture was experimentally established.C. autoethanogenumgrew on CO2/H2producing acetate and traces of ethanol. Acetate was in turn, consumed byC. beijerinckiitogether with lactate, producing butyrate. These results show that community modelling of metabolism is a valuable tool to guide the design of microbial consortia for the tailored production of chemicals from renewable resources.
AtSWEET13 transporter discriminates sugars by selective facial and positional substrate recognition
Authors: Weigle Austin T. , Shukla Diwakar 
Published: October 2022

ABSTRACTTransporters are targeted by endogenous metabolites and exogenous molecules to reach cellular destinations, but it is generally not understood how different substrate classes exploit the same transporter’s mechanism. Any disclosure of plasticity in transporter mechanism when treated with different substrates becomes critical for developing general selectivity principles in membrane transport catalysis. Using extensive molecular dynamics simulations with an enhanced sampling approach, we select theArabidopsissugar transporter AtSWEET13 as a model system to identify the basis for glucose versus sucrose molecular recognition and transport. We find that AtSWEET13 chemical selectivity originates from a conserved substrate facial selectivity demonstrated when committing alternate access, despite mono-/di-saccharides experiencing differing degrees of conformational and positional freedom throughout other stages of transport. In summary, our results point to a potentially generalizable finding that selectivity in transporters emerges from molecular recognition events occurring within regions distal from any conserved (non)functional binding sites.