bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis of mechano-chemical coupling by the mitotic kinesin KIF14
Authors: Benoit Matthieu P.M.H. , Asenjo Ana B. , Paydar Mohammadjavad , Dhakal Sabin , Kwok Benjamin H. , Sosa Hernando 
Published: June 2020

AbstractKIF14 is a mitotic kinesin protein important for cytokinesis. Its overexpression is associated with a variety of cancers and mutations in KIF14 result in cerebral and renal development defects. Like other kinesins, KIF14 contains a highly conserved catalytic motor domain where the energy from ATP hydrolysis is converted to directed movement along microtubules. Although much is known regarding the molecular mechanism of kinesin motility, there is a lack of structural information of kinesin-microtubule interactions at sufficient resolution to unambiguously assess how conformational changes related to ATP hydrolysis, microtubule binding and translocation are coupled. Here we determined the near-atomic resolution cryo-electron microscopy structures of five different KIF14 constructs bound to microtubules in the presence of different nucleotide analogues mimicking distinct steps of the ATPase cycle. Eighteen independent structures together with supporting functional assays provide a comprehensive view of the kinesin conformational changes occurring with microtubule and nucleotide binding. Our data shows that: 1) microtubule binding induces opening of the KIF14 nucleotide binding pocket; 2) AMP-PNP and ADP-AlFxinduce closure of the nucleotide binding pocket in microtubule bound KIF14 and this conformational change is allosterically controlled by the neck-linker domain; 3) the neck-linker domain when undocked prevents the nucleotide-binding-pocket to fully close and dampens ATP hydrolysis; 4) fifteen neck-linker residues are required to assume the docked conformation; 5) the nucleotide analogue ADP-AlFxadopts a distinct configuration in an open nucleotide-binding-pocket; 6) the neck-linker position controls the hydrolysis step rather than nucleotide binding in the KIF14 ATPase cycle; 7) the two motor domains of a KIF14 dimer adopt distinct conformations when simultaneously bound to the microtubule. These observations provide the structural basis for a coordinated chemo-mechanical kinesin plus end translocation model.
Deep learning classification of lipid droplets in quantitative phase images
Authors: Sheneman L. , Stephanopoulos G. , Vasdekis A. E. 
Published: June 2020

AbstractWe report the application of supervised machine learning to the automated classification of lipid droplets in label-free, quantitative-phase images. By comparing various machine learning methods commonly used in biomedical imaging and remote sensing, we found convolutional neural networks to outperform others, both quantitatively and qualitatively. We describe our imaging approach, all implemented machine learning methods, and their performance with respect to computational efficiency, required training resources, and relative method performance measured across multiple metrics. Overall, our results indicate that quantitative-phase imaging coupled to machine learning enables accurate lipid droplet classification in single living cells. As such, the present paradigm presents an excellent alternative of the more common fluorescent and Raman imaging modalities by enabling label-free, ultra-low phototoxicity, and deeper insight into the thermodynamics of metabolism of single cells.Author SummaryRecently, quantitative-phase imaging (QPI) has demonstrated the ability to elucidate novel parameters of cellular physiology and metabolism without the need for fluorescent staining. Here, we apply label-free, low photo-toxicity QPI to yeast cells in order to identify lipid droplets (LDs), an important organelle with key implications in human health and biofuel development. Because QPI yields low specificity, we explore the use of modern machine learning methods to rapidly identify intracellular LDs with high discriminatory power and accuracy. In recent years, machine learning has demonstrated exceptional abilities to recognize and segment objects in biomedical imaging, remote sensing, and other areas. Trained machine learning classifiers can be combined with QPI within high-throughput analysis pipelines, allowing for efficient and accurate identification and quantification of cellular components. Non-invasive, accurate and high-throughput classification of these organelles will accelerate research and improve our understanding of cellular functions with beneficial applications in biofuels, biomedicine, and more.
A septin GTPase scaffold of dynein-dynactin motors triggers retrograde lysosome transport
Authors: Kesisova Ilona A. , Robinson Benjamin P. , Spiliotis Elias T. 
Published: June 2020

AbstractThe metabolic and signaling functions of lysosomes depend on their intracellular positioning and trafficking, but the underlying mechanisms are little understood. Here, we have discovered a novel septin GTPase-based mechanism for retrograde lysosome transport. We found that septin 9 (SEPT9) associates with lysosomes, promoting the perinuclear localization of lysosomes in a Rab7-independent manner. SEPT9 targeting to mitochondria and peroxisomes is sufficient to recruit dynein and cause perinuclear clustering. We show that SEPT9 interacts with both dynein and dynactin through its GTPase domain and N-terminal extension, respectively. Strikingly, SEPT9 associates preferentially with the dynein intermediate chain (DIC) in its GDP-bound state, which favors dimerization and assembly into septin multimers. In response to oxidative cell stress induced by arsenite, SEPT9 localization to lysosomes is enhanced, promoting the perinuclear clustering of lysosomes. We posit that septins function as GDP-activated scaffolds for the cooperative assembly of dynein-dynactin, providing an alternative mechanism of retrograde lysosome transport at steady state and during cellular adaptation to stress.SummaryThe intracellular position of lysosomes is critical for cell metabolism and signaling. Kesisova et al discovered a membrane-associated septin GTPase scaffold of dynein-dynactin that promotes retrograde traffic and perinuclear lysosome clustering at steady state and in response to oxidative stress.
Sex-specific recombination predicts parent of origin for recurrent genomic disorders
Authors: Mosley Trenell , Richard Johnston H. , Cutler David J. , Zwick Michael E. , Mulle Jennifer G. 
Published: June 2020

SUMMARYGenomic disorders are caused by structural rearrangements of the genome that generally occur during meiosis1. Often the rearrangements result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb)2,3. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR)3,4. Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin ofde novoCNVs5–9. However, the mechanism underlying these biases is not well understood. Here we have curated parent of origin data for multiple pathogenic CNV loci and demonstrate a significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci. Our results suggest that parental-origin of CNVs is largely controlled by sex-specific recombination rates and bring into light the need to consider these differences when seeking to determine the factors underlying risk for structural variation.
Test, track, and trace: How is the NHSX Covid app performing in a hospital setting?
Authors: Filer Joshua , Gheorghiu Daniel 
Published: June 2020

AbstractObjectiveTo assess the uptake and use of the trial contact tracing app developed by NHSX by healthcare workers.DesignCross-sectional study using survey questionnaire.SettingHealthcare industry: St Mary’s Hospital, a small NHS district hospital on the Isle of Wight, United Kingdom.ParticipantsNHS staff members employed by the Isle of Wight NHS Trust.ResultsOf 3100 eligible staff members, 462 (~15%) responded to the survey. Of the respondents, 90% were aged between 31 and 65, and half had direct patient contact through their job role. Almost three quarters (73%) used social media apps on their smartphones. 421 out of 460 respondents had no trouble downloading and installing the NHSX Covid app on their smartphones. 20% of respondents were left confused by instructions to turn off Bluetooth when wearing PPE. Only 35 people either had to report symptoms or received an alert of contact with a suspected covid case. Of these over 20% were not clear what to do in such a situation.ConclusionsThe trial app has been embraced and adopted well. Many have experienced no problems with it. However, some healthcare workers have been unable to download or install the app due to compatibility issues and some have been left confused by having to turn off Bluetooth whilst wearing PPE.This raises questions as to the effectiveness of the app for its intended purpose in contact tracing efforts.RecommendationsWe recommend that the wording of alerts and guidance provided by the app be made clearer and more accessible. We also recommend developments to the app to facilitate use by healthcare workers in a clinical setting. We also propose that ‘app instructors’ be made available in hospitals to ensure that patients and staff can access help and advice on use of the app.
It’s the very time to learn a pandemic lesson: why have predictive techniques been ineffective when describing long-term events?
Authors: Kovriguine D. , Nikitenkova S. 
Published: June 2020

AbstractWe have detected a regular component of the monitoring error of officially registered total cases of the spread of the current pandemic. This regular error component explains the reason for the failure of a priori mathematical modelling of probable epidemic events in different countries of the world. Processing statistical data of countries that have reached an epidemic peak has shown that this regular monitoring obeys a simple analytical regularity which allows us to answer the question: is this or that country that has already passed the threshold of the epidemic close to its peak or is still far from it?
The impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bi-directional Mendelian randomization study
Authors: Au Yeung SL , Borges MC , Lawlor DA , Schooling CM 
Published: June 2020

AbstractBackgroundObservational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be susceptible to residual confounding. We conducted a 2 sample Mendelian randomization study using summary statistics from genome wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function.MethodsWe obtained genetic instruments for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from publicly available UK Biobank summary statistics (n = 421,986). We applied these genetic instruments for FEV1 (260) and FVC (320) to publicly available GWAS summary statistics for coronary artery disease (CAD) (n = 184,305), stroke and its subtypes (n = 446,696), atrial fibrillation (n = 1,030,836), and heart failure (n = 977,320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes. Sensitivity analyses included MR-Egger, weighted median, MR-PRESSO, and multivariable Mendelian randomization. We also conducted bi-directional Mendelian randomization to assess whether CVD affects lung function.ResultsFEV1 and FVC were inversely associated with CAD (odds ratio (OR) per standard deviation (SD) increase, 0.72 (95% confidence interval (CI) 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (0.82 to 1.00)), ischemic stroke (0.87 (95%CI 0.77 to 0.99), 0.90 (95%CI 0.80 to 1.00)), small vessel stroke (0.78, (95%CI 0.61 to 1.00), 0.74 (95%CI 0.61 to 0.92)), and large artery stroke (0.69 (95%CI 0.54 to 0.89), 0.72 (95%CI 0.57 to 0.91)). FEV1 and FVC were inversely associated with type 2 diabetes (0.75 (95%CI 0.62 to 0.90), 0.67 (95%CI 0.58 to 0.79)) and systolic blood pressure. Sensitivity analyses produced similar direction for most outcomes although the magnitude sometimes differed. Adjusting for height attenuated results for CAD (e.g. OR for 1SD FEV1 0.95 (0.76 to 1.20), but this may reflect weak instrument bias. This adjustment did not attenuate effects for stroke or type 2 diabetes. No strong evidence was observed for CVD affecting lung function.ConclusionHigher lung function likely protect against CAD and stroke.
Dynamic functional connectivity analysis reveals transiently increased segregation in patients with severe stroke
Authors: Bonkhoff Anna K. , Schirmer Markus D. , Bretzner Martin , Etherton Mark , Donahue Kathleen , Tuozzo Carissa , Nardin Marco , Giese Anne-Katrin , Wu Ona , Calhoun Vince , Grefkes Christian , Rost Natalia S. 
Published: June 2020

AbstractBackground and PurposeTo explore the whole-brain dynamic functional network connectivity patterns in acute ischemic stroke (AIS) patients and their relation to stroke severity in the short and long term.MethodsWe investigated large-scale dynamic functional network connectivity of 41 AIS patients two to five days after symptom onset. Re-occurring dynamic connectivity configurations were obtained using a sliding window approach and k-means clustering. We evaluated differences in dynamic patterns between three NIHSS-stroke severity defined groups (mildly, moderately, and severely affected patients). Furthermore, we established correlation analyses between dynamic connectivity estimates and AIS severity as well as neurological recovery within the first 90 days after stroke (DNIHSS). Finally, we built Bayesian hierarchical models to predict acute ischemic stroke severity and examine the inter-relation of dynamic connectivity and clinical measures, with an emphasis on white matter hyperintensity lesion load.ResultsWe identified three distinct dynamic connectivity configurations in the early post-acute stroke phase. More severely affected patients (NIHSS 10–21) spent significantly more time in a highly segregated dynamic connectivity configuration that was characterized by particularly strong connectivity (three-level ANOVA: p<0.05, post hoc t-tests: p<0.05, FDR-corrected for multiple comparisons). Recovery, as indexed by the realized change of the NIHSS over time, was significantly linked to the acute dynamic connectivity between bilateral intraparietal lobule and left angular gyrus (Pearson’s r = –0.68, p<0.05, FDR-corrected). Increasing dwell times, particularly those in a very segregated connectivity configuration, predicted higher acute stroke severity in our Bayesian modelling framework.ConclusionsOur findings demonstrate transiently increased segregation between multiple functional domains in case of severe AIS. Dynamic connectivity involving default mode network components significantly correlated with recovery in the first three months post-stroke.
Genetic variants of PIEZO1 associate with COVID-19 fatality
Authors: Cheng C.W. , Deivasikamani V. , Ludlow M.J. , De Vecchis D. , Kalli A.C. , Beech D.J. , Sukumar P. 
Published: June 2020

ABSTRACTFatality from coronavirus disease 19 (COVID-19) is a major problem globally and so identification of its underlying molecular mechanisms would be helpful. The combination of COVID-19 clinical data and genome sequence information is providing a potential route to such mechanisms. Here we took a candidate gene approach to UK Biobank data based on the suggested roles of endothelium and membrane proteins in COVID-19. We focussed on the PIEZO1 gene, which encodes a non-selective cation channel that mediates endothelial responses to blood flow. The analysis suggests 3 missense PIEZO1 single nucleotide polymorphisms (SNPs) associated with COVID-19 fatality independently of risk factors. All of them affect amino acids in the proximal N-terminus of PIEZO1, which is an unexplored region of the protein. By using molecular modelling we predict location of all 3 amino acids to a common outward-facing structure of unknown functional significance at the tips of the PIEZO1 propeller blades. Through genome sequence analysis we show that these SNPs vary in prevalence with ethnicity and that the most significant SNP (rs7184427) varies between 65 to 90% even though the reference amino acid is evolutionarily conserved. The data suggest PIEZO1 as a contributor to COVID-19 fatality and factor in ethnic susceptibility.
Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8
Authors: Das Amitabh , Wang Xiaobei , Kang Jessica , Coulter Alyssa , Shetty Amol C. , Bachu Mahesh , Brooks Stephen R. , Dell’Orso Stefania , Foster Brian L. , Fan Xiaoxuan , Ozato Keiko , Somerman Martha J. , Thumbigere-Math Vivek 
Published: June 2020

SUMMARYOsteoclasts (OCs) are bone resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild-type mice, Ly6Chiand Ly6Cintmonocytes are the primary source of OC formation when compared to Ly6C−monocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of pre-established transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of IRF8, a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis inIrf8deficient mice. Collectively, our study provides novel insights into the transcription factors and activecis-regulatory elements that regulate OC differentiation.
EarlyC. elegansembryos modulate cell division timing to compensate for, and survive, the discordant conditions of a severe temperature gradient
Authors: Terry Eric , Birsoy Bilge , Bothman David , Sigurdson Marin , Joshi Pradeep M. , Meinhart Carl , Rothman Joel H. 
Published: June 2020

AbstractDespite a constant barrage of intrinsic and environmental noise, embryogenesis is remarkably reliable, suggesting the existence of systems that ensure faithful execution of this complex process. We report that earlyC. elegansembryos, which normally show a highly reproducible lineage and cellular geometry, can compensate for deviations imposed by the discordant conditions of a steep temperature gradient generated in a microfluidic device starting at the two-cell stage. Embryos can survive a gradient of up to 7.5°C across the 50-micron axis through at least three rounds of division. This response is orientation-dependent: survival is higher when the normally faster-dividing anterior daughter of the zygote, AB, but not its sister, the posterior P1, is warmer. We find that temperature-dependent cellular division rates in the early embryo can be effectively modeled by a modification of the Arrhenius equation. Further, both cells respond to the gradient by dramatically reducing division rates compared to the predicted rates for the temperature experienced by the cell even though the temperature extremes are well within the range for normal development. This finding suggests that embryos may sense discordance and slow development in response. We found that in the cohort of surviving embryos, the cell on the warmer side at the two-cell stage shows a greater average decrease in expected division rate than that on the cooler side, thereby preserving the normal cellular geometry of the embryo under the discordant conditions. A diminished average slow-down response correlated with lethality, presumably owing to disruption of normal division order and developmental fidelity. Remarkably, some inviable embryos in which the canonical division order was reversed nonetheless proceeded through relatively normal morphogenesis, suggesting a subsequent compensation mechanism independent of cell division control. These findings provide evidence for a previously unrecognized process inC. elegansembryos that may serve to compensate for deviations imposed by aberrant environmental conditions, thereby resulting in a high-fidelity output.
Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes
Authors: Grzadkowski Michal R. , Manning Hannah , Somers Julia , Demir Emek 
Published: June 2020

ABSTRACTGenes implicated in tumorigenesis often exhibit diverse sets of genomic variants in the tumor cohorts within which they are frequently mutated. We sought to identify the downstream expression effects of these perturbations and to find whether or not this heterogeneity at the genomic level is reflected in a corresponding heterogeneity at the transcriptomic level. Applying a novel hierarchical framework for organizing the mutations present in a cohort along with machine learning pipelines trained on sample expression profiles we systematically interrogated the signatures associated with combinations of perturbations recurrent in cancer. This allowed us to catalogue the mutations with discernible downstream expression effects across a number of tumor cohorts as well as to uncover and characterize a multitude of cases where subsets of a genes mutations are clearly divergent in their function from the remaining mutations of the gene.
Membrane potential regulates Hedgehog signaling and compartment boundary maintenance in theDrosophilawing disc
Authors: Emmons-Bell Maya , Yasutomi Riku , Hariharan Iswar K. 
Published: June 2020

AbstractTheDrosophilawing imaginal disc is composed of two lineage-restricted populations of cells separated by a smooth boundary. Hedgehog (Hh) from posterior cells activates a signaling pathway in anterior cells near the boundary which is necessary for boundary maintenance. Here, we show that membrane potential is patterned in the wing disc. Anterior cells near the boundary, where Hh signaling is most active, are more depolarized than posterior cells across the boundary. Elevated expression of the ENaC channel Ripped Pocket (Rpk), observed in these anterior cells, requires Hh. Antagonizing Rpk reduces depolarization and disrupts the compartment boundary. Using genetic and optogenetic manipulations, we show that membrane depolarization promotes membrane localization of Smoothened and augments Hh signaling. Thus, membrane depolarization and Hh-dependent signaling mutually reinforce each other in this region. Finally, clones of depolarized cells survive preferentially in the anterior compartment and clones of hyperpolarized cells survive preferentially in the posterior compartment.