bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computed cancer interactome explains the effects of somatic mutations in cancers
Authors: Zhang Jing , Pei Jimin , Durham Jesse , Bos Tasia , Cong Qian 
Published: January 2022

AbstractProtein-protein interactions (PPIs) are involved in almost all essential cellular processes. Perturbation of PPI networks plays critical roles in tumorigenesis, cancer progression and metastasis. While numerous high-throughput experiments have produced a vast amount of data for PPIs, these datasets suffer from high false positive rates and exhibit a high degree of discrepancy. Coevolution of amino acid positions between protein pairs has proven to be useful in identifying interacting proteins and providing structural details of the interaction interfaces with the help of deep learning methods like AlphaFold (AF). In this study, we applied AF to investigate the cancer protein-protein interactome. We predicted 1,798 PPIs for cancer driver proteins involved in diverse cellular processes such as transcription regulation, signal transduction, DNA repair and cell cycle. We modeled the spatial structure for the predicted binary protein complexes, 1,087 of which lacked previous 3D structure information. Our predictions offer novel structural insight into many cancer-related processes such as the MAP kinase cascade and Fanconi anemia pathway. We further investigated the cancer mutation landscape by mapping somatic missense mutations (SMMs) in cancer to the predicted PPI interfaces and performing enrichment and depletion analyses. Interfaces enriched or depleted with SMMs exhibit different preferences for functional categories. Interfaces enriched in mutations tend to function in pathways that are deregulated in cancers and they may help explain the molecular mechanisms of cancers in patients; interfaces lacking mutations appear to be essential for the survival of cancer cells and thus may be future targets for PPI modulating drugs.
Bacteria-mediated stabilization of murine norovirus
Authors: Budicini Melissa R. , Pfeiffer Julie K. 
Published: January 2022

AbstractEnteric viruses encounter various bacteria in the host which can impact infection outcomes. The interactions between noroviruses and enteric bacteria are not well understood. Previous work determined that murine norovirus (MNV), a model norovirus, had decreased replication in antibiotic-treated mice compared with conventional mice. Although this suggests that microbiota promote MNV infection, the mechanisms are not completely understood. Additionally, prior work with other enteric viruses such as poliovirus and coxsackievirus B3 demonstrated that virions bind bacteria, and exposure to bacteria stabilizes viral particles and limits premature RNA release. Therefore, we examined interactions between MNV and specific bacteria and the consequences of these interactions. We found that the majority of Gram-positive bacteria tested stabilized MNV, while Gram-negative bacteria did not stabilize MNV. Both Gram-positive and Gram-negative bacteria bound to MNV. However, bacterial binding alone was not sufficient for virion stabilization since Gram-negative bacteria bound MNV but did not stabilize virions. Additionally, we found that bacterial conditioned media also stabilized MNV and this stabilization may be due to a small heat stable molecule. Overall this work identifies specific bacteria and bacterial components that stabilize MNV and may impact virion stability in the environment.ImportanceEnteric viruses are exposed to a wide variety of bacteria in the intestine, but effects of bacteria on viral particles are incompletely understood. We found that murine norovirus (MNV) virion stability is enhanced in the presence of several Gram-positive bacterial strains. Virion stabilizing activity was also present in bacterial culture medium, and activity was retained upon heat or protease treatment. These results suggest that certain bacteria and bacterial products may promote MNV stability in the environment, which could influence viral transmission.
A characteristic cerebellar biosignature for bipolar disorder, identified with fully automatic machine learning
Authors: Thomaidis Georgios V. , Papadimitriou Konstantinos , Michos Sotirios , Chartampilas Evangelos , Tsamardinos Ioannis 
Published: January 2022

AbstractBackroundTranscriptomic profile differences between patients with bipolar disorder and healthy controls can be identified using machine learning and can provide information about the potential role of the cerebellum in the pathogenesis of bipolar disorder.With this aim, user-friendly, fully automated machine learning algorithms can achieve extremely high classification scores and disease-related predictive biosignature identification, in short time frames and scaled down to small datasets.MethodA fully automated machine learning platform, based on the most suitable algorithm selection and relevant set of hyper-parameter values, was applied on a preprocessed transcriptomics dataset, in order to produce a model for biosignature selection and to classify subjects into groups of patients and controls. The parent GEO datasets were originally produced from the cerebellar and parietal lobe tissue of deceased bipolar patients and healthy controls, using Affymetrix Human Gene 1.0 ST Array.ResultsPatients and controls were classified into two separate groups, with no close-to-the-boundary cases, and this classification was based on the cerebellar transcriptomic biosignature of 25 features (genes), with Area Under Curve 0.929 and Average Precision 0.955. Using 6 of the characteristic features (genes) discovered during the selection process, 99,6% of predictive performance was achieved. The 3 genes contributing most to the predictive power of the model (92,7% predictive performance) are also deregulated in temporal lobe epilepsy. KEGG analysis revealed participation of 4 identified features in 6 pathways which have been associated with bipolar disorder.Conclusion93% Area Under Curve, 96% Average Precision, and complete separation between unaffected controls and patients with bipolar disorder, were achieved in ∼2 hours. The cerebellar transcriptomic biosignature suggests a potential genetic overlap with temporal lobe epilepsy and new genetic contributions to the pathogenesis of bipolar disorder.
Expert Surgeons and Deep Learning Models Can Predict the Outcome of Surgical Hemorrhage from One Minute of Video
Authors: Pangal Dhiraj J , Kugener Guillaume , Zhu Yichao , Sinha Aditya , Unadkat Vyom , Cote David J , Strickland Ben , Rutkowski Martin , Hung Andrew , Anandkumar Animashree , Han X.Y. , Papyan Vardan , Wrobel Bozena , Zada Gabriel , Donoho Daniel A 
Published: January 2022

AbstractBackgroundMajor vascular injury resulting in uncontrolled bleeding is a catastrophic and often fatal complication of minimally invasive surgery. At the outset of these events, surgeons do not know how much blood will be lost or whether they will successfully control the hemorrhage (achieve hemostasis). We evaluate the ability of a deep learning neural network (DNN) to predict hemostasis control ability using the first minute of surgical video and compare model performance with human experts viewing the same video.MethodsThe publicly available SOCAL dataset contains 147 videos of attending and resident surgeons managing hemorrhage in a validated, high-fidelity cadaveric simulator. Videos are labeled with outcome and blood loss (mL). The first minute of 20 videos was shown to four, blinded, fellowship trained skull-base neurosurgery instructors, and to SOCALNet (a DNN trained on SOCAL videos). SOCALNet architecture included a convolutional network (ResNet) identifying spatial features and a recurrent network identifying temporal features (LSTM). Experts independently assessed surgeon skill, predicted outcome and blood loss (mL). Outcome and blood loss predictions were compared with SOCALNet.ResultsExpert inter-rater reliability was 0.95. Experts correctly predicted 14/20 trials (Sensitivity: 82%, Specificity: 55%, Positive Predictive Value (PPV): 69%, Negative Predictive Value (NPV): 71%). SOCALNet correctly predicted 17/20 trials (Sensitivity 100%, Specificity 66%, PPV 79%, NPV 100%) and correctly identified all successful attempts.Expert predictions of the highest and lowest skill surgeons and expert predictions reported with maximum confidence were more accurate. Experts systematically underestimated blood loss (mean error −131 mL, RMSE 350 mL, R20.70) and fewer than half of expert predictions identified blood loss > 500mL (47.5%, 19/40). SOCALNet had superior performance (mean error −57 mL, RMSE 295mL, R20.74) and detected most episodes of blood loss > 500mL (80%, 8/10).In validation experiments, SOCALNet evaluation of a critical on-screen surgical maneuver and high/low-skill composite videos were concordant with expert evaluation.ConclusionUsing only the first minute of video, experts and SOCALNet can predict outcome and blood loss during surgical hemorrhage. Experts systematically underestimated blood loss, and SOCALNet had no false negatives. DNNs can provide accurate, meaningful assessments of surgical video. We call for the creation of datasets of surgical adverse events for quality improvement research.
Impact of accelerating booster vaccination amidst Omicron surge in the United States
Authors: Sah Pratha , Vilches Thomas N , Moghadas Seyed M. , Fitzpatrick Meagan C. , Schneider Eric C , Galvani Alison P. 
Published: January 2022

AbstractCOVID-19 infections driven by the Omicron variant are sweeping across the United States. Although early evidence suggests that the Omicron variant may cause less severe disease than previous variants, the explosive spread of infections threatens to drive hospitalizations and deaths to unprecedented high levels, swamping already overburdened hospitals. Booster vaccination appears to be effective at preventing severe illness and hospitalization. However, the pace of booster vaccination in the US has been slow despite the available infrastructure to administer doses at a much higher rate.We used an age-stratified, multi-variant agent-based model to project the reduction in COVID-related deaths and hospitalizations that could be achieved by accelerating the current daily pace of booster vaccination in the US. We found that doubling the rate of booster vaccination would prevent over 400,000 hospitalizations and 48,000 deaths. Tripling the booster vaccination rate would avert over 600,000 hospitalizations and save 70,000 lives during the first four months of 2022.
The positive dimension of schizotypy is associated with a reduced attenuation and precision of self-generated touch
Authors: Asimakidou Evridiki , Job Xavier , Kilteni Konstantina 
Published: January 2022

AbstractThe brain predicts the sensory consequences of our movements and uses these predictions to attenuate the perception of self-generated sensations. Accordingly, self-generated touch feels weaker than externally generated touch of identical intensity. In schizophrenia, this somatosensory attenuation is substantially reduced, suggesting that patients with positive symptoms fail to accurately predict and process self-generated touch. Here we hypothesized that a similar impairment might exist in healthy nonclinical individuals with high positive schizotypal traits. One hundred healthy participants (53 female) scored for schizotypal traits and underwent a well-established psychophysics force discrimination task to quantify how they perceived self-generated and externally generated touch. The perceived intensity of tactile stimuli delivered to their left index finger (magnitude) and the ability to discriminate the stimuli (precision) were measured. We observed that higher positive schizotypal traits were associated with reduced somatosensory attenuation and poorer somatosensory precision of self-generated touch. These effects were specific to positive schizotypy and were not observed for the negative or disorganized dimensions of schizotypy. The results suggest that positive schizotypal traits are associated with a reduced ability to predict and process self-generated tactile stimuli. Given that the positive dimension of schizotypy represents the analogue of positive psychotic symptoms of schizophrenia, deficits in processing self-generated tactile information could indicate increased liability to schizophrenia.
Plant longevity, drought and island isolation favoured rampant evolutionary transitions towards insular woodiness
Authors: Zizka Alexander , Onstein Renske E. , Rozzi Roberto , Weigelt Patrick , Kreft Holger , Steinbauer Manuel J. , Bruelheide Helge , Lens Frederic 
Published: January 2022

AbstractInsular woodiness (IW)—the evolutionary transition from herbaceousness towards woodiness on islands—is one of the most iconic features of island floras. Since pioneering work by Darwin and Wallace, five IW drivers have been proposed: (i) favourable aseasonal climate and (ii) lack of large native herbivores promote plant longevity that (iii) results in prolonged flowering favouring outcrossing. Alternatively, (iv) competition for sunlight requires taller and stronger stems, and (v) drought favours woodiness to safeguard root-to-shoot water transport. However, information on the occurrence of IW is fragmented, hampering tests of these potential drivers. Here, we identify 1,097 insular woody species (IWS) on 375 islands, and infer at least 175 evolutionary transitions on 31 archipelagos, concentrated in six angiosperm families. Structural equation models reveal that the IWS richness on oceanic islands correlates with aseasonal favourable climate, followed by increased drought and island isolation (approximating competition). When continental islands are included, reduced herbivory pressure by large native mammals, increased drought and island isolation are most relevant. The repeated evolution of IW opens promising avenues to disentangle the variation in gene regulatory networks triggering wood formation, and emphasize individual archipelagos as laboratories of evolution, where similar environmental conditions replicate convergent evolution of similar traits.
Single-Cell Transcriptomics reveals relaxed evolutionary constraint of spermatogenesis in two passerine birds as compared to mammals
Authors: Segami J. Carolina , Semon Marie , Cunha Catarina , Bergin Claudia , Mugal Carina F , Qvarnström Anna 
Published: January 2022

AbstractSpermatogenesis is a complex process where spermatogonia develop into haploid, mobile sperm cells. The genes guiding this process are subject to an evolutionary trade-off between preserving basic functions of sperm while acquiring new traits ensuring advantages in competition over fertilization of female gametes. In species with XY sex chromosomes, the outcome of this trade-off is found to vary across the stages of spermatogenesis but remains unexplored for species with ZW sex chromosomes. Here we characterize avian spermatogenesis at single cell resolution from testis of collared and pied flycatchers. We find evidence for relaxed evolutionary constraint of genes expressed in spermatocyte cells going through meiosis. An overrepresentation of Z-linked differentially expressed genes between the two species at this stage suggests that this relaxed constraint is associated with the lack of sex-chromosome silencing during meiosis. We conclude that the high throughput of bird spermatogenesis, at least partly, is explained by relaxed developmental constraint.
Alteration of myocardial structure and function in RAF1-associated Noonan syndrome: Insights from cardiac disease modeling based on patient-derived iPSCs
Authors: Nakhaei-Rad Saeideh , Bazgir Farhad , Dahlmann Julia , Busley Alexandra Viktoria , Buchholzer Marcel , Haghighi Fereshteh , Schänzer Anne , Hahn Andreas , Kötter Sebastian , Schanze Denny , Anand Ruchika , Funk Florian , Borchardt Andrea , Kronenbitter Annette Vera , Scheller Jürgen , Piekorz Roland P. , Reichert Andreas S. , Volleth Marianne , Wolf Matthew J. , Cirstea Ion Cristian , Gelb Bruce D. , Tartaglia Marco , Schmitt Joachim , Krüger Martina , Kutschka Ingo , Cyganek Lukas , Zenker Martin , Kensah George , Ahmadian Mohammad R. 
Published: January 2022

AbstractNoonan syndrome (NS), the most common among the RASopathies, is caused by germline variants in genes encoding components of the RAS-MAPK pathway. Distinct variants, including the recurrent Ser257Leu substitution in RAF1, are associated with severe hypertrophic cardiomyopathy (HCM). Here, we investigated the elusive mechanistic link between NS-associated RAF1S257L and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic RAF1 c.770C>T missense change. We characterize the molecular, structural and functional consequences of aberrant RAF1 –associated signaling on the cardiac models. Ultrastructural assessment of the sarcomere revealed a shortening of the I-bands along the Z disc area in both iPSC-derived RAF1S257L cardiomyocytes, and myocardial tissue biopsies. The disease phenotype was partly reverted by using both MEK inhibition, and a gene-corrected isogenic RAF1L257S cell line. Collectively, our findings uncovered a direct link between a RASopathy gene variant and the abnormal sarcomere structure resulting in a cardiac dysfunction that remarkably recapitulates the human disease. These insights represent a basis to develop future targeted therapeutic approaches.
Tracing 3D apoplasmic complexity in vascular tissue of live conifer needles by X-ray computed tomography
Authors: Gao Chen , Marker Sean J. V. , Gundlach Carsten , Poulsen Henning F. , Bohr Tomas , Schulz Alexander 
Published: January 2022

SummaryArchitecture and conducting area of vascular elements along conifer needles are fundamentally different from broad leaves. We hypothesised that the needles’ unique transfusion tissue offers different mechanisms for water allocation and used multimodal imaging to dissect the critical water exchange interfaces in this xerophytic leaf type. Our study examined intact conifer needles with X-ray computed tomography (μXCT) and water-soluble tracers, allowing to render the functional 3D structure of the water-filled apoplast and the complementary symplasmic domain inside the bundle sheath. Segmentation of these data, together with fluorescence and electron microscopy of axial phloem and xylem elements along the needle, enabled quantification of the dimensions of the conducting tissue complex. The transfusion tracheid system between the endodermis-type bundle sheath and the axial venation formed a sponge-like apoplast domain. Transfusion parenchyma cell chains bridged this domain not directly but as tortuous symplasmic pathways between bundle sheath and axial phloem, which is nearly exclusively accessible at flanks. The transfusion tissue extends the plasma membrane surface for phloem loading and provides a large volume space. We discuss that this unique tissue plays an important role in the subtle interplay between water uptake/storage and sugar transport that has evolved to cope with desiccation stress.
Human genetic variations reveal Chromosomal Instability aiding Variants (CIVa) in kinetochore-microtubule associated proteins
Authors: Islam Asifa , Manjarrez-González Janeth Catalina , Gore Trupti , Song Xinhong , Draviam Viji M. 
Published: January 2022

ABSTRACTThe vast majority of Chromosomal Instability (CIN) promoting mutations remain unknown. We assess the prevalence of Chromosomal Instability aiding Variants (CIVa) by collating Loss-of-Function (LoF) variants predicted in 135 chromosome segregation genes from over 150,000 humans, including consanguineous individuals. Surprisingly, we observe heterozygous and homozygous CIVa in Astrin and SKA3 genes that encode evolutionarily conserved microtubule-associated proteins essential for chromosome segregation. By combining high-resolution microscopy and controlled protein expression, we show the naturally occurring Astrin variant, p.Q1012*, as potentially harmful because it fails to localise normally, delays anaphase onset, induces chromosome misalignment and promotes chromosome missegregation. We show that N-terminal frameshift variants in Astrin and SKA3 are likely to generate shorter isoforms that do not compromise chromosome segregation revealing resilient mechanisms to cope with harmful variants. This study provides a framework to predict and stratify naturally occurring CIVa, an important step towards precision medicine for CIN syndromes.
Structure and function of BcpE2, the most promiscuous GH3-family beta-glucosidase for scavenging glucose from heterosides
Authors: Deflandre Benoit , Jadot Cédric , Planckaert Sören , Thiébaut Noémie , Stulanovic Nudzejma , Herman Raphaël , Devreese Bart , Kerff Frédéric , Rigali Sébastien 
Published: January 2022

AbstractCellulose being the most abundant polysaccharide on earth, beta-glucosidases hydrolyzing cello-oligosaccharides are key enzymes to fuel glycolysis in microorganisms developing on plant material. InStreptomyces scabiei, the causative agent of common scab in root and tuber crops, a genetic compensation phenomenon safeguards the loss of the gene encoding the cello-oligosaccharide hydrolase BglC by awakening the expression of alternative beta-glucosidases. Here we reveal that the BglC compensating enzyme BcpE2 is the GH3-family beta-glucosidase that displays the highest reported substrate promiscuity able to release the glucose moiety of all tested types of plant-derived heterosides (aryl β-glucosides, monolignol glucosides, cyanogenic glucosides, anthocyanosides, and coumarin heterosides). BcpE2 structure analysis highlighted a large cavity in the PA14 domain that covers the active site, and the high flexibility of this domain would allow proper adjustment of this cavity for disparate heterosides. The exceptional substrate promiscuity of BcpE2 provides microorganisms a versatile tool for scavenging glucose from plant-derived nutrients that widely vary in size and structure. Importantly, scopolin is the only substrate commonly hydrolyzed by both BglC and BcpE2 thereby generating the potent virulence inhibitor scopoletin. Next to fueling glycolysis, both enzymes thus also interfere with the plant defense mechanisms to fine-tune the strength of virulence.
Novel orthonairovirus in rodents and shrews, Gabon
Authors: Ozeki Takehiro , Abe Haruka , Ushijima Yuri , Nze-Nkogue Chiméne , Akomo-Okoue Etienne F , Ella Ghislain W.E , Koumba Lilian B.M , Nzo Branly C.B.B , Mintsa-Nguema Rodrigue , Makouloutou-Nzassi Patrice , Makanga Boris K , Nguelet Fred L.M , Ondo Georgelin N , Mbadinga Marien J.V.M , Igasaki Yui , Okada Sayaka , Lell Bertrand , Bonney Laura C. , Hewson Roger , Kurosaki Yohei , Yasuda Jiro 
Published: January 2022

AbstractSmall mammals harbor various zoonotic viruses and are natural reservoirs for emerging viruses. Here, we identified a novel orthonairovirus, which is genetically close to the virus suggested the association with human neural diseases. The virus was found in 24.6% of the small mammals captured in Gabon, Central Africa.