bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced Gene Dosage of Histone H4 Prevents CENP-A Mislocalization inSaccharomyces cerevisiae
Authors: Eisenstatt Jessica R. , Ohkuni Kentaro , Au Wei-Chun , Preston Olivia , Suva Evelyn , Costanzo Michael , Boone Charles , Basrai Munira A.
Published: May 2020

Mislocalization of the centromeric histone H3 variant (Cse4 in budding yeast, CID in flies, CENP-A in humans) to non-centromeric regions contributes to chromosomal instability (CIN) in yeast, fly, and human cells. Overexpression and mislocalization of CENP-A has been observed in cancers, however, the mechanisms that facilitate the mislocalization of overexpressed CENP-A have not been fully explored. Defects in ubiquitin-mediated proteolysis of overexpressed Cse4 (GALCSE4) leads to its mislocalization and synthetic dosage lethality (SDL) in mutants for E3 ubiquitin ligases (Psh1, Slx5, SCFMet30, SCFCdc4), Doa1, Hir2, and Cdc7. In contrast, defects in sumoylation ofGALcse4K215/216/A/Rprevent its mislocalization and do not cause SDL in apsh1Δ strain. Here, we used a genome-wide screen to identify factors that facilitate the mislocalization of overexpressed Cse4 by characterizing suppressors of thepsh1ΔGALCSE4SDL. Deletions of histone H4 alleles (HHF1orHHF2), which were among the most prominent suppressors, also suppressslx5Δ, cdc4-1, doa1Δ, hir2Δ, andcdc7-4 GALCSE4SDL. Reduced dosage ofH4contributes to defects in sumoylation and reduced mislocalization of overexpressed Cse4. We determined that thehhf1-20, cse4-102, andcse4-111mutants, which are defective in the Cse4-H4 interaction, also exhibit reduced sumoylation of Cse4 and do not displaypsh1ΔGALCSE4SDL. In summary, we have identified genes that contribute to the mislocalization of overexpressed Cse4 and defined a role for the gene dosage ofH4in facilitating Cse4 sumoylation and mislocalization to non-centromeric regions, contributing to SDL when Cse4 is overexpressed in mutant strains.
A 3D Reconstruction Algorithm for Real-time Simultaneous Multi-Source EIT Imaging for Lung Function Monitoring
Authors: Kao Tzu-Jen , Amm Bruce , Isaacson David , Newell Jonathan , Saulnier Gary , Mueller Jennifer L.
Published: May 2020

Monitoring regional pulmonary ventilation and pulsatile perfusion changes in a 3D region of interest (ROI) of the lung is a promising application for electrical impedance tomography (EIT). This paper describes a 3D analytical reconstruction algorithm that was embedded in a prototype EIT system to enable a real-time image reconstruction at nearly 20 frames per second for monitoring impedance changes in the chest in real-time. The derivation and results of the 3D analytical forward solution and inverse solution and details of the real-time reconstruction algorithm are given. The algorithm and EIT system are validated with simulated data, in-vitro phantoms, and finally shown to be capable of imaging ventilation and pulsatile perfusion in human subjects. The human subject data was obtained using a high-precision, high-speed and simultaneous multiple current source (SMS-EIT) developed by GE Research. Data was collected using four rows of 8 electrodes for a healthy adult male subject and 2 rows of 16 electrodes for six healthy human female subjects, with one row placed above the breasts and a second row placed at the infra-mammary fold. Each of the female subjects performed a breathing maneuver with a volumetric incentive spirometer, and the volume of air inhaled was calculated from the EIT images. Pulsatile perfusion images were computed from this data, and regional lung filling was also analyzed.
Unexpected Specificity within Dynamic Transcriptional Protein-Protein Complexes
Authors: Henley Matthew J. , Linhares Brian M. , Morgan Brittany S. , Cierpicki Tomasz , Fierke Carol A. , Mapp Anna K.
Published: May 2020

A key functional event in eukaryotic gene activation is the formation of dynamic protein-protein interaction networks between transcriptional activators and transcriptional coactivators. Seemingly incongruent with the tight regulation of transcription, many biochemical and biophysical studies suggest that activators use nonspecific hydrophobic and/or electrostatic interactions to bind to coactivators, with few if any specific contacts. Here a mechanistic dissection of a set of representative dynamic activator•coactivator complexes, comprised of the ETV/PEA3 family of activators and the coactivator Med25, reveals a different molecular recognition model. The data demonstrate that small sequence variations within an activator family significantly redistribute the conformational ensemble of the complex while not affecting overall affinity, and distal residues within the activator—not often considered as contributing to binding—play a key role in mediating conformational redistribution. The ETV/PEA3•Med25 ensembles are directed by specific contacts between the disordered activator and the Med25 interface, which is facilitated by structural shifts of the coactivator binding surface. Taken together, these data highlight the critical role coactivator plasticity plays in recognition of disordered activators, and indicates that molecular recognition models of disordered proteins must consider the ability of the binding partners to mediate specificity.
Structural basis for stereospecific inhibition of ASCT2 from rational design
Authors: Garibsingh Rachel-Ann A. , Ndaru Elias , Garaeva Alisa A. , Bonomi Massimiliano , Slotboom Dirk J. , Paulino Cristina , Grewer Christof , Schlessinger Avner
Published: May 2020

ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. ASCT2 is upregulated in cancer, where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides an emerging strategy for cancer therapy. Here, guided by a homology model of ASCT2 in an outward-facing conformation, we rationally designed novel inhibitors exploiting stereospecific pockets in the substrate binding site. A cryo-EM structure of ASCT2 in complex with inhibitor (Lc-BPE) validated our predictions and was subsequently refined based on computational analysis. The final structures, combined with MD simulations, show that the inhibitor samples multiple conformations in the ASCT2 binding site. Our results demonstrate the utility of combining computational modeling and cryo-EM for SLC ligand discovery, and a viable strategy for structure determination of druggable conformational states for challenging membrane protein targets.
Improved pure tone sensitivity after simulated hearing loss
Authors: Krauss Patrick
Published: May 2020

Recently, it was proposed that a processing principle calledadaptive stochastic resonanceplays a major role in the auditory system, and serves to maintain optimal sensitivity even to highly variable sound pressure levels. As a side effect, in case of reduced auditory input, such as permanent hearing loss, this mechanism may eventually lead to the perception of phantom sounds like tinnitus or the Zwicker tone illusion. Using computational modeling, the biological plausibility of this processing principle was already demonstrated. Here, we provide empirical results that further support the stochastic resonance model of auditory perception. In particular, Mongolian gerbils were exposed to long-term notched noise, which mimics hearing loss for frequencies within the notch. Remarkably, the animals developed increased sensitivity, i.e. improved hearing thresholds, for the frequency centered within the notch, but nut for frequencies outside the notch. In addition, most animals treated with the new paradigm showed identical behavioral signs of phantom sound perception as animals with acoustic trauma induced tinnitus. In contrast, animals treated with broadband noise as a control condition did not show any significant threshold change, nor behavioral signs of phantom sound perception.
Development of an Ocean Protein Portal for Interactive Discovery and Education
Authors: Saito Mak A. , Saunders Jaclyn K. , Chagnon Michael , Gaylord David , Shepherd Adam , Held Noelle A. , Dupont Chris , Symmonds Nick , York Amber , Charron Matt , Kinkade Danie
Published: May 2020

Proteins are critical in catalyzing chemical reactions, forming key cellular structures, and in regulating cellular processes. Investigation of marine microbial proteins by metaproteomics methods enables the discovery of numerous aspects of microbial biogeochemistry processes. However, these datasets present big-data challenges as they often involve many samples collected across broad geospatial and temporal scales, resulting in thousands of protein identifications, abundances, and corresponding annotation information. The Ocean Protein Portal (OPP) was created to enable data sharing and discovery among multiple scientific domains and serve both research and education functions. The portal focuses on three use case questions: “Where is my protein of interest?”, “Who makes it?”, and “How much is there?”, and provides profile and section visualizations, real-time taxonomic analysis, and links to metadata, sequence analysis, and other external resources to enabling connections to be made between biogeochemical and proteomics datasets.
Deletion and overexpression of the scaffolding protein IQGAP1 promotes HCC
Authors: Delgado Evan R , Erickson Hanna L , Tao Junyan , Monga Satdarshan P , Duncan Andrew W , Anakk Sayeepriyadarshini
Published: May 2020

IQ motif–containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that is overexpressed in a number of cancers, including liver cancer, and is associated with many pro-tumorigenic processes including cell proliferation, motility, and adhesion. IQGAP1 can integrate multiple signaling pathways and could be an effective anti-tumor target. Therefore, we examined the role for IQGAP1 in tumor initiation and promotion during liver carcinogenesis. Unexpectedly, we found thatIqgap1-/-mice had a higher tumor burden thanIqgap1+/+andIqgap1+/-mice following DEN-induced liver carcinogenesis.Iqgap1-/-tumors as well as knocking downIQGAP1in hepatocellular carcinoma (HCC) cell lines resulted in increased MET activation and cellular proliferation. On the other hand, we uncovered IQGAP1 overexpression accelerates HCC development by YAP activation and subsequent NUAK2 expression. We demonstrate that increasing IQGAP1 expressionin vivodoes not alter β-catenin or MET activation. Taken together, we identify that both loss and gain of function of IQGAP1 promotes HCC development by two separate mechanisms in the liver. These results demonstrate that adequate amount of IQGAP1 is necessary to maintain a quiescent status of liver.
Spatially displaced excitation contributes to the encoding of interrupted motion by the retinal direction-selective circuit
Authors: Ding Jennifer , Chen Albert , Chung Janet , Ledesma Hector Acaron , Wu Mofei , Berson David M. , Palmer Stephanie E. , Wei Wei
Published: May 2020

Spatially distributed excitation and inhibition collectively shape a visual neuron’s receptive field (RF) properties. In the direction-selective circuit of the mammalian retina, the role of strong null-direction inhibition of On-Off direction-selective ganglion cells (ON-OFF DSGCs) on their direction selectivity is well-studied. However, how excitatory inputs influence the On-Off DSGC’s visual response is underexplored. Here, we report that On-Off DSGCs have a spatially displaced glutamatergic receptive field along their preferred-null motion axis. This displaced receptive field contributes to DSGC null-direction spiking during interrupted motion trajectories. Theoretical analyses indicate that population responses during interrupted motion may help populations of On-Off DSGCs signal the spatial location of moving objects in complex, naturalistic visual environments. Our study highlights that the direction-selective circuit exploits separate sets of mechanisms under different stimulus conditions, and these mechanisms may help encode multiple visual features.
Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart
Authors: Dostal Vishantie , Wood Silas D. , Thomas Cody T. , Han Yu , Lau Edward , Lam Maggie P.Y.
Published: May 2020

The heart is sensitive to oxidative damage but a global view on how the cardiac proteome responds to oxidative stressors has yet to fully emerge. Using quantitative tandem mass spectrometry, we assessed the effects of acute exposure of the oxidative stress inducer paraquat on protein expression in mouse hearts. We observed widespread protein expression changes in the paraquat-exposed heart especially in organelle-containing subcellular fractions. During cardiac response to acute oxidative stress, proteome changes are consistent with a rapid reduction of mitochondrial metabolism, coupled with activation of multiple antioxidant proteins, reduction of protein synthesis and remediation of proteostasis. In addition to differential expression, we saw evidence of spatial reorganizations of the cardiac proteome including the translocation of hexokinase 2 to more soluble fractions. Treatment with the antioxidants Tempol and MitoTEMPO reversed many proteomic signatures of paraquat but this reversal was incomplete. We also identified a number of proteins with unknown function in the heart to be triggered by paraquat, suggesting they may have functions in oxidative stress response. Surprisingly, protein expression changes in the heart correlate poorly with those in the lung, consistent with differential sensitivity or stress response in these two organs. The results provide insights into oxidative stress responses in the heart and may avail the search for new therapeutic targets.
COVID-3D: An online resource to explore the structural distribution of genetic variation in SARS-CoV-2 and its implication on therapeutic development
Authors: Portelli Stephanie , Olshansky Moshe , Rodrigues Carlos H.M. , D’Souza Elston N. , Myung Yoochan , Silk Michael , Alavi Azadeh , Pires Douglas E.V. , Ascher David B.
Published: May 2020

The emergence of the COVID-19 pandemic has spurred a global rush to uncover basic biological mechanisms, to inform effective vaccine and drug development. Despite viral novelty, global sequencing efforts have already identified genomic variation across isolates. To enable easy exploration and spatial visualization of the potential implications of SARS-CoV-2 mutations on infection, host immunity and drug development we have developed COVID-3D (http://biosig.unimelb.edu.au/covid3d/).
Inferences on a Multidimensional Social Hierarchy Use a Grid-like Code
Authors: Park Seongmin A. , Miller Douglas S. , Boorman Erie D.
Published: May 2020

Generalizing experiences to guide decision making in novel situations is a hallmark of flexible behavior. It has been hypothesized such flexibility depends on a cognitive map of an environment or task, but directly linking the two has proven elusive. Here, we find that discretely sampled abstract relationships between entities in an unseen two-dimensional (2-D) social hierarchy are reconstructed into a unitary 2-D cognitive map in the hippocampus and entorhinal cortex. We further show that humans utilize a grid-like code in several brain regions, including entorhinal cortex and medial prefrontal cortex, forinferreddirect trajectories between entities in the reconstructed abstract space during discrete decisions. Moreover, these neural grid-like codes in the entorhinal cortex are associated with neural decision value computations in the medial prefrontal cortex and temporoparietal junction area during choice. Collectively, these findings show that grid-like codes are used by the human brain to infer novel solutions, even in abstract and discrete problems, and suggest a general mechanism underpinning flexible decision making and generalization.
Influence of isolation by environment and landscape heterogeneity on genetic structure of wild riceZizania latifoliaalong a latitudinal gradient
Authors: Wagutu Godfrey Kinyori , Fan Xiangrong , Fu Wenlong , Li Wei , Chen Yuanyuan
Published: May 2020

Global aquatic habitats are undergoing rapid degradation and fragmentation as a result of land-use change and climate change. Understanding the genetic variability and adaptive potential of aquatic plant species is thus important for conservation purposes. In this study, we investigated the role of environment, landscape heterogeneity and geographical distance in shaping the genetic structure of 28 natural populations ofZizania latifolia(Griseb.) Turcz. Ex Stapf in China based on 25 microsatellite markers. Genetic structure was investigated by analysis of molecular variance (AMOVA), estimation ofFST, Bayesian clustering and Thermodynamic Integration (TI) methods. Isolation by environment (IBE), isolation by resistance (IBR) and isolation by distance (IBD) hypotheses were compared using a reciprocal causal model (RCM). Further, generalized linear models and spatially explicit mixed models, by using geographic, landscape and genetic variables, were developed to elucidate the role of environment in drivingZ. latifoliagenetic diversity. The genetic differentiation across all populations was high:FST= 0.579; Øpt= 0.578. RCM exclusively supported IBE in shaping genetic structuring, only partial support for IBR, but not for IBD. Maximum temperature of the warmest month and precipitation seasonality were the plausible parameters responsible for genetic diversity. After controlling for spatial effect and landscape complexity, precipitation seasonality was significantly associated with genetic diversity. Based on these findings, genetic structure ofZ. latifoliaacross China seem to be as a result of local adaptation. Environmental gradient and topographical barriers, rather than geographical isolation, influence genetic differentiation of aquatic species across China resulting in instances of local adaptation.
SoxS represses flagellar gene expression through RflP inSalmonella entericaSerovar Typhimurium
Authors: Thota Srinivas S. , Henry Brittany N. , Chubiz Lon M.
Published: May 2020

Flagellar gene expression is subject to regulation by many global transcription factors in response to environmental and nutritional signals. One of the primary ways this occurs inSalmonella entericaserovar Typhimurium, and its close relatives, is through controlling levels of FlhD4C2(the flagellar master regulator) via transcriptional, post-transcriptional, and post-translational mechanisms. Recently, we found the homologous transcription factors MarA, Rob, and SoxS repressflhDCexpression by distinct mechanisms. MarA and Rob, regulators involved in inducible multidrug resistance, repressedflhDCtranscription by interacting directly with theflhDCpromoter. Alternatively, SoxS, the oxidative stress response regulator, altered FlhD4C2levels independent offlhDCtranscription by post-transcriptional or post-translational mechanism. Here, using a forward genetic screen, we discovered that SoxS-dependent repression of flagellar gene expression occurs through RflP, an anti-FlhD4C2factor that targets FlhD4C2for proteolytic degradation. ElevatedsoxSexpression resulted in concomitant increases inrflPexpression, indicating SoxS may work through RflP at the level ofrflPtranscription. Mapping of therflPpromoter and a bioinformatic search yielded a putative SoxS binding site proximal to therflPtranscription start site. Comparison of therflPpromoter region inS. Typhimurium andEscherichia coliindicate substantial differences, providing a possible mechanism for differential expression ofrflPbetween these species.

IMPORTANCE

Salmonella entericais a major cause of foodborne illness. Understanding environmental and intracellular signals used bySalmonellato control expression of virulence-associated traits is critical to advancing treatment and prevention ofSalmonella-related disease. Reduced expression of flagella at key points duringSalmonellainfection aids in evasion of the host innate immune system. Within macrophagesSalmonellais non-flagellated and exposed to oxidative stress. SoxS-dependent repression of flagellar genes may provide a potential link between oxidative stress and reductions in flagellar expression.
Novel Ultra-Rare Exonic Variants Identified in a Founder Population Implicate Cadherins in Schizophrenia
Authors: Lencz Todd , Yu Jin , Rashid Khan Raiyan , Carmi Shai , Lam Max , Ben-Avraham Danny , Barzilai Nir , Bressman Susan , Darvasi Ariel , Cho Judy H. , Clark Lorraine N. , Gümüş Zeynep H. , Vijai Joseph , Klein Robert J. , Lipkin Steven , Offit Kenneth , Ostrer Harry , Ozelius Laurie J. , Peter Inga , Malhotra Anil K. , Atzmon Gil , Pe’er Itsik
Published: May 2020

Identification of rare genetic variants associated with schizophrenia has proven challenging due to multiple sources of heterogeneity, which may be reduced in founder populations. We examined ultra-rare exonic variants in 786 patients with schizophrenia and 463 healthy comparison subjects, all drawn from the Ashkenazi Jewish population. Cases had a higher frequency of novel missense or loss of function (MisLoF) variants compared to controls. Characterizing 141 “case-only” genes (in which ≥ 3 cases in our dataset had MisLoF variants with none found in controls), we identified cadherins as a novel gene set associated with schizophrenia, including a recurrent mutation in PCDHA3. Modeling the effects of purifying selection demonstrated that deleterious ultra-rare variants are greatly over-represented in the Ashkenazi population, resulting in enhanced power for rare variant association. Identification of cell adhesion genes in the cadherin/protocadherin family helps specify the synaptic abnormalities central to the disorder, and suggests novel potential treatment strategies.
COVID-19 :Determinants of Hospitalization, ICU and Death among 20,293 reported cases in Portugal
Authors: Ricoca Peixoto Vasco , Vieira André , Aguiar Pedro , Sousa Paulo , Carvalho Carlos , Thomas Daniel , Abrantes Alexandre , Nunes Carla
Published: May 2020

Introduction

Determinants of hospitalization, intensive care unit (ICU) admission and death are still unclear for Covid-19 and only a few studies have adjusted for confounding for different clinical outcomes including all reported cases in a country. We used routine surveillance data from Portugal to identify risk factors for COVID-19 outcomes, in order to support risk stratification, clinical and public health interventions, and scenarios to plan health care resources.

Methods

We conducted a retrospective cohort study including 20,293 laboratory confirmed cases of COVID-19 in Portugal extracted in April 28 2020, electronically through the National Epidemic Surveillance System of the Directorate-General of Health(DGS). We calculated absolute risks, relative risks (RR) and adjusted relative risks (aRR) to identify demographic and clinical factors associated with hospitalization, admission to ICU and death using Poisson regressions.

Results

Increasing age after 60 years was the greatest determinant for all outcomes. Assuming 0–50 years as reference, being aged 80–89 years was the strongest determinant of hospital admission (aRR-5.7), 70–79 years for ICU(aRR-10.4) and > 90 years for death(aRR-226.8) with an aRR of 112.7 in those 70–79. Among comorbidities, Immunodeficiency, cardiac disease, kidney disease, and neurologic disease were independent risk factors for hospitalization (aRR 1.83,1.79,1.56, 1.82), for ICU these were cardiac, Immunodeficiency, kidney and lung disease (aRR 4.33, 2.76, 2.43, 2.04), and for death they were kidney, cardiac and chronic neurological disease (aRR: 2.9, 2.6, 2.0) Male gender was a risk factor for all outcomes. There were small statistically significant differences for the 3 outcomes between regions.

Discussion and Conclusions

Older age stands out as the strongest risk factor for all outcomes specially for death as absolute is risk was small for those younger than 50. These findings have implications in terms of risk stratified public health measures that should prioritize protecting older people although preventive behavior is needed in all ages. Epidemiologic scenarios and clinical guidelines may consider these estimated risks, even though under-ascertainment of mild and asymptomatic cases should be considered.
Digital proximity tracing on empirical contact networks for pandemic control
Authors: Cencetti G. , Santin G. , Longa A. , Pigani E. , Barrat A. , Cattuto C. , Lehmann S. , Salathé M. , Lepri B.
Published: May 2020

Digital contact tracing is a relevant tool to control infectious disease outbreaks, including the COVID-19 epidemic. Early work evaluating digital contact tracing omitted important features and heterogeneities of real-world contact patterns influencing contagion dynamics. We fill this gap with a modeling framework informed by empirical high-resolution contact data to analyze the impact of digital contact tracing in the COVID-19 pandemic. We investigate how well contact tracing apps, coupled with the quarantine of identified contacts, can mitigate the spread in real environments. We find that restrictive policies are more effective in containing the epidemic but come at the cost of unnecessary large-scale quarantines. Policy evaluation through their efficiency and cost results in optimized solutions which only consider contacts longer than 15-20 minutes and closer than 2-3 meters to be at risk. Our results show that isolation and tracing can help control re-emerging outbreaks when some conditions are met: (i) a reduction of the reproductive number through masks and physical distance; (ii) a low-delay isolation of infected individuals; (iii) a high compliance. Finally, we observe the inefficacy of a less privacy-preserving tracing involving second order contacts. Our results may inform digital contact tracing efforts currently being implemented across several countries worldwide.
Investigation of subsequent and co-infections associated with SARS-CoV-2 (COVID-19) in hospitalized patients
Authors: Crotty Matthew P. , Akins Ronda , Nguyen An , Slika Rania , Rahmanzadeh Kristen , Wilson Marie H. , Dominguez Edward A.
Published: May 2020

Background

SARS-CoV-2 has drastically affected healthcare globally and causes COVID-19, a disease that is associated with substantial morbidity and mortality. We aim to describe rates and pathogens involved in co-infection or subsequent infections and their impact on clinical outcomes among hospitalized patients with COVID-19.

Methods

Incidence of and pathogens associated with co-infections, or subsequent infections, were analyzed in a multicenter observational cohort. Clinical outcomes were compared between patients with a bacterial respiratory co-infection (BRC) and those without. A multivariable Cox regression analysis was performed evaluating survival.

Results

A total of 289 patients were included, 48 (16.6%) had any co-infection and 25 (8.7%) had a BRC. No significant differences in comorbidities were observed between patients with co-infection and those without. Compared to those without, patients with a BRC had significantly higher white blood cell counts, lactate dehydrogenase, C-reactive protein, procalcitonin and interleukin-6 levels. ICU admission (84.0 vs 31.8%), mechanical ventilation (72.0 vs 23.9%) and in-hospital mortality (45.0 vs 9.8%) were more common in patients with BRC compared to those without a co-infection. In Cox proportional hazards regression, following adjustment for age, ICU admission, mechanical ventilation, corticosteroid administration, and pre-existing comorbidities, patients with BRC had an increased risk for in-hospital mortality (adjusted HR, 3.37; 95% CI, 1.39 to 8.16; P = 0.007). Subsequent infections were uncommon, with 21 infections occurring in 16 (5.5%) patients.

Conclusions

Co-infections are uncommon among hospitalized patients with COVID-19, however, when BRC occurs it is associated with worse clinical outcomes including higher mortality.
Atorvastatin and standard treatment of Helicobacter pylori: Randomized Clinical Trial
Authors: Azar Mohammad Reza Mohammad Hoseini , Portaghali Parham , Sedokani Amin , Jafari Ali
Published: May 2020

Background

Considering the increase in drug resistance over time to Helicobacter pylori treatment relying on the anti-inflammatory and antibacterial effects of atorvastatin to increase the success rate of H. pylori eradication, we examined the effect of adding atorvastatin to standard treatment of H. pylori eradication.

Materials and Methods

A total of 186 symptomatic patients who had been diagnosed with Helicobacter pylori infection and tested for H. pylori eradication were examined by a pathological response or positive urea breath test. Patients who received atorvastatin in addition to standard treatment were also identified based on a table of random numbers. Standard treatment included a 240mg bismuth subcitrate tablet, a 40mg pantoprazole tablet, a 500mg metronidazole tablet, and 2 capsules of 500mg amoxicillin, all taken BID for 14 days. After 4 weeks of treatment, all patients underwent stool testing for H. pylori fecal antigen. If the test was positive, the request was considered a failure of treatment, and if the test was negative, it was considered a successful eradication of H. pylori. The clinical trial registration code for this study is IRCT20190823044589N1.

Results

The eradication rate of H. pylori was 80% in the control group and 80.9% in the intervention group, which did not show a statistically significant difference between the two groups (P-value=0.971).

Conclusion

Adding atorvastatin to 4-drug regimen of PPI, bismuth subcitrate, amoxicillin, and metronidazole as the first line of treatment for H. pylori eradication is ineffective.

Significance of this Study (Summary box)

What is already known about this subject?

Infection of H. pylori is common worldwide and the antibiotic resistance is increasing

Atorvastatin, has anti-inflammatory and antibacterial effects. But also, have D grade interaction with clarithromycin in H. pylori eradication regimen and increases the toxic and lethal risk of atorvastatin toxicity.

What are the new findings?

Eradication rate of H. pylori using the standard treatment of a 240mg bismuth subcitrate tablet, a 40mg pantoprazole tablet, a 500mg metronidazole tablet, and 2 capsules of 500mg amoxicillin, BID for 14 days, is at least 80%.

Adding atorvastatin to 4-drug regimen of PPI, bismuth subcitrate, amoxicillin, and metronidazole as the first line of treatment for H. pylori eradication is ineffective.

How might it impact on clinical practice in the foreseeable future?

There should be more analysis on cost-benefice of adding atorvastatin to standard regimen of treatment for H. pylori eradication, but adding the atorvastatin to metronidazole-based H. pylori treatment is ineffective and for clarithromycin-based treatment is dangerous.
Social Distancing Interventions in the United States: An Exploratory Investigation of Determinants and Impacts
Authors: Guo Shenyang , An Ruopeng , McBride Timothy D. , Yu Danlin , Fu Linyun , Yang Yuanyuan
Published: May 2020

Background

To combat the Covid-19 pandemic in the United States, many states and Washington DC enacted Stay-at-Home order and nonpharmaceutical mitigation interventions. This study examined the determinants of the timing to implement an intervention. Through an impact analysis, the study explored the effects of the interventions and the potential risks of removing them under the context of reopening the economy.

Method

A content analysis identified nine types of mitigation interventions and the timing at which states enacted these strategies. A proportional hazard model, a multiple-event survival model, and a random-effect spatial error panel model in conjunction with a robust method analyzing zero-inflated and skewed outcomes were employed in the data analysis.

Findings

To our knowledge, we provided in this article the first explicit analysis of the timing, determinants, and impacts of mitigation interventions for all states and Washington DC in the United States during the first five weeks of the pandemic. Unlike other studies that evaluate the Stay-at-Home order by using simulated data, the current study employed the real data of various case counts of Covid-19. The study obtained two meritorious findings: (1) states with a higher prevalence of Covid-19 cases per 10,000 population reacted more slowly to the outbreak, suggesting that some states may have missed the optimal timing to prevent the wide spread of the Covid-19 disease; and (2) of nine mitigation measures, three (non-essential business closure, large-gathering bans, and restaurant/bar limitations) showed positive impacts on reducing cumulative cases, new cases, and death rates across states.

Interpretation

The opposite direction of the prevalence rate on the timing of issuing the mitigation interventions partially explains why the Covid-19 caseload in the U.S. remains high. A swift implementation of social distancing is crucial— the key is not whether such measures should be taken but when. Because there is no preventive vaccine and because there are few potentially effective treatments, recent reductions in new cases and deaths must be due, in large part, to the social interventions delivered by states. The study suggests that the policy of reopening economy needs to be implemented carefully.
Monitoring the post-containment COVID-19 crisis in Guadeloupe: Early-warning signals of destabilisation through bootstrapped probability density functions
Authors: ALLALI Meriem , Portecop Patrick , Carles Michel , Gibert Dominique
Published: May 2020

We propose a method to detect early-warning information in relation with subtle changes occurring in the trend of evolution in data time series of the COVID-19 epidemic spread (e.g. daily new cases). The method is simple and easy to implement on laptop computers. It is designed to be able to provide reliable results even with very small amounts of data (i.e. ≈ 10 − 20). The results are given as compact graphics easy to interpret. The data are separated into two subsets: the old data used as control points to statistically define a "trend" and the recent data that are tested to evaluate their conformity with this trend. The trend is characterised by bootstrapping in order to obtain probability density functions of the expected misfit of each data point. The probability densities are used to compute distance matrices where data clusters and outliers are easily visually recognised. In addition to be able to detect very subtle changes in trend, the method is also able to detect outliers. A simulated case is analysed where R0 is slowly augmented (i.e. from 1.5 to 2.0 in 20 days) to pass from a stable damped control of the epidemic spread to an exponentially diverging situation. The method is able to give an early warning signal as soon as the very beginning of the R0 variation. Application to the data of Guadeloupe shows that a small destabilising event occurred in the data near April 30, 2020. This may be due to an increase of R0 ≈ 0.7 around April 13-15, 2020.
Trend analysis, modelling and impact assessment of COVID-19 in Nepal
Authors: Bhandary Shital , Shrestha Srijan Lal , Khatiwada Ram Prasad , Shah Deep Narayan , Munankarmi Nabin Narayan , Banjara Megha Raj , Thapa-Parajuli Resham , Manandhar Krishna Das , Adhikari Rameshwar , Tuladhar Reshma
Published: May 2020

With continued global expansion of COVID-19 transmission and mounting threat of the the timely analysis of its trend in Nepal and forecasting the potential situation in the country has been deemed necessary. We analyzed the trend, modelling and impact assessment of COVID-19 disease, cases of Nepal from 23rdJanuary 2020 to 30thApril 2020 to portray the scenario of COVID-19 after the first phase of lockdown. Exponential smoothing state-space and autoregressive integrated moving average (ARIMA) models were constructed to forecast the cases. Susceptible-infectious-recovered (SIR) model was fit to estimate the basic reproduction number (Ro) of COVID-19 in Nepal. There has been increase in the number of cases but the overall growth in COVID-19 was not high. Statistical modelling has shown that COVID-19 cases may continue to increase exponentially in Nepal. The basic reproduction number in Nepal being maintained at low level of 1.08 for the period of 23rdJanuary to 30thApril 2020 is an indication of effectiveness of lockdown in containing the COVID-19 spread. The models further suggest that COVID-19 might persist until December 2020 with peak cases in August 2020. On the other hand, basic reproduction number of 1.25 was computed for total cases reported for the 22ndMarch to 30thApril 2020 period implying that COVID-19 may remain for at least for a year in the country. Thus, maintaining social distance and stay home policy with an implementation of strict lockdown in COVID-19 affected district is highly recommended.
CUE: CpG impUtation Ensemble for DNA Methylation Levels Across the Human Methylation450 (HM450) and EPIC (HM850) BeadChip Platforms
Authors: Li Gang , Raffield Laura , Logue Mark , Miller Mark W , Santos Hudson P. , O’Shea T.Michael , Fry Rebecca C. , Li Yun
Published: May 2020

DNA methylation at CpG dinucleotides is one of the most extensively studied epigenetic marks. With technological advancements, geneticists can profile DNA methylation with multiple reliable approaches. However, profiling platforms can differ substantially in the CpGs they assess, consequently hindering integrated analysis across platforms. Here, we present CpG impUtation Ensemble (CUE), which leverages multiple classical statistical and modern machine learning methods, to impute from the Illumina HumanMethylation450 (HM450) BeadChip to the Illumina HumanMethylationEPIC (HM850) BeadChip. Data were analyzed from two population cohorts with methylation measured both by HM450 and HM850: the Extremely Low Gestational Age Newborns (ELGAN) study (n=127, placenta) and the VA Boston Posttraumatic Stress Disorder (PTSD) genetics repository (n=144, whole blood). Cross-validation results show that CUE achieves the lowest predicted root mean square error (RMSE) (0.026 in PTSD) and the highest accuracy (99.97% in PTSD) compared with five individual methods tested, including k-nearest-neighbors, logistic regression, penalized functional regression, random forest and XGBoost. Finally, among all 339,033 HM850-only CpG sites shared between ELGAN and PTSD, CUE successfully imputed 289,604 (85.4%) sites, where success was defined as RMSE < 0.05 and accuracy >95% in PTSD. In summary, CUE is a valuable tool for imputing CpG methylation from the HM450 to HM850 platform.
Accurate prediction of genetic circuit behavior requires multidimensional characterization of parts
Authors: Dods Galen , Gómez-Schiavon Mariana , El-Samad Hana , Ng Andrew H.
Published: May 2020

Mathematical models can aid the design of genetic circuits, but may yield inaccurate results if individual parts are not modeled at the appropriate resolution. To illustrate the importance of this concept, we study transcriptional cascades consisting of two inducible synthetic transcription factors connected in series. Despite the simplicity of this design, we find that accurate prediction of circuit behavior requires mapping the dose responses of each circuit component along the dimensions of both its expression level and its inducer concentration. With such multidimensional characterizations, we were able to computationally explore the behavior of 16 different circuit designs. We experimentally verified a subset of these predictions and found substantial agreement. This method of biological part characterization enables the use of models to identify (un)desired circuit behaviors prior to experimental implementation, thus shortening the design-build-test cycle for more complex circuits.
Epigenome dysregulation resulting from NSD1 mutation in head and neck squamous cell carcinoma
Authors: Farhangdoost Nargess , Horth Cynthia , Hu Bo , Bareke Eric , Chen Xiao , Li Yinglu , Coradin Mariel , Garcia Benjamin A. , Lu Chao , Majewski Jacek
Published: May 2020

Epigenetic dysregulation has emerged as an important mechanism of oncogenesis. To develop targeted treatments, it is important to understand the epigenetic and transcriptomic consequences of mutations in epigenetic modifier genes. Recently, mutations in the histone methyltransferase gene NSD1 have been identified in a subset of head and neck squamous cell carcinomas (HNSCCs) – one of the most common and deadly cancers. Here, we use whole (epi)genome approaches and genome editing to dissect the downstream effects of loss of NSD1 in HNSCC. We demonstrate that NSD1 mutations are directly responsible for loss of intergenic H3K36me2 domains, followed by loss of DNA methylation, and gain of H3K27me3 in the affected genomic regions. We further show that those regions are enriched in cis-regulatory elements and that subsequent loss of H3K27ac correlates with reduced expression of their target genes. Our analysis identifies genes and pathways affected by the loss of NSD1 and paves the way to further understanding the interplay among chromatin modifications in cancer.
Quantifying Structural Diversity of CNG Trinucleotide Repeats Using Diagrammatic Algorithms
Authors: Phan Ethan N. H. , Mak Chi H.
Published: May 2020

Trinucleotide repeat expansion disorders (TREDs) exhibit complex mechanisms of pathogenesis, some of which have been attributed to RNA transcripts of overexpanded CNG repeats, resulting in possibly a gain-of-function. In this paper, we aim to probe the structures of these expanded transcript by analyzing the structural diversity of their conformational ensembles. We used graphs to catalog the structures of an NG-(CNG)16-CN and NG-(CNG)50-CN oligomer and grouped them into sub-ensembles based on their characters and calculated the structural diversity and thermodynamic stability for these ensembles using a previously described graph factorization scheme. Our findings show that the generally assumed structure for CNG repeats—a series of canonical helices connected by two-way junctions and capped with a hairpin loop—may not be the most thermodynamically favorable, and the ensembles are characterized by largely open and less structured conformations. Furthermore, a length-dependence is observed for the behavior of the ensembles’ diversity as higher-order diagrams are included, suggesting that further studies of CNG repeats are needed at the length scale of TREDs onset to properly understand their structural diversity and how this might relate to their functions.

STATEMENT OF SIGNIFICANCE

Trinucleotide repeats are DNA satellites that are prone to mutations in the human genome. A family of diverse disorders are associated with an overexpansion of CNG repeats occurring in noncoding regions, and the RNA transcripts of the expanded regions have been implicated as the origin of toxicity. Our understanding of the structures of these expanded RNA transcripts is based on sequences that have limited lengths compared to the scale of the expanded transcripts found in patients. In this paper, we introduce a theoretical method aimed at analyzing the structure and conformational diversity of CNG repeats, which has the potential of overcoming the current length limitations in the studies of trinucleotide repeat sequences.
Intra-tumor heterogeneity of Diffuse Large B-cell Lymphoma involves the induction of diversified stroma-tumor interfaces
Authors: Sangaletti Sabina , Iannelli Fabio , Zanardi Federica , Cancila Valeria , Portararo Paola , Botti Laura , Vacca Davide , Chiodoni Claudia , Di Napoli Arianna , Valenti Cesare , Vegliante Maria Carmela , Pisati Federica , Gulino Alessandro , Ponzoni Maurilio , Colombo Mario Paolo , Tripodo Claudio
Published: May 2020

Intra-tumor heterogeneity in lymphoid malignancies is articulated around several fundamentals, encompassing selection of genetic subclonal events and epigenetic regulation of transcriptional programs. Clonally-related neoplastic cell populations are unsteadily subjected to immune editing and metabolic adaptations within different tissue microenvironments. How tissue-intrinsic mesenchymal determinants impact on the diversification of aggressive lymphomas is still unknown. In this study we adopted the established A20 line-based model of Diffuse Large B-cell Lymphoma (DLBCL), to investigate the intra-tumor heterogeneity associated with the infiltration of different tissue microenvironments and the specific mesenchymal modifications that characterize stromal adaptation to lymphoma seeding. Combiningin situquantitative immunophenotypical analyses and RNA sequencing, we found that the tissue microenvironment casts a relevant influence over A20 transcriptional landscape also impacting on Myc and DNA damage response programs. Extending the investigation to mice deficient for the matricellular protein Sparc, a stromal determinant endowed with a strong prognostic significance in human DLBCL, we demonstrated a different immune imprint on A20 cells related to stromalSparcproficiency. The study provides the first evidence of human DLBCL intra-lesional heterogeneity arising from diversified mesenchymal contextures and impacting on MYC expression, advancing the challenge for resolving intra-tumor heterogeneity probing stromal/immune interfaces.

KEY POINTS

Diversified stromal adaptations of infiltrated tissues shape DLBCL intra-tumor heterogeneity regulating transcriptional/phenotypic features

Stromal Sparc, which endorses prognostic significance in DLBCL, tunes the immune pressure exerted on lymphoma cells by the microenvironment
On the Ontological Foundations of Cellular Development
Authors: Burek Patryk , Scherf Nico , Herre Heinrich
Published: May 2020

Time-lapse microscopy is a principal tool to unravel the mystery of how cells form and maintain organisms. The complexity of the domain of cellular dynamics demands a conceptual architecture as a solid theoretical foundation that supports the integration of knowledge obtained across experiments and theories. In this work, we outline the ontological foundation of cellular genealogies, a key concept for describing and representing of cellular development. We build the conceptual framework following the onto-axiomatic method: We first analyse the domain within the context of a top-level ontology (GFO). The resulting domain-specification provides the basis for a conceptualisation where we introduce concepts and relations. From these conceptualisations, we then construct model-structures adhering to the principles of model-theory. We finally elaborate axioms based on these model-structures. The developed framework provides the fundamental concepts underlying a Cell Tracking Ontology (CTO) that supports extraction and integration of biological knowledge from systems-level experiments across different types of observations at the single-cell level.
Structure and lipid dynamics in theA. baumanniimaintenance of lipid asymmetry (MLA) inner membrane complex
Authors: Mann Daniel , Fan Junping , Farrell Daniel P. , Somboon Kamolrat , Muenks Andrew , Tzokov Svetomir B. , Khalid Syma , Dimaio Frank , Miller Samuel I. , Bergeron Julien R. C.
Published: May 2020

Multi-resistant bacteria are a major threat in modern medicine. The gram-negative coccobacillusAcinetobacter baumanniicurrently leads the WHO list of pathogens in critical need for new therapeutic development. The maintenance of lipid asymmetry (MLA) protein complex is one of the core machineries that transport lipids from/to the outer membrane in gram-negative bacteria. It also contributes to broad-range antibiotic resistance in several pathogens, most prominently inA. baumannii. Nonetheless, the molecular details of its role in lipid transport has remained largely elusive.

Here, we report the cryo-EM structures of the core MLA complex, MlaBDEF, from the pathogenA. baumannii, in the apo-, ATP- and ADB-bound states. These structures reveal multiple lipid binding sites, in the cytosolic and periplasmic side of the complex. Molecular dynamics simulations suggest their potential trajectory across the membrane. Collectively with the recently-reported structures of theE.coliorthologue, these data also allows us to propose a molecular mechanism of lipid transport by the MLA system.