bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is the impact of social distancing on coronavirus growth rates effective across different settings? A non-parametric and local regression approach to test and compare the growth rate
Authors: Lancastle Neil 
Published: April 2020

AbstractEpidemiologists use mathematical models to predict epidemic trends, and these results are inherently uncertain when parameters are unknown or changing. In other contexts, such as climate, modellers use multi-model ensembles to inform their decision-making: when forecasts align, modellers can be more certain. This paper looks at a sub-set of alternative epidemiological models that focus on the growth rate, and it cautions against relying on the method proposed in (Pike & Saini, 2020): relying on the data for China to calculate future trajectories is likely to be subject to overfitting, a common problem in financial and economic modelling. This paper finds, surprisingly, that the data for China are double-exponential, not exponential; and that different countries are showing a range of different trajectories. The paper proposes using non-parametric and local regression methods to support epidemiologists and policymakers in assessing the relative effectiveness of social distancing policies. All works contained herein are provided free to use worldwide by the author underCC BY 2.0.
Further Evidence of a Possible Correlation Between the Severity of Covid-19 and BCG Immunization
Authors: Dolgikh Serge 
Published: April 2020

AbstractIn this work we observe a number of cases supporting the possible correlation between the administration of BCG tuberculosis vaccine and the severity of Covid-19 effects in the population proposed in the earlier works [1]. Based on the early preliminary analysis of the publicly available data we propose a number of arguments and observations providing further support for the correlation hypothesis and make an observation that the effectiveness of the protection effect of BCG immunization, if confirmed, may depend to a significant extent on the age of administration, with the early age inoculation more effective for the lasting protection.
Global access to handwashing: implications for COVID-19 control in low-income countries
Authors: Brauer Michael , Zhao Jeff T , Bennitt Fiona B , Stanaway Jeffrey D 
Published: April 2020

AbstractBackgroundLow-income countries have reduced health care system capacity and are therefore at risk of substantially higher COVID-19 case fatality rates than those currently seen in high-income countries. Handwashing is a key component of guidance to reduce transmission of the SARS-CoV-2 virus, responsible for the COVID-19 pandemic. Prior systematic reviews have indicated the effectiveness of handwashing to reduce transmission of respiratory viruses. In low-income countries, reduction of transmission is of paramount importance but social distancing is challenged by high population densities and access to handwashing facilities with soap and water is limited.ObjectivesTo estimate global access to handwashing with soap and water to inform use of handwashing in the prevention of COVID-19 transmission.MethodsWe utilized observational surveys and spatiotemporal Gaussian process regression modeling in the context of the Global Burden of Diseases, Injuries, and Risk Factors Study, to estimate access to a handwashing station with available soap and water for 1062 locations from 1990 to 2019.ResultsDespite overall improvements from 1990 (33.6% [95% uncertainty interval 31.5–35.6] without access) to 2019, globally in 2019, 2.02 (1.91–2.14) billion people—26.1% (24.7–27.7) of the global population lacked access to handwashing with available soap and water. More than 50% of the population in sub-Saharan Africa and Oceania were without access to handwashing in 2019, while in eight countries, more 50 million or more persons lacked access.DiscussionFor populations without handwashing access, immediate improvements in access or alternative strategies are urgently needed, while disparities in handwashing access should be incorporated into COVID-19 forecasting models when applied to low-income countries.FundingBill & Melinda Gates Foundation. MB was supported in part by the Pathways to Equitable Healthy Cities grant from the Wellcome Trust.
The Risk of Secondary Malignancies in Patients with Ovarian Cancer: A Systematic Review and Meta-Analysis
Authors: Heydari Keyvan , Rismantab Sahar , Alizadeh-Navaei Reza , Shamshirian Amir , Shadmehri Nima , Lotfi Parisa , Zamani-Kiasari Alieh , Shamshirian Danial 
Published: April 2020

AbstractThis study was performed to systematically asses the risk of secondary malignancies in patients with ovarian cancer. We conducted a systematic search in PubMed, Web of Science, and Scopus databases up to September 2019 to find target studies. In this study, the overall SIR has been calculated with fixed/random-effects models. Sixteen cohort studies including 122715 ovarian cancer patients with 4458 secondary malignancies have been included in this meta-analysis. Combined SIRs showed an increased risk of secondary malignancies prevalence (SIR: 1.81, 95%CI 1.58-2.03). The most prevalence diagnosed malignancies were as follows: breast cancer (1.34, 95%CI 1.5-1.18), intestine (2.36, 95%CI 1.11-3.61), colorectal (1.73, 95%CI 1.44-2.02), pancreatic (1.42, 95%CI 1.13-1.71), cervical cancer (11.57, 95%CI 6.94-16.21), renal (1.43, 95%CI 1.11-1.74), bladder (2.13, 95%CI 1.77-2.50), leukemia (3.33, 95%CI 2.23-4.43), connective tissue (2.61, 95%CI 1.56-3.66), and thyroid (1.59, 95%CI 1.13-2.04). In regards to the results, various malignancies have a greater prevalence in patients with ovarian cancer in comparison to the general public. Corpus cancer, leukemia cancer, endometrium cancer, connective tissue malignancy, and bladder cancer are among the high risks in these patients and need to be considered for them. Hence, the survival rate of the patients can be increased through prevention and early diagnosis.
An amino-terminal point mutation increases EAAT2 anion currents without affecting glutamate transport rates
Authors: Mertens Bettina M I , Kortzak Daniel , Franzen Arne , Fahlke Christoph 
Published: April 2020

ABSTRACTExcitatory amino acid transporters (EAATs) are prototypic dual function proteins that function as coupled glutamate/Na+/H+/K+transporters and as anion-selective channels. Both transport functions are intimately intertwined at the structural level: secondary active glutamate transport is based on elevator-like movements of the mobile transport domain across the membrane, and the lateral movement of this domain results in anion channel opening. This particular anion channel gating mechanism predicts the existence of mutant transporters with changed anion channel properties, but without alteration in glutamate transport. We here report that the L46P mutation in the human EAAT2 transporter fulfils this prediction. L46 is a pore-forming residue of the EAAT2 anion channels at the cytoplasmic entrance into the ion conduction pathway. In whole-cell patch clamp recordings, we observed larger macroscopic anion current amplitudes for L46P than for WT EAAT2. Moreover, changes in selectivity made gluconate permeant in L46P EAAT2. Non-stationary noise analysis revealed unchanged unitary current amplitudes in mutant EAAT2 anion channels. Rapid L-glutamate application under forward transport conditions demonstrated that L46P does not reduce the transport rate of individual transporters. Since individual transport rates and unitary anion current amplitudes are unaffected, absolute open probabilities of EAAT2 anion channels were quantified as ratio of anion currents by glutamate uptake currents. We found up to sevenfold increased absolute open probability of L46P EAAT2 anion channels. Our results reveal an important determinant of the diameter of EAAT2 anion pore and demonstrate the existence of anion channel gating processes outside the EAAT uptake cycle.
Sonication of the Anterior Thalamus with MRI-Guided Low Intensity Focused Ultrasound Pulsation (LIFUP) Changes Pain Thresholds in Healthy Adults: A Double-Blind, Concurrent LIFUP/MRI Study
Authors: Badran Bashar W. , Caulfield Kevin , Stomberg-Firestein Sasha , Summers Philip , Dowdle Logan T. , Savoca Matt , Li Xingbao , Austelle Christopher W. , Short E. Baron , Borckardt Jeffrey J. , Spivak Norman , Bystritsky Alexander , George Mark S. 
Published: April 2020

AbstractBackgroundLow Intensity Focused Ultrasound Pulsation (LIFUP) is a noninvasive brain stimulation method that may modulate deep brain structures using ultrasonic waves. Presently there are limited studies in humans rigorously assessing behavioral effects following LIFUP sonication of deep brain nuclei. As an initial test, we investigated whether sonication of the anterior thalamus, a central relay structure of nociception, would modulate thermal pain thresholds in healthy individuals.MethodsWe enrolled 19 healthy individuals in this three-visit, double-blind, randomized, sham-controlled, crossover trial. Participants attended a first MRI screening visit to acquire anatomical scans for LIFUP targeting. They then attended two identical experimental LIFUP/MRI visits (counterbalanced by condition) at least one-week apart. Within the MRI scanner, participants received two, 10-minute sessions of either active or sham LIFUP spread 10 minutes apart to the right anterior thalamus [Fundamental frequency:650khz, pulse repetition frequency: 10 HZ, Pulse Width: 5ms, Duty Cycle: 5%, Sonication Duration: 30s, Inter-Sonication Interval: 30 s, Number of Sonications: 10, ISPTA.3 719 mW/cm2]. Each 10-minute session was delivered in a block design (30s ON, 30s OFF). The primary outcome measure was quantitative sensory thresholding (QST), measuring sensory, pain, and tolerance thresholds to a thermal stimulus applied to the left forearm before and after LIFUP. Thermal stimuli were also applied in the scanner during certain blocks, either alone, or during LIFUP.ResultsTwo 10-minute sessions of thalamic LIFUP produced a significant antinociceptive effect on pain thresholds. Temperature sensitivity increases were significantly attenuated (timeXcondition p=0.046) after active LIFUP (0.51 degree change) relative to sham stimulation (1.08 degrees). LIFUP also changed sensory and tolerance thresholds mathematically but this was not statistically significant with this sample. LIFUP delivered concurrently with thermal pain had no immediate behavioral effect.ConclusionsTwo, 10-minute sessions of anterior thalamic LIFUP has antinociceptive effects in healthy individuals. Future studies should optimize the parameter space and dose and perhaps investigate multi-session LIFUP interventions for pain disorders.
Zoledronate extends healthspan and survival via the mevalonate pathway in a FOXO-dependent manner
Authors: Chen Zhengqi. , Cordero Julia , Slack Cathy , Zeidler Martin , Bellantuono Ilaria 
Published: April 2020

ABSTRACTIncreased longevity has not been paralleled by extended healthspan, resulting in more years spent with multiple diseases in older age. As such, interventions to improve healthspan are urgently required. Zoledronate is a nitrogen containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase (FPPS) enzyme, central to the mevalonate pathway. It is already used clinically to prevent fractures in osteoporotic patients, who have been reported to derive unexpected and unexplained survival benefits. In this study we show that zoledronate has beneficial effects on both lifespan and healthspan usingDrosophilaas a model. We found that zoledronate extended lifespan, improved climbing activity and reduced intestinal epithelial dysplasia and permeability in aged flies. Mechanistic studies showed that zoledronate conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of FPPS. Moreover, zoledronate inhibited pAKT in the mTOR pathway and functioned via dFOXO, a molecule associated with increased longevity, downstream of the mevalonate pathway. Taken together, our work indicates that zoledronate, a drug already widely used and dosed only once a year to prevent osteoporosis, modulates important mechanisms of ageing. Its repurposing holds great promise as a treatment to improve healthspan.
Human Transcription Factor and Protein Kinase Gene Fusions in Human Cancer
Authors: Salokas Kari , Weldatsadik Rigbe G. , Markku Varjosalo 
Published: April 2020

ABSTRACTOncogenic gene fusions are estimated to account for up-to 20 % of cancer morbidity. Originally, oncofusions were identified in blood cancer, but recently multiple sequence-level studies of cancer genomes have established oncofusions throughout all tissue types. However, the functional implications of the identified oncofusions have often not been investigated. In this study, the identified oncofusions from a fusion detection approach (DEEPEST) were analyzed in more detail. In total, DEEPEST contains 28863 unique fusions. From sequence analysis, we found that almost 30% of them (8225) are expected to produce functional fusion proteins with features from both parent genes. Kinases and transcription factors were found to be the main gene families of the protein producing fusions. Considering their role as initiators, actors, and termination points of cellular signaling pathways, we focused our in-depth analyses on them. The domain architecture of the fusions, as well as of their expected interactors, suggests that abnormal molecular context of intact protein domains brought about by fusion events may unlock the oncogenic potential of the wild type counterparts of the fusion proteins. To understand overall effects of oncofusions on cellular signaling, we performed differential expression analysis using TCGA cancer project samples. Results indicated oncofusion-specific alterations in expression levels of individual genes, and overall lowering of the expression levels of key cellular pathways, such as signal transduction, proteolysis, microtubule cytoskeleton organization, and in particular regulation of transcription. The sum of our results suggests that kinase and transcription factor oncofusions globally deregulate cellular signaling, possibly via acquiring novel functions.
High contribution of canopy to oleoresin accumulation in loblolly pine trees
Authors: Parrish Amber N. , Turner Glenn W. , Lange B. Markus 
Published: April 2020

ABSTRACTThe shoot system of all loblolly pine (Pinus taedaL.) contains abundant resin ducts, and the oleoresins contained within them have demonstrated roles in constitutive defenses. This study is providing a quantitative assessment of oleoresin biosynthesis and accumulation in resin ducts. Morphometric analyses of representative tissue sections indicate that the fractional volume of resin ducts is particularly high in the cortex of young stems and their needles, representing a major portion of total pine resins from primary growth of the canopy. We demonstrate that it is possible to extrapolate oleoresin formation from the microscopic scale (tissues sections) to the macroscale (entire trees), which has implications for assessing resins as renewable feedstocks for bioproducts.
The Ephrin receptor A2 and Roundabout Guidance Receptor 1 heterodimer: A potential theranostic for squamous cell carcinomas
Authors: Pang Ka M. , Srivastava Saumya , Iida Mari , Nelson Michael , Liu Jiayi , Nam Arin , Wang Jiale , Mambetsariev Isa , Mohanty Atish , McDaniel Nellie , Behal Amita , Kulkarni Prakash , Wheeler Deric L. , Salgia Ravi 
Published: April 2020

AbstractSquamous cell carcinomas (SCC) of the lung (LSCC) and head and neck (HNSCC) are very prevalent with poor prognosis and limited treatment options. In both cancer types, Ephrin receptor A2 (EPHA2) is known to be overexpressed and exhibit opposing effects via two distinct signaling mechanisms. While it can inhibit cancer cell survival and migration by ligand-dependent signaling through tyrosine kinase phosphorylation at Y588 and Y772, it can promote tumor progression and cell migration in a ligand-independent manner via phosphorylation at S897. Variable ABnormal morphology (VAB-1) is theC. elegansortholog of the human ephrin receptor (EPHR) that interacts genetically and biochemically in a dose-dependent manner with the axon guidance receptor, SAX3, the worm ortholog of ROBO. Double mutants ofvab-1(EPHR)/sαx-3(ROBO) are synthetic lethal, underscoring the interaction between the two signaling pathways which prompted us to investigate their role in SCC. Using biochemical and biophysical techniques, we show that EPHA2 and ROBO1 reside in the same complex and interact physically to form a functional heterodimer in LSCC and HNSCC. Furthermore, we show that treating squamous cells with the SLIT2, ligand of ROBO1, hinders phosphorylation of EPHA2 at S897, and thereby, attenuates cell proliferation. Interestingly, SLIT2 can interact with EPHA2 and attenuate the proliferation of cells that have low ROBO1 expression. Additionally, SLIT2 can act synergistically with the EPHA2 inhibitor, Ensartinib to attenuate cell growth in LSCC and HNSCC cells. Taken together, the data suggest that SLIT2 may serve as a novel therapeutic for LSCC and HNSCC. Here, we propose to stratify patients for treatment with SLIT2 and/or Ensartinib, based on their EPHA2 and ROBO1 expression levels in the diseased tissue. Thus 85% of LSCC cases can be treated with combination of SLIT2+Ensartinib and 55% of HNSCC cases can be treated with either SLIT2 or Ensartinib. Furthermore, EPHA2 and ROBO1 may represent novel theranostics in these two diseases.One sentence summaryHeterodimerization of EPHA2 and ROBO1 receptors attenuates growth of squamous cell carcinomas of the lung and head and neck.
A role for the autophagic receptor, SQSTM1/p62, in trafficking NF-κB/RelA to nucleolar aggresomes
Authors: Lobb Ian T , Morin Pierre , Martin Kirsty , Lieshi Xhordi , Olsen Karl , Duncan Rory R , Stark Lesley A 
Published: April 2020

AbstractElevated NF-κB activity is a contributory factor in many haematological and solid malignancies. Nucleolar sequestration of NF-κB/RelA represses this elevated activity and mediates apoptosis of cancer cells. Here we set out to understand the mechanisms that control the nuclear/nucleolar distribution of RelA and other regulatory proteins, so that agents can be developed that specifically target these proteins to the organelle. We demonstrate that RelA accumulates in intra-nucleolar aggresomes in response to specific stresses. We also demonstrate that the autophagy receptor, SQSTM1/p62, accumulates alongside RelA in these nucleolar aggresomes. This accumulation is not a consequence of inhibited autophagy. Indeed, our data suggest nucleolar and autophagosomal accumulation of p62 are in active competition. We identify a conserved motif at the N-terminus of p62 that is essential for nucleoplasmic-to nucleolar transport of the protein. Furthermore, using a dominant negative mutant deleted for this nucleolar localisation signal (NoLS), we demonstrate a role for p62 in trafficking RelA and other aggresome-related proteins to nucleoli. Together, these data identify a novel role for p62 in trafficking nuclear proteins to nucleolar aggresomes under conditions of cell stress, thus maintaining nuclear proteostasis. They also provide invaluable information on the mechanisms that regulate the nuclear/nucleolar distribution of RelA that could be exploited for therapeutic purpose.SignificanceAberrant NF-κB activity drives many of the hallmarks of cancer and plays a key role in cancer progression. Nucleolar sequestration of NF-κB/RelA is one mechanism that switches off this activity and induces the death of cancer cells. Here we define a novel role for the autophagy receptor, SQSTM1/p62 in transport of nucleoplasmic NF-κB/RelA to nucleoli. Identification of this new trafficking mechanism opens up avenues for the development of a unique class of therapeutic agents that transport RelA and other cancer regulatory proteins to this organelle.
MgrA regulates interaction ofStaphylococcus aureuswith mucin
Authors: Parker Connor P. , Akil Nour , Shanrock Cullen R. , Allen Patrick D. , Chaly Anna L. , Crosby Heidi A. , Kwiecinski Jakub , Horswill Alexander R. , Fischer Anthony J. 
Published: April 2020

AbstractBackgroundTo defend the lungs, mucus adheres to bacterial cells and facilitates their removal by ciliary transport. Our goals were to measure the affinity of mucus for the respiratory pathogenStaphylococcus aureusand identify bacterial genes that regulate this interaction.MethodsS. aureuswas added to pig tracheas to determine whether it binds mucus or epithelial cells. To quantify its affinity for mucus, we developed a competition assay in microtiter plates. Mucin was added over a dose range as an inhibitor of bacterial attachment. We then examined how transcriptional regulator MgrA and cell wall transpeptidase sortase (SrtA) affect bacterial interaction with mucin.ResultsIn pig tracheas,S. aureusbound mucus strands from submucosal glands more than epithelial cells. In microtiter plate assays, ΔsrtAfailed to attach even in the absence of mucin. Mucin blocked wild typeS. aureusattachment in a dose-dependent manner. Higher concentrations were needed to inhibit binding of ΔmgrA. Co-deletion ofebhandsraP, which encode surface proteins repressed by MgrA, suppressed the ΔmgrAbinding phenotype. No differences between ΔmgrAand wild type were observed when methylcellulose or heparin sulfate were substituted for mucin, indicating specificity.ConclusionsMucin decreases attachment ofS. aureusto plastic, consistent with its physiologic role in host defense.S. aureusdeficient in MgrA has decreased affinity for mucin. Ebh and SraP, which are normally repressed by MgrA, may function as inhibitors of attachment to mucin. These data show that specific bacterial factors may regulate the interaction ofS. aureuswith mucus.
Crystal Structure of INTS3/INTS6 complex reveals Functional Importance of INTS3 dimerization in DSB Repair
Authors: Jia Yu , Cheng Zixiu , Bharath Sakshibeedu R , Sun Qiangzu , Su Nannan , Huang Jun , Song Haiwei 
Published: April 2020

AbstractSOSS1 is a single-stranded DNA (ssDNA)-binding protein complex that plays a critical role in double-strand DNA break (DSB) repair. SOSS1 consists of three subunits: INTS3, SOSSC, and hSSB1 with INTS3 serving as a scaffold to stabilize this complex. Moreover, the integrator complex subunit 6 (INTS6) participates in the DNA damage response through direct binding to INTS3 but how INTS3 interacts with INTS6 thereby, impacting DBS repair is not clear. Here, we determined the crystal structure of the C-terminus of INTS3 (INTS3c) in complex with the C-terminus of INTS6 (INTS6c) at a resolution of 2.4 Å. Structure analysis revealed that two INTS3c subunits dimerize and interact with INTS6c via conserved residues. Subsequent biochemical analyses confirmed that INTS3c forms a stable dimer and INTS3 dimerization is important for recognizing the longer ssDNA. Perturbation of INTS3c dimerization and disruption of the INTS3c/INTS6c interaction, impair the DSB repair process. Altogether, these results unravel the underappreciated role of INTS3 dimerization and the molecular basis of INTS3/INTS6 interaction in DSB repair.