bluuebunny/crossref_metadata_2025 huggingface dataset:
Covid-19 Pandemic Data Analysis and Forecasting using Machine Learning Algorithms
Authors: Sengupta Sohini , Mugde Sareeta , Sharma Garima
Published: June 2020

India reported its first Covid-19 case on 30th Jan 2020 and the number of cases reported heavily escalated from March, 2020. This research paper analyses COVID -19 data initially at a global level and then drills down to the scenario obtained in India. Data is gathered from multiple data sources-several authentic government websites. The need of the hour is to accurately forecast when the numbers will reach at its peak and then diminish. It will be of huge help to public welfare professionals to plan the preventive measures to be taken keeping the economic balance of the country as well. Variables such as gender, geographical location, age etc. have been represented using Python and Data Visualization techniques. Time Series Forecasting techniques including Machine Learning models like Linear Regression, Support Vector Regression, Polynomial Regression and Deep Learning Forecasting Model like LSTM(Long short-term memory) are deployed to study the probable hike in cases and in the near future. A comparative analysis is also done to understand which model fits the best for our data. Data is considered till 30thJuly, 2020. The results show that a statistical model named sigmoid model is outperforming other models. Also the Sigmoid model is giving an estimate of the day on which we can expect the number of active cases to reach its peak and also when the curve will start to flatten. Strength of Sigmoid model lies in providing a count of date that no other model offers and thus it is the best model to predict Covid cases counts –this is unique feature of analysis in this paper. Certain feature engineering techniques have been used to transfer data into logarithmic scale as is affords better comparison removing any data extremities or outliers. Based on the predictions of the short-term interval, our model can be tuned to forecast long time intervals.
Discriminative Subtyping of Lung Cancers from Histopathology Images via Contextual Deep Learning
Authors: Lengerich Benjamin J. , Al-Shedivat Maruan , Alavi Amir , Williams Jennifer , Labbaki Sami , Xing Eric P.
Published: June 2020

Summarizing multiple data modalities into a parsimonious cancer “subtype” is difficult because the most informative representation of each patient’s disease is not observed. We propose to model these latent summaries asdiscriminative subtypes: sample representations which induce accurate and interpretable sample-specific models for downstream predictions. In this way, discriminative subtypes, which are shared between data modalities, can be estimated from one data modality and optimized according to the predictions induced in another modality. We apply this approach to lung cancer by training a deep neural network to predict discriminative subtypes from histopathology images, and use these predicted subtypes to generate models which classify adenocarcinoma, squamous cell carcinoma, and healthy tissue based on transcriptomic signatures. In this way, we optimize the latent discriminative subtypes through induced prediction loss, and the discriminative subtypes are interpreted with standard interpretation of transcriptomic predictive models. Our framework achieves state-of-the-art classification accuracy (F1-score of 0.97) and identifies discriminative subtypes which link histopathology images to transcriptomic explanations without requiring pre-specification of morphological patterns or transcriptomic processes.
Meningoencephalitis associated with COVID-19: A systematic review
Authors: Mondal Ritwick , Ganguly Upasana , Deb Shramana , Shome Gourav , Pramanik Subhasish , Bandyopadhyay Deebya , Lahiri Durjoy
Published: June 2020

Background and aims

With the growing number of COVID-19 cases in recent times, the varied range of presentations is progressively becoming an addressing issue among clinicians. A significant set of patients with extra pulmonary symptoms has been reported worldwide. Neurological involvement in the form of altered mental status, loss of consciousness in considerable amounts has drawn attention of physicians all across the globe. Here we venture out to summarise the clinical profile, investigations and radiological findings among patients with SARS-CoV-2 associated meningoencephalitis in the form of a systematic review, which may aid clinicians in early diagnosis and prognostic evaluation of the disease.

Methodology

This review was carried out based on the existing PRISMA (Preferred Report for Systemic Review and Meta analyses) consensus statement. The data for this review was collected from four databases: Pubmed/Medline, NIH Litcovid, Embase and Cochrane library and Preprint servers up till 10th June, 2020. Search strategy comprised of a range of keywords from relevant medical subject headings which includes “SARS-COV-2”, “COVID-19”, “meningoencephalitis” etc. All peer reviewed, case control, case report, pre print articles satisfying our inclusion criteria were involved in the study. The inclusion prerequisites comprised of confirmed SARS-CoV-2 cases with neurological manifestations, previous cases of SARS-CoV, MERS-CoV with neurological involvement provided all the studies were published in English language. Quantitative data was expressed in mean+/-SD, while the qualitative date in percentages. Paired t test was used for analysing the data based on differences between mean and respective values with a p value of <0.05 considered to be statistically significant.

Results

A total of 43 cases were involved from 24 studies after screening from databases and preprint servers, out of which 29 of them had completed investigation profile and were included in the final analysis. Clincial and Laboratory findings as well as neuroimaging findings (CT, MRI and MRS) revealed consistent presentations towards association of COVID-19 with meningoencephalitis. Epileptogenic pictures were also evident on EEG (electroencephalogram) findings.

Conclusion

SARS-CoV-2 has been isolated from CSF as well as cerebrum of cases with meningoencephalitis depicting the natural tendency of the virus to invade the central nervous system. Speculations about retrograde olfactory transport or alternative haematogenous spread seem to be correlating with above findings. This review may raise the index of suspicion about COVID-19 among clinicians while attending patients with neurological manifestations.
Maternal obesity and metabolic disorders associate with congenital heart defects in the offspring: a systematic review
Authors: Hedermann Gitte , Hedley Paula L , Thagaard Ida N , Krebs Lone , Ekelund Charlotte Kvist , Sørensen Thorkild IA , Christiansen Michael
Published: June 2020

Congenital heart defects (CHDs) are the most common congenital malformations and affect neonatal mortality and morbidity. The aetiology of CHDs is complex. Large cohort studies have reported an association between higher risk of CHDs in the offspring and individual maternal metabolic disorders such as obesity, diabetes, hypertension, and preeclampsia, all conditions that can be related to insulin resistance or hyperglycaemia and possibly metabolic syndrome (MetS). The aim of this review is to evaluate the existing evidence on the association between maternal metabolic disorders, defined as obesity, diabetes, hypertension, preeclampsia, dyslipidaemia, and MetS, or combinations thereof and CHDs overall as well as by subtype in the offspring. A literature search of PubMed and Embase databases identified 2,076 studies, 30 qualified for inclusion. All but one study investigated the individual metabolic disorders and their association with CHDs. Some disorders (obesity, gestational diabetes, and hypertension) increased risk of CHDs marginally whereas pre-gestational diabetes and early-onset preeclampsia were strongly associated with CHDs, without consistent differences between CHD subtypes. Future studies of the role of aberrations of the glucose-insulin homeostasis in the common aetiology and mechanisms of metabolic disorders, present during pregnancy, and their association with CHDs as well as subtypes of CHDs are needed.
Assessment of respiratory droplet transmission during the ophthalmic slit lamp exam: a particle tracking analysis
Authors: Shah Sahil H. , Garg Anupam K. , Patel Shiv , Yim Wonjun , Jokerst Jesse , Chao Daniel L.
Published: June 2020

Importance

The global COVID-19 pandemic, which began in late 2019, has resulted in a renewed focus on the importance of personal protective equipment (PPE) and other interventions to decrease the spread of infectious diseases. While several ophthalmology organizations have recently released guidance on appropriate PPE for surgical procedures and ophthalmology clinics, there is limited experimental evidence demonstrating the efficacy of the various interventions that have been suggested. In this study, we evaluate high-risk aspects of the slit-lamp exam and the effect of various PPE interventions.

Objective

To determine the effectiveness of surgical masks, slit lamp shields, and gloves in decreasing the spread of large droplets in an ophthalmology clinical setting and evaluating high-risk sources of contamination.

Design

Experimental cough simulation using a fluorescent surrogate of respiratory droplets during an ophthalmic slit lamp examination.

Setting

Single-center

Participants

Patient Simulation

Main outcomes and measure(s)

Presence of fluorescent particles in the air near or on slit lamp and simulated slit lamp examiner.

Results

Simulated coughing without a mask or slit lamp shield resulted in widespread dispersion of fluorescent droplets on the model slit lamp examination. Coughing with a mask resulted in the most significant decrease in fluorescent droplets, however, particles were still seen to escape from the top of the mask. Coughing with the slit lamp shield alone blocked the majority of forward particle dispersion; however significant distributions of respiratory droplets were found on the slit lamp joystick as well as table. Coughing with both mask and slit lamp shield resulted in the least dispersion on to the simulated examiner. Scanning electron microscopy demonstrated particle sizes of 3-100μm.

Conclusion and relevance

Masking has the greatest effect in limiting spread of respiratory droplets, while slit lamp shields, and gloves also contribute to limiting exposure to respiratory droplets from SARS-CoV-2 during slit lamp examination.

Key Points

Question

How effective are certain personal protective equipment and interventions in the clinic in preventing respiratory droplet spread?

Findings

Simulating patient coughing during the slit lamp exam demonstrated that masking appeared to be the most effective intervention to prevent spread of respiratory droplets. Slit lamp shields and gloves were also effective in decreasing exposure to respiratory droplets.

Meaning

This study confirms the importance of masking, slit lamp shields, as well as gloves as important interventions to limit exposure to respiratory droplets from respiratory viruses such as SARS-CoV-2.
Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance
Authors: Li Li , Lin Ling , Veeraraghavan Jamunarani , Hu Yiheng , Wang Xian , Lee Sanghoon , Tan Ying , Schiff Rachel , Wang Xiao-Song
Published: June 2020

Background

Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes and recent studies suggest the important role ofESR1mutations and fusions in endocrine resistance. Previously we reported a recurrentESR1fusion calledESR1-CCDC170in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequentESR1fusion, its functional role in endocrine resistance have not been studiedin vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized.

Methods

The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays.

Results

Our results suggested that differentESR1-CCDC170fusions endow different levels of reduced endocrine sensitivityin vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib.

Conclusion

ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.
Novel reference transcriptomes for the sponges Carteriospongia foliascens and Cliona orientalis and associated algal symbiont Gerakladium endoclionum
Authors: Strehlow Brian W. , Pineda Mari-Carmen , Kenkel Carly D. , Laffy Patrick , Duckworth Alan , Renton Michael , Clode Peta L. , Webster Nicole S
Published: June 2020

Transcriptomes from sponges are important resources for studying the stress responses of these ecologically important filter feeders, the interactions between sponges and their symbionts, and the evolutionary history of metazoans. Here, we generated reference transcriptomes for two common and cosmopolitan Indo-Pacific sponge species: Carteriospongia foliascens and Cliona orientalis. We also created a reference transcriptome for the primary symbiont of C. orientalis – Gerakladium endoclionum. To ensure a full repertoire of transcripts were included, clones of each sponge species were exposed to a range of individual stressors: decreased salinity, elevated temperature, elevated suspended sediment concentrations, sediment deposition and light attenuation. RNA extracted from all treatments was pooled for each species, using equal concentrations from each clone. Sequencing of pooled RNA yielded 409 and 418 million raw reads for C. foliascens and C. orientalis holobionts (host and symbionts), respectively. Reads underwent quality trimming before assembly with Trinity. Assemblies were filtered into sponge-specific or, for G. endoclionum, symbiont-specific assemblies. Assemblies for C. foliascens, C. orientalis, and G. endoclionum contained 67,304, 82,895, and 28,670 contigs, respectively. Contigs represented 15,248-37,344 isogroups (∼genes) per assembly, and N50s ranged 1,672-4,355 bp. Gene ortholog analysis verified a high level of completeness and quality for sponge-specific transcriptomes, with an average 93% of core EuKaryotic Orthologous Groups (KOGs) and 98% of single-copy metazoan core gene orthologs identified. The G. endoclionum assembly was partial with only 56% of core KOGs and 32% of single-copy eukaryotic core gene orthologs identified. These reference transcriptomes are a valuable resource for future molecular research aimed at assessing sponge stress responses.
Antibiotics effects on the fecal metabolome in preterm infants
Authors: Patton Laura , Li Nan , Garrett Timothy J. , Ruoss J. Lauren , Russell Jordan T. , de la Cruz Diomel , Bazacliu Catalina , Polin Richard A. , Triplett Eric W. , Neu Josef
Published: June 2020

Within a randomized prospective pilot study of preterm infants born less than 33 weeks gestation, fecal samples were collected weekly and metabolomic analysis was performed. The objective is to evaluate for differences in fecal metabolites in infants exposed to antibiotics vs not exposed to antibiotics in the first 48hours after birth. Significant differences were seen in the antibiotics vs no antibiotics group, including pathways related to vitamin biosynthesis, bile acids, amino acid metabolism and neurotransmitters. Early antibiotic exposure in preterm infants may alter metabolites in the intestinal tract of preterm infants. Broader multi-omic studies that address mechanisms will guide more prudent antibiotic use in this population.
Anin vitrohuman-based fracture gap model – Mimicking the crosstalk between bone and immune cells
Authors: Pfeiffenberger Moritz , Damerau Alexandra , Ponomarev Igor , Bucher Christian H. , Chen Yuling , Barnewitz Dirk , Thöne-Reineke Christa , Hoff Paula , Buttgereit Frank , Gaber Timo , Lang Annemarie
Published: June 2020

The interaction between the bone and immune cells plays a crucial role in bone pathologies such as disturbed fracture healing. After a trauma, the initially formed fracture hematoma in the fracture gap contains all important components (immune/stem cells, mediators) to directly induce bone regeneration and is therefore of great importance but most susceptible to negative influences. Thus, reliablein vitromodels are needed to study the underlying mechanisms and to predict the efficiency of novel therapeutic approaches. Since common bioengineering approaches exclude the immune component, we introduce anin vitro3D fracture gap model which combines scaffold-free bone-like constructs with a fracture hematoma model consisting of human peripheral blood (immune cells) and bone marrow-derived mesenchymal stromal cells. Ourin vitro3D fracture gap model provides all osteogenic cues to induce the initial bone healing processes, which were further promoted by applying the osteoinductive deferoxamine (DFO). Thus, we were able to distinctly mimic processes of the initial fracture phase and demonstrated the importance of including the crosstalk between bone and immune cells.
Dynamic configurations of meiotic hotspot determinants
Authors: Chuang Yu-Chien , Smith Gerald R.
Published: June 2020

During meiosis, appropriate DNA double-strand break (DSB) and crossover distributions are required for proper homologous chromosome segregation in most species. Linear element proteins (LinEs) ofSchizosaccharomyces pombeare DSB hotspot determinants. Clusters of LinE-bound hotspots form within ∼200 kb chromosomal regions independent of DSB formation. Previous reports showed that LinEs form chromatin-bound, dot-like nuclear foci in nuclear spreads and in fixed cells. Here, we investigated the regulation of LinE configuration and distribution in live cells using super-resolution fluorescence microscopy. In live cells at optimal meiotic temperature (∼25°C), LinEs made long linear forms, not previously reported, in both zygotic and azygotic meiosis and shared other characteristics with the synaptonemal complex in other species. LinE structures appeared around the time of replication, underwent a dotty-to-linear-to-dotty configurational transition, and disassembled before the first meiotic division. DSB formation and repair did not detectably influence LinE structure formation, but failure of DSB formation delayed LinE structure disassembly. Several LinE missense mutations formed dotty but not linear LinE configurations. Our study reveals a second, important configuration of LinEs, which suggests that LinE complexes are involved in regulating meiotic events, such as DSB repair, in addition to their established role in DSB formation.
HLH-30 dependent rewiring of metabolism during starvation inC. elegans
Authors: Dall Kathrine B. , Havelund Jesper F. , Harvald Eva Bang , Witting Michael , Færgeman Nils J.
Published: June 2020

One of the most fundamental challenges for all living organisms is to sense and respond to alternating nutritional conditions in order to adapt their metabolism and physiology to promote survival and achieve balanced growth. Here, we applied metabolomics and lipidomics to examine temporal regulation of metabolism during starvation in wildtypeCaenorhabditis elegansand in animals lacking the transcription factor HLH-30. Our findings show for the first time that starvation alters the abundance of hundreds of metabolites and lipid species in a temporal- and HLH-30-dependent manner. We demonstrate that premature death ofhlh-30animals under starvation can be prevented by supplementation of exogenous fatty acids, and that HLH-30 is required for complete oxidation of long-chain fatty acids. We further show that RNAi-mediated knockdown of the gene encoding carnitine palmitoyl transferase I (cpt-1) only impairs survival of wildtype animals and not ofhlh-30animals. Strikingly, we also find that compromised generation of peroxisomes byprx-5knockdown rendershlh-30animals hypersensitive to starvation, which cannot be rescued by supplementation of exogenous fatty acids. Collectively, our observations show that mitochondrial functions are compromised inhlh-30animals and thathlh-30animals rewire their metabolism to largely depend on functional peroxisomes during starvation, underlining the importance of metabolic plasticity to maintain survival.

Abstract Figure
Sustained neural rhythms reveal endogenous oscillations supporting speech perception
Authors: van Bree Sander , Sohoglu Ediz , Davis Matthew H , Zoefel Benedikt
Published: June 2020

Rhythmic sensory or electrical stimulation will produce rhythmic brain responses. These rhythmic responses are often interpreted as endogenous neural oscillations aligned (or “entrained”) to the stimulus rhythm. However, stimulus-aligned brain responses can also be explained as a sequence of evoked responses, which only appear regular due to the rhythmicity of the stimulus, without necessarily involving underlying neural oscillations. To distinguish evoked responses from true oscillatory activity, we tested whether rhythmic stimulation produces oscillatory responses which continue after the end of the stimulus. Such sustained effects provide evidence for true involvement of neural oscillations. In Experiment 1, we found that rhythmic intelligible, but not unintelligible speech produces oscillatory responses in magnetoencephalography (MEG) which outlast the stimulus at parietal sensors. In Experiment 2, we found that transcranial alternating current stimulation (tACS) leads to rhythmic fluctuations in speech perception outcomes after the end of electrical stimulation. We further report that the phase relation between electroencephalography (EEG) responses and rhythmic intelligible speech can predict the tACS phase that leads to most accurate speech perception. Together, we provide fundamental results for several lines of research – including neural entrainment and tACS – and reveal endogenous neural oscillations as a key underlying principle for speech perception.
Mutation Maker, An Open Source Oligo Design Platform for Protein Engineering
Authors: Hiraga Kaori , Mejzlik Petr , Marcisin Matej , Vostrosablin Nikita , Gromek Anna , Arnold Jakub , Wiewiora Sebastian , Svarba Rastislav , Prihoda David , Clarova Kamila , Klempir Ondrej , Navratil Josef , Tupa Ondrej , Vazquez-Otero Alejandro , Walas Marcin W. , Holy Lukas , Spale Martin , Kotowski Jakub , Dzamba David , Temesi Gergely , Russell Jay H. , Marshall Nicholas M. , Murphy Grant S. , Bitton Danny A.
Published: June 2020

Protein engineering is the discipline of developing useful proteins for applications in research, therapeutic and industrial processes by modification of naturally occurring proteins or by invention ofde novoproteins. Modern protein engineering relies on the ability to rapidly generate and screen diverse libraries of mutant proteins. However, design of mutant libraries is typically hampered by scale and complexity, necessitating development of advanced automation and optimization tools that can improve efficiency and accuracy. At present, automated library design tools are functionally limited or not freely available. To address these issues, we developed Mutation Maker, an open source mutagenic oligo design software for large-scale protein engineering experiments. Mutation Maker is not only specifically tailored to multi-site random and directed mutagenesis protocols, but also pioneers bespoke mutagenic oligo design forde novogene synthesis workflows. Enabled by a novel bundle of orchestrated heuristics, optimization, constraint-satisfaction and backtracking algorithms, Mutation Maker offers a versatile toolbox for gene diversification design at industrial scale. Supported byin-silicosimulations and compelling experimental validation data, Mutation Maker oligos produce diverse gene libraries at high success rates irrespective of genes or vectors used. Finally, Mutation Maker was created as an extensible platform on the notion that directed evolution techniques will continue to evolve and revolutionize current and future-oriented applications.
Nucleosome composition regulates the histone H3 tail conformational ensemble and accessibility
Authors: Morrison Emma A. , Baweja Lokesh , Poirier Michael G. , Wereszczynski Jeff , Musselman Catherine A.
Published: June 2020

Sub-nucleosomal complexes including hexasomes and tetrasomes have been identified as intermediates in nucleosome assembly and disassembly. Their formation is promoted by certain histone chaperones and ATP-dependent remodelers, as well as through transcription by RNA polymerase II. In addition, hexasomes appear to be maintained in transcribed genes and could be an important regulatory factor. While nucleosome composition affects the structure and accessibility of the nucleosomal DNA, its influence on the histone tails is largely unknown. Previously, we found that the H3 tail accessibly is occluded in the context of the nucleosome due to interactions with DNA (Morrison et al, 2018). Here, we investigate the conformational dynamics of the H3 tail in the hexasome and tetrasome. Using a combination of NMR spectroscopy, MD simulations, and trypsin proteolysis, we find that the conformational ensemble of the H3 tail is regulated by nucleosome composition. Similar to what we previously found for the nucleosome, the H3 tails bind robustly to DNA within the hexasome and tetrasome, but upon loss of the H2A/H2B dimer, we determined that the adjacent H3 tail has an altered conformational ensemble, increase in dynamics, and increase in accessibility. Similar to observations of DNA dynamics, this is seen to be asymmetric in the hexasome. Our results indicate that nucleosome composition has the potential to regulate chromatin signaling at the histone tails and ultimately help shape the chromatin landscape.
Investigating the accuracy of imputed genotypes in Nellore cattle using the ARS-UCD1.2 assembly of the bovine genome
Authors: da Costa Hermisdorff Isis , Costa Raphael Bermal , de Albuquerque Lucia Galvão , Pausch Hubert , Kadri Naveen Kumar
Published: June 2020

Background

Imputation accuracy among other things depends on the size of the reference panel, the marker’s minor allele frequency (MAF), and the correct placement of variants on the reference genome assembly. Using high-density genotypes of 3938 Nellore cattle from Brazil, we investigated the accuracy of imputation from 50K to 777K SNP density, using map positions determined according to the bovine genome assemblies UMD3.1 and ARS-UCD1.2. We assessed the effect of reference and target panel sizes on the pre-phasing-based imputation quality using ten-fold cross-validation. Further, we compared the reliability of the model-based imputation quality score (Rsq) from Minimac3 to empirical imputation accuracy.

Results

The overall accuracy of imputation measured as the squared correlation between true and imputed allele dosages (R2dose) was virtually identical using either the UMD3.1 or ARS-UCD1.2 genome assembly. When the size of the reference panel increased from 250 to 2000, R2doseincreased from 0.845 to 0.917, and the number of polymorphic markers in the imputed data set increased from 586,701 to 618,660. Advantages in both accuracy and marker density were also observed when larger target panels were imputed, likely resulting from more accurate haplotype inference. Imputation accuracy and the marker density in the imputed data increased from 0.903 to 0.913 and from 593,239 to 595,570 when haplotypes were inferred in 500 and 2900 target animals, respectively. The model-based imputation quality scores from Minimac3 (Rsq) were highly correlated to but systematically higher than empirically estimated accuracies. The correlation between these metrics increased with the size of the reference panel and MAF of imputed variants.

Conclusions

Accurate imputation of BovineHD BeadChip markers is possible in Nellore cattle using the new bovine reference genome assembly ARS-UCD1.2. The use of large reference and target panels improves the accuracy of the imputed genotypes and provides genotypes for more markers segregating at low frequency for downstream genomic analyses. The model-based imputation quality score from Minimac3 (Rsq) can be used to detect poorly imputed variants but its reliability depends on the size of the reference panel used and MAF of the imputed variants.
Preferred endocytosis of amyloid precursor protein from cholesterol-enriched lipid raft microdomains
Authors: Cho Yoon Young , Kwon Oh-Hoon , Chung Sungkwon
Published: June 2020

Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis, and delivered to endosomes and lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to non-raft localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results indicate that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer’s disease.
Transparency and open science reporting guidelines in sleep research and chronobiology journals
Authors: Spitschan Manuel , Schmidt Marlene H. , Blume Christine
Published: June 2020

“Open science” is an umbrella term describing various aspects of transparent and open science principles. The adoption of open science principles at different levels of the scientific process (e.g., individual researchers, laboratories, institutions) has been rapidly changing the scientific research landscape in the past years, but uptake of these principles differ from discipline to discipline. Here, we asked to what extent journals in the field of sleep and chronobiology research encourage or even require following transparent and open science principles in their author guidelines. To this end, we scored the author guidelines of a comprehensive set of 28 sleep and chronobiology journals, including the major outlets in the field, using the standardised Transparency and Openness (TOP) Factor. This instrument rates the extent to which journals encourage or require following various aspects of open science, including data citation, data transparency, analysis code transparency, materials transparency, design and analysis guidelines, study pre-registration, analysis plan pre-registration, replication, registered reports, and the use of open science badges. Across the 28 journals, we find low values on the TOP Factor (median [25th, 75thpercentile] 2.5 [1, 3], min. 0, max. 9, out of a total possible score of 28). This suggests an opportunity for sleep and chronobiology journals to further support the recent developments by implementing transparency and openness principles in their guidelines and making adherence to them mandatory.
TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
Authors: Cunningham Kathleen M. , Zhang Ke , Ruan Kai , Maulding Kirstin , Senturk Mumine , Grima Jonathan , Sung Hyun , Zuo Zhongyuan , Song Helen , Rothstein Jeffrey D. , Bellen Hugo J. , Lloyd Thomas E.
Published: June 2020

Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which impaired NCT causes neurodegeneration remain unclear. In aDrosophilascreen, we identified Ref(2)p/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy ofDrosophilatissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.
Identification of regulatory microRNAs for hypoxia induced coagulation mechanism byIn-silicoanalysis
Authors: Hembrom Anju A. , Srivastava Swati , Garg Iti , Kumar Bhuvnesh
Published: June 2020

Background

Hypoxia (oxygen deprivation) is known to induce a prothrombotic state by activating the process of coagulation. Hypoxia inducible factor (HIF), is a major transcription factor involved in cellular response to low oxygen tension. MicroRNAs (miRNAs) are non-coding regulatory sequences capable of post-translational modification of multiple genes. Present study aimed to identify common regulatory miRNAs of HIF gene family and coagulation pathway byIn-silicoapproach in order to understand the molecular mechanism underlying the process of hypoxia induced coagulation.

Methods

HIF family and Coagulation pathway genes along with their receptors and mediators were enlisted after comprehensive literature review. Thorough search of three highly cited database was done to identify the miRNAs targeting these genes. The extracted miRNA list was then prioritized on the basis of number and functional relevance of genes targeted. The target genes of all prioritized miRNAs were listed and subjected to followed by gene ontology (GO) study and pathway analysis.

Result

PresentIn-silicoanalysis identified five candidate miRNAs, viz., hsa-mir-4433a-3p, hsa-mir-4667-5p, hsa-mir-6735-5p, hsa-mir-6777-3p and hsa-mir-6815-3p that co-regulate genes of HIF family and coagulation pathway. GO and pathway analysis revealed that genes regulated by these five microRNAs, predominantly modulate genes facilitating coagulation and hypoxic response.

Conclusion

We identified five key microRNAs involved in body’s response to hypoxia and potentially involved in the blood coagulation cascade as well. These five candidate miRNAs may serve as putative epigenetic biomarkers and therapeutic targets to modulate the process of hypoxia induced coagulation.
The immune-opioid axis in prediabetes: prediction of prediabetes with insulin resistance by plasma interleukin-10 and Endomorphin-2 to kappa-opioid receptors ratio
Authors: Moustafa Shatha Rouf
Published: June 2020

Background

Prediabetes is characterized by a hemoglobin A1c of 5.7%–6.4% and fasting blood glucose of 100–125 mg/dl. A high percentage of prediabetes subjects develops into type 2 diabetes mellitus in the following years. The effect of opioid peptides and their receptors, in addition to immunological cytokines on prediabetes, is not well understood.

Objective

We hypothesize that opioid peptides and their receptors affect the insulin and the insulin resistance (IR) in patients with prediabetes and that the immune cytokines, IL-6 (inflammatory factor) and IL-10 (anti-inflammatory factor), influence the opioid system.

Methods

A total of 60 patients with prediabetes and IR (prediabetes+IR), 60 patients with prediabetes without IR (prediabetes-IR), and 60 controls participated in the study. The IR state was HOMAIR > 2.5. The enzyme linked immunosorbent assay was used to measure interleukin (IL)-6, IL-10, μ- and κ-opioid receptors (MOR and KOR), endomorphin-2 (EM2), and β- endorphin (βEP).

Results

The subjects with prediabetes had dyslipidemia, and not all of them underwent the IR state. The IL-6, IL-10, β-endorphin, MOR, and endomorphin-2 were higher in the prediabetes subgroups compared with the control group. MOR was correlated with IL-10 and KOR. Prediabetes+IR can be predicted by the increased levels of the combination of IL-10, βEP, and EM2 and by the combination of IL-10 and endomorphin-2/KOR with good sensitivity and specificity.

Conclusion

Opioid peptides and their receptors were upregulated in patients with prediabetes depending on the significance of IR. These changes in the opioid system depend on the immune cytokines. Both systems need to be normalized to prevent further development into diabetes mellitus.
What happens after a blood meal? A transcriptome response from the main tissues involved in egg production inRhodnius prolixus, an insect vector of Chagas disease
Authors: Leyria Jimena , Orchard Ian , Lange Angela B.
Published: June 2020

The blood-sucking hemipteranRhodnius prolixusis a vector of Chagas disease, one of the most neglected tropical diseases affecting several million people, mostly in Latin America. The blood meal is an event with a high epidemiological impact since in adult mated females it initiates the production of hundreds of eggs. By means of RNA-Sequencing (RNA-Seq) we have examined how a blood meal influences mRNA expression in the central nervous system (CNS), fat body and ovaries in order to promote egg production, focusing on tissue-specific responses under controlled nutritional conditions. We illustrate the cross talk between reproduction and a) lipids, proteins and trehalose metabolism, b) neuropeptide and neurohormonal signaling, and c) the immune system. Overall, our molecular evaluation confirms and supports previous studies and provides an invaluable molecular resource for future investigations on different tissues involved in successful reproductive events. Analyses like this can be used to increase the chances of developing novel strategies of vector population control by translational research, with less impact on the environment and more specificity for a particular organism.

Author summary

The blood-sucking hemipteranRhodnius prolixusis one of the main vectors of Chagas disease. The blood meal is an event with a high epidemiological impact since in adult mated females, blood-gorging leads to the production of hundreds of eggs. This work describes an in-depth central nervous system (CNS), ovary and fat body transcriptome analysis, focusing on transcripts related to blood intake which may be relevant in promoting egg production. To date, the principle focus in Chagas disease prevention is on the elimination of triatomine vectors and their progeny. This work will serve as a starting point for initiating novel investigations on targets identified with a potential for use in vector control; for example using specific genes to generated symbiont-mediated RNAi, a powerful technology which provides a novel means in biocontrol against tropical disease vectors.
Food-Poisoning Bacteria Employ a Citrate Synthase and a Type II NRPS to Synthesize Bolaamphiphilic Lipopeptide Antibiotics
Authors: Dose Benjamin , Ross Claudia , Niehs Sarah P. , Scherlach Kirstin , Bauer Johanna P. , Hertweck Christian
Published: June 2020

Mining the genome of the food-spoiling bacteriumBurkholderia gladiolipv.cocovenenansrevealed five non-ribosomal peptide synthetase (NRPS) gene clusters, including an orphan gene locus(bol).Gene inactivation and metabolic profiling linked thebolgene cluster to novel bolaamphiphilic lipopeptides with antimycobacterial activity. A combination of chemical analyses and bioinformatics elucidated the structures of bolagladin A and B, lipocyclopeptides featuring an unusual dehydro-β-alanine enamide linker fused to an unprecedented tricarboxylic fatty acid tail. Through a series of targeted gene deletions we proved the involvement of a designated citrate synthase (CS), priming ketosynthases (KS III), a type II NRPS including a novel desaturase for enamide formation, and a multimodular NRPS generating the cyclopeptide. Network analyses revealed the evolutionary origin of the CS and identified cryptic CS/NRPS gene loci in various bacterial genomes.
Urbanization promotes specific bacteria in freshwater microbiomes including potential pathogens
Authors: Numberger Daniela , Zoccarato Luca , Woodhouse Jason , Ganzert Lars , Sauer Sascha , Grossart Hans-Peter , Greenwood Alex
Published: June 2020

Freshwater ecosystems are characterized by complex and highly dynamic microbial communities that are strongly structured by their local environment and biota. Growing city populations and the process of urbanization substantially alter freshwater environments. To determine the changes in freshwater microbial communities associated with urbanization, full-length 16S rRNA gene PacBio sequencing was performed from surface water and sediments from a wastewater treatment plant, urban and rural lakes in the Berlin-Brandenburg region, Northeast Germany. Water samples exhibited highly habitat specific bacterial communities with multiple genera showing clear urban signatures. We identified potentially harmful bacterial groups associated with environmental parameters specific to urban habitats such asAlistipes, Escherichia/Shigella, RickettsiaandStreptococcus. We demonstrate that urbanization alters natural microbial communities in lakes and, via simultaneous eutrophication, creates favorable conditions that promote specific bacterial genera including potential pathogens. Our findings are of global relevance highlighting a long-term health risk in urbanized waterbodies, at a time of accelerated global urbanization. The results demonstrate the urgency for undertaking mitigation measures such as targeted lake restoration projects and sustainable water management efforts.
A neural surveyor to map touch on the body
Authors: Miller Luke E. , Fabio Cécile , Azaroual Malika , Muret Dollyane , van Beers Robert J. , Farnè Ales-sandro , Medendorp W. Pieter
Published: June 2020

Perhaps the most recognizable sensory map in all of neuroscience is the somatosensory homunculus. Though it seems straightforward, this simple representation belies the complex link between an activation in a somatotopic map and the associated touch location on the body. Any isolated activation is spatially ambiguous without a neural decoder that can read its position within the entire map, but how this is computed by neural networks is unknown. We propose that the somatosensory system implements multilateration, a common computation used by surveying and GPS systems to localize objects. Specifically, to decode touch location on the body, multilateration estimates the relative distance between the afferent input and the boundaries of a body part (e.g., the joints of a limb). We show that a simple feedforward neural network, which captures several fundamental receptive field properties of cortical somatosensory neurons, can implement a Bayes-optimal multilateral computation. Simulations demonstrated that this decoder produced a pattern of localization variability between two boundaries that was unique to multilateration. Finally, we identify this computational signature of multilateration in actual psychophysical experiments, suggesting that it is a candidate computational mechanism underlying tactile localization.
Activation of the Integrated Stress Response in drug-tolerant melanoma cells confers vulnerability to mitoribosome-targeting antibiotics
Authors: Vendramin Roberto , Konnova Angelina , Adnane Sara , Cinque Sonia , Katopodi Vicky , Knezevic Zorica , Karras Panangiotis , Demesmaeker Ewout , Bosisio Francesca M , Rizzotto Lara , Bechter Oliver , Marine Jean-Christophe , Leucci Eleonora
Published: June 2020

Therapy resistance remains a major clinical challenge for the management of metastatic melanoma. Here we show that activation of the Integrated Stress Response (ISR), which we show is common in drug-tolerant and resistant melanoma, promotes selective synthesis of mitochondrial proteins in the cytosol. Since mitochondrial translation adapts to the influx of nuclear-encoded mitochondrial proteins, ISR activation indirectly enhances mitochondrial translation and makes these cells highly vulnerable to mitochondrial translation inhibitors. Treatment of melanoma with mitoribosome-targeting antibiotics, induces proteotoxic stress and significantly compromises the growth ofNRAS-mutant and immunotherapy-resistant skin melanoma as well as uveal melanoma. Additionally, a triple BRAFi/MEKi/Tigecycline combination reduces intratumour heterogeneity by abrogating emergence of dedifferentiated drug-tolerant cells, and delayed or even prevented the development of resistance in BRAFV600EPDX models. Consistently, a melanoma patient exposed to Doxycycline, a mitoribosome-targeting antibiotic commonly used to treat infections, experienced a complete and long-lasting response of a treatment-resistant lesion.

Significance

Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy inBRAF-mutant melanoma, and a therapeutic option to targetNRAS-driven and immunotherapy-resistant cutaneous melanoma and uveal melanomas.
Adhesive Contact Between Cylindrical (Ebola) and Spherical (SARS-CoV-2) Viral Particles and a Cell Membrane
Authors: Wang Jiajun , Lapinski Nicole , Zhang X. Frank , Jagota Anand
Published: June 2020

A critical event during the process of cell infection by a viral particle is attachment, which is driven by adhesive interactions and resisted by bending and tension. The biophysics of this process has been studied extensively but the additional role of externally applied force or displacement has generally been neglected. In this work we study the adhesive force-displacement response of viral particles against a cell membrane. We have built two models: one in which the viral particle is cylindrical (say, representative of filamentous virus such as Ebola) and another in which it is spherical (such as SARS-CoV-2 and Zika). Our interest is in initial adhesion, in which case deformations are small and the mathematical model for the system can be simplified considerably. The parameters that characterize the process combine into two dimensionless groups that represent normalized membrane bending stiffness and tension. In the limit where bending dominates, for sufficiently large values of normalized bending stiffness, there is no adhesion between viral particles and the cell membrane without applied force. (The zero-external-force contact width and pull-off force are both zero.) For large values of normalized membrane tension, the adhesion between virus and cell membrane is weak but stable. (The contact width at zero external force has a small value.) Our results for pull-off force and zero force contact width help to quantify conditions that could aid the development of therapies based on denying the virus entry into the cell by blocking its initial adhesion.