bluuebunny/crossref_metadata_2025 huggingface dataset:
Social Disadvantage, Politics, and SARS-CoV-2 Trends: A County-Level Analysis of United States Data
Authors: Mourad Ahmad , Turner Nicholas A. , Baker Arthur W. , Okeke Nwora Lance , Narayanasamy Shanti , Rolfe Robert , Engemann John J. , Cox Gary M. , Stout Jason E.
Published: July 2020

Background

Understanding the epidemiology of SARS-CoV-2 is essential for public health control efforts. Social, demographic, and political characteristics at the US county level might be associated with the trajectories of SARS-CoV-2 case incidence.

Objective

To understand how underlying social, demographic, and political characteristics at the US county level might be associated with the trajectories of SARS-CoV-2 case incidence.

Design

Retrospective analysis of the trajectory of reported SARS-CoV-2 case counts at the US county level during June 1, 2020 – June 30,2020 and social, demographic, and political characteristics of the county.

Setting

United States.

Participants

Reported SARS-CoV-2 cases.

Exposures

Metropolitan designation, Social Deprivation Index (SDI), 2016 Republican Presidential Candidate Victory.

Main Outcomes and Measures

SARS-CoV-2 case incidence.

Results

1023/3142 US counties were included in the analysis. 678 (66.3%) had increasing SARS-CoV-2 case counts between June 1 – June 30, 2020. In univariate analysis, counties with increasing case counts had a significantly higher SDI (median 48, IQR 24 – 72) than counties with non-increasing case counts (median 40, IQR 19 – 66; p=0.009). In the multivariable model, metropolitan areas of 250,000 – 1 million population, higher percentage of Black residents and a 10-point or greater Republican victory were independently associated with increasing case counts.

Limitations

The data examines county-level voting patterns and does not account for individual voting behavior, subjecting this work to the potential for ecologic fallacy.

Conclusion

Increasing case counts of SARS-CoV-2 in the US are likely driven by a combination of social disadvantage, social networks, and behavioral factors. Addressing social disadvantage and differential belief systems that may correspond with political alignment will be essential for pandemic control.
Efficient Sequencing, Assembly, and Annotation of Human KIR Haplotypes
Authors: Roe David , Williams Jonathan , Ivery Keyton , Brouckaert Jenny , Downey Nick , Locklear Chad , Kuang Rui , Maiers Martin
Published: July 2020

The homology, recombination, variation, and repetitive elements in the natural killer-cell immunoglobulin-like receptor (KIR) region has made full haplotype DNA interpretation impossible without physical separation of chromosomes. Here, we present a new approach using long-read sequencing to efficiently capture, sequence, and assemble diploid human KIR haplotypes. Sequences for capture probe design were derived from public full-length gene and haplotype sequences. IDT xGen® Lockdown probes were used to capture 2-8 kb of sheared DNA fragments followed by sequencing on a PacBio Sequel. The sequences were error corrected, binned, and then assembled using the Canu assembler. The assembly was evaluated on 16 individuals (8 African American and 8 Europeans) from whom ground truth was known via long-range sequencing on fosmid-isolated chromosomes. Using only 18 capture probes, the results show that the assemblies cover 97% of the GenBank reference, are 99.97% concordant, and it takes only 1.8 contigs to cover 75% of the reference. We also report the first assembly of diploid KIR haplotypes from long-read WGS, including the first sequencing of cB05∼tB01, which pairs aKIR2DS2/KIR2DS3fusion with the tB01 region. Our targeted hybridization probe capture and sequencing approach is the first of its kind to fully sequence and phase all diploid human KIR haplotypes, and it is efficient enough for population-scale studies and clinical use.
Modulating the transcriptional landscape of SARS-CoV-2 as an effective method for developing antiviral compounds
Authors: Hoagland Daisy A. , Clarke Daniel J.B. , Møller Rasmus , Han Yuling , Yang Liuliu , Wojciechowicz Megan L. , Lachmann Alexander , Oguntuyo Kasopefoluwa Y. , Stevens Christian , Lee Benhur , Chen Shuibing , Ma’ayan Avi , tenOever Benjamin R
Published: July 2020

To interfere with the biology of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, we focused on restoring the transcriptional response induced by infection. Utilizing expression patterns of SARS-CoV-2-infected cells, we identified a region in gene expression space that was unique to virus infection and inversely proportional to the transcriptional footprint of known compounds characterized in the Library of Integrated Network-based Cellular Signatures. Here we demonstrate the successful identification of compounds that display efficacy in blocking SARS-CoV-2 replication based on their ability to counteract the virus-induced transcriptional landscape. These compounds were found to potently reduce viral load despite having no impact on viral entry or modulation of the host antiviral response in the absence of virus. RNA-Seq profiling implicated the induction of the cholesterol biosynthesis pathway as the underlying mechanism of inhibition and suggested that targeting this aspect of host biology may significantly reduce SARS-CoV-2 viral load.
Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer’s-associated protein sorLA
Authors: Christensen Sofie K. , Narimatsu Yoshiki , Simoes Sabrina , Goth Christoffer K. , Vægter Christian B. , Small Scott A. , Clausen Henrik , Andersen Olav M.
Published: July 2020

The sorting receptor sorLA encoded by theSORL1gene is implicated in Alzheimer’s disease (AD) pathogenesis. Genetic studies have identified AD-associatedSORL1mutations and the expression of sorLA in AD brains is reported to be reduced. SorLA is a receptor of the retromer trafficking complex and functions at the endosome, and deficiency in sorLA phenocopies the endosomal pathologies found in AD. SorLA undergoes posttranslational modifications and maturation with ultimate ectodomain shedding, however knowledge of these processes remains limited. Here we demonstrate that sorLA exists at the cell membrane in two forms, an immature and a mature form, characterized by distinctN-glycosylation profiles. The mature sorLA form has acquired complex typeN-glycans and is shed from the cell surface by the TACE juxtmembrane cleavage. The immature form of sorLA present at the cell surface is shown to have immature ER-typeN-glycans (high-mannose type susceptible to endo H) and does not undergo shedding, however, upon endocytosis and recycling to the cell surface via endosomal trafficking pathways the immature sorLA form acquires complex-typeN-glycans. These results suggest an unusual secretion model for sorLA whereby that immature sorLA first traffics to the cell membrane without acquiring Golgi processing ofN-glycans, and only upon retrograde trafficking does sorLA acquire normal Golgi maturation ofN-glycans and become susceptible to TACE regulated shedding. Supportive evidence for this model include a sorLA mutant with deficient endosomal trafficking andin vivostudies demonstrating requirement of retromer for sorLA trafficking in the brain of retromer VPS26 deficient mice. Collectively, our study establishes the role endosomal trafficking plays in sorLA’s normal maturation, and point to impaired maturation as a signature of AD-associated sorLA dysfunction.
Causal influence of dietary habits on the risk of major depressive disorder: A diet-wide Mendelian randomization analysis
Authors: Chen Tzu-Ting , Chen Chia-Yen , Fang Chiu-Ping , Cheng Ying-Chih , Lin Yen-Feng
Published: July 2020

Background & aims

Some evidence suggests that diet may potentially increase or decrease the risk of major depressive disorder (MDD). However, the association between dietary habits and MDD remains controversial. The aim of this study is to systemically investigate the causal influence of dietary habits on the risk of MDD by Mendelian randomization (MR) using diet- and genome-wide summary data.

Methods

To perform two-sample MR, we collected publicly available genome-wide association studies’ summary statistics for dietary habits from Benjamin Neale’s lab (n= 361,194) and MDD from the Psychiatric Genomics Consortium(n =142,646). We used a weighted median approach to synthesize MR estimates across genetic instruments. For the robustness of our results, we compared weighted median results with results from the inverse-variance weighted method, the weighted mode method, and MR-PRESSO.

Results

Beef intake showed a significant protective effect against MDD (β = -1.25; p-value = 0.002; Bonferroni-corrected p-value = 0.034; 9 single nucleotide polymorphisms [SNPs]); and cereal intake was nominally significantly protective (β = -0.52; p-value = 0.011; 21 SNPs). In contrast, non-oily fish intake showed a nominally significantly effect on the risk of MDD (β = 0.84; p-value = 0.030; 6 SNPs). We obtained similar results by using an inverse-variance weighted method and weighted mode approach, although some results were non-significant. On the other hand, we did not observe any significant causal effect of MDD on dietary habits.

Conclusions

In this two-sample MR analysis, we observed that higher beef and cereal intake may be protective factors for MDD, and that higher non-oily fish intake might increase the risk for MDD. However, MDD did not appear to affect dietary habits. Potential mechanisms need to be further investigated to support our novel findings.
Locating cephalometric landmarks with multi-phase deep learning
Authors: Nishimoto Soh , Kawai Kenichiro , Fujiwara Toshihiro , Ishise Hisako , Kakibuchi Masao
Published: July 2020

Cephalometric analysis has long been one of the most helpful approaches in evaluating cranio-maxillo-facial skeletal profile. To perform this, locating anatomical landmarks on an X-ray image is a crucial step, demanding time and expertise. An automated cephalogram analyzer, if developed, will be a great help for practitioners. Artificial intelligence, including machine learning is emerging these days. Deep learning is one of the most developing techniques in data science field. The authors attempted to enhance the accuracy of an automated landmark predicting system utilizing multi-phase deep learning and voting. To guarantee objectivity, an open-to-the-public dataset, cephalometric images accompanied with coordinate values of 19 landmarks, were used. A regressional system was developed, consisted with convolutional neural networks of three phases. First phase network was to determine approximate position of each landmark, inputting whole area of compressed original images. Five secondary networks were to narrow down the area, based on the first phase prediction. Third phase networks were trained by small areas around respective landmarks, with original resolution. Third phase prediction with voting was done inputting 81 shifted areas. Successful detection rates improved as the phase advances. Voting in third phase improved successful detection rate. In comparison with previously reported benchmarks, using the same dataset, proposed system marked better results. Within the physical limitation of memory and computation, multi-phase deep learning may be a solution to deal with large images.
Age-specific social mixing of school-aged children in a US setting using proximity detecting sensors and contact surveys
Authors: Grantz Kyra H. , Cummings Derek A.T. , Zimmer Shanta , Vukotich Charles , Galloway David , Schweizer Mary Lou , Guclu Hasan , Cousins Jennifer , Lingle Carrie , Yearwood Gabby M.H. , Li Kan , Calderone Patti , Noble Eva , Gao Hongjiang , Rainey Jeanette , Uzicanin Amra , Read Jonathan M.
Published: July 2020

Comparisons of the utility and accuracy of methods for measuring social interactions relevant to disease transmission are rare. To increase the evidence base supporting specific methods to measure social interaction, we compared data from self-reported contact surveys and wearable proximity sensors from a cohort of schoolchildren in the Pittsburgh metropolitan area. Although the number and type of contacts recorded by each participant differed between the two methods, we found good correspondence between the two methods in aggregate measures of age-specific interactions. Fewer, but longer, contacts were reported in surveys, relative to the generally short proximal interactions captured by wearable sensors. When adjusted for expectations of proportionate mixing, though, the two methods produced highly similar, assortative age-mixing matrices. These aggregate mixing matrices, when used in simulation, resulted in similar estimates of risk of infection by age. While proximity sensors and survey methods may not be interchangeable for capturing individual contacts, they can generate highly correlated data on age-specific mixing patterns relevant to the dynamics of respiratory virus transmission.
Covid19, 2020 - a tutorial of sorts on reading data
Authors: Meilijson Isaac
Published: July 2020

The SIR differential equations in Epidemiology are re-examined in the context of Covid19, 2020. The number of recovered cases is calibrated in time. Methods for estimating all pertinent parameters are described. A notion of implied susceptible population size ISPS is introduced, as the potential target population size for which the solution to the SIR equations would yield the current number of new affected cases. Analysis is applied to the Covid19 2020 data of a number of countries, as reported by the Johns Hopkins University data repository. It will be observed that some countries under-report consistently the number of recovered cases.
Power law behaviour in the saturation regime of fatality curves of the COVID-19 pandemic
Authors: Vasconcelos Giovani L. , Macêdo Antônio M. S. , Duarte-Filho Gerson C. , Brum Arthur A. , Ospina Raydonal , Almeida Francisco A. G.
Published: July 2020

ABSTRAC

We apply a versatile growth model, whose growth rate is given by a generalised beta distribution, to describe the complex behaviour of the fatality curves of the COVID-19 disease for several countries in Europe and North America. We show that the COVID-19 epidemic curves not only may present a subexponential early growth but can also exhibit a similar subexponential (power-law) behaviour in the saturation regime. We argue that the power-law exponent of the latter regime, which measures how quickly the curve approaches the plateau, is directly related to control measures, in the sense that the less strict the control, the smaller the exponent and hence the slower the diseases progresses to its end. The power-law saturation uncovered here is an important result, because it signals to policymakers and health authorities that it is important to keep control measures for as long as possible, so as to avoid a slow, power-law ending of the disease. The slower the approach to the plateau, the longer the virus lingers on in the population, and the greater not only the final death toll but also the risk of a resurgence of infections.
Outcomes and factors influencing care decisions in life-threatening fetal and neonatal anomalies
Authors: Lee Esther J. , Stenekes Simone , Harlos Michael
Published: July 2020

Objective

A retrospective chart review was undertaken to describe the outcomes following the diagnosis of a life-threatening fetal and neonatal anomaly.

Study Design

Criteria for a life-threatening anomaly included genetic conditions, renal and pulmonary diseases, central nervous system anomalies (CNS), and cardiac defects. Information that could impact decision making was collected from provincial databases

Results

176 patients met the inclusion criteria. The majority of the diagnoses were in the genetic and CNS categories. 58% (n=103) decided to terminate the pregnancy. When a live birth occurred (n=39), the mean length of survival was 13.5 days (range 1-156 days), with one death occurring at home.

Conclusions

Ethnicity and geographical factors were associated with the decision to terminate a pregnancy. The involvement of the palliative care service was associated with decreased interventions. Further research to determine the needs of families would be helpful in identifying program priorities in perinatal palliative care.
The lncRNAAPOLOinteracts with the transcription factor WRKY42 to trigger root hair cell expansion in response to cold
Authors: Moison Michaël , Martínez Pacheco Javier , Lucero Leandro , Fonouni-Farde Camille , Rodríguez-Melo Johan , Mansilla Natanael , Christ Aurélie , Bazin Jérémie , Benhamed Moussa , Ibañez Fernando , Crespi Martin , Estevez José M. , Ariel Federico
Published: July 2020

Plant long noncoding RNAs (lncRNAs) have emerged as important regulators of chromatin dynamics, impacting on transcriptional programs leading to different developmental outputs. The lncRNAAUXIN REGULATED PROMOTER LOOP(APOLO) directly recognizes multiple independent loci across theArabidopsisgenome and modulates their three-dimensional chromatin conformation, leading to transcriptional shifts. Here, we show thatAPOLOrecognizes the locus encoding the root hair (RH) master regulator ROOT HAIR DEFECTIVE 6 (RHD6) and controlsRHD6transcriptional activity leading to cold-enhanced RH elongation through the consequent activation of the transcription factor gene RHD6-likeRSL4. Furthermore, we demonstrate thatAPOLOinteracts with the transcription factor WRKY42 and modulates its binding to theRHD6promoter. WRKY42 is required for the activation ofRHD6by low temperatures andWRKY42deregulation impairs cold-induced RH expansion. Collectively, our results indicate that a novel ribonucleoprotein complex involvingAPOLOand WRKY42 forms a regulatory hub which activatesRHD6by shaping its epigenetic environment and integrates signals governing RH growth and development.

The lncRNAAPOLOdirectly regulates the transcription of the root hair-master geneRHD6. In response to cold,APOLOis induced and it decoys the H3K27me3-binding protein LHP1 away fromRHD6. In addition,APOLOmodulates the binding of the transcription factor WRKY42 to theRHD6promoter at low temperatures.
A Meta-analysis of the known Global Distribution and Host Range of theRalstoniaSpecies Complex
Authors: Lowe-Power Tiffany M. , Avalos Jason , Bai Yali , Munoz Maria Charco , Chipman Kyle , Elmgreen Vienna N. , Prasad Neha , Ramirez Benjamin , Sandhar Ajay , Tom Cloe E. , Williams Darrielle
Published: July 2020

TheRalstoniaspecies complex is a group of genetically diverse plant wilt pathogens. Our goal is to create a database that contains the reported global distribution and host range ofRalstoniaclades (e.g. phylotypes and sequevars). In this fifth release, we have cataloged information from 304 sources that report one or moreRalstoniastrains isolated from 107 geographic regions. Metadata for nearly 10,000 strains are available as a supplemental table. The aggregated data suggest that the pandemic brown rot lineage (IIB-1) is the most widely dispersed lineage, and the phylotype I and IIB-4 lineages have the broadest natural host range. Although phylotype III is largely restricted to Africa, one strain collection reports a phylotype III strain isolated from Jamaica in the mid-1900s. In the previous release, we included reported presence of phylotype III strains in Brazil, but closer inspection of those results reveals that the strains were actually phylotype I strains that were mis-identified. Similarly, although phylotype IV is mostly found in East and Southeast Asia, phylotype IV strains are reported to be present in Kenya.

Additionally, we have created an open science resource for phylogenomics of the RSSC. We associated strain metadata (host of isolation, location of isolation, and clade) with almost 700 genomes in a public KBase narrative. Our colleagues can use this narrative to identify the phylogenetic position of newly sequenced strains. We further curate a set of 601 high quality genomes based on low contamination and high completeness by CheckM. Our colleagues can use the curated dataset for comparative genomics studies.
Active synthesis of type I collagen homotrimer in Dupuytren’s fibrosis is unaffected by anti-TNF-α treatment
Authors: Williamson Kate , Lee Katie J. , Beamish Emma L. , Carter Alan , Gumbs Jade A. , Cooper Gabriella , Cheung Graham , Brown Daniel , Pettitt Rob , Comerford Eithne J. , Clegg Peter D. , Canty-Laird Elizabeth G.
Published: July 2020

Dupuytren’s disease is a common fibroproliferative disease of the palmar fascia of the hand with advanced cases treated surgically. Anti-tumour necrosis factor (TNF) injection has undergone phase 2 trials and may be effective in slowing early-stage disease progression. Here we sought to determine how new synthesis of type I collagen in Dupuytren’s differs from normal palmar fascia samples and to analyse the role of TNF in aberrant collagen synthesis. Model non-fibrotic, but fibrous connective tissues, were used to analyse active type I collagen protein synthesis in development, ageing and degenerative disease, where it was restricted to early development and ruptured tissue. Dupuytren’s tissue was shown to actively synthesise type I collagen, including abnormal type I collagen homotrimer. TNF-α reducedCOL1A2gene expression only in the presence of serum in 2D cell culture and had opposing effects on collagen protein production in the presence or absence of serum. TNF-α had only limited effects in 3D tendon-like constructs. Anti-TNF did not reduce type I collagen synthesis in 3D tendon-like constructs or prevent type I collagen homotrimer synthesis in Dupuytren’s tissue. Hence, modulation of the TNF-α pathway in Dupuytren’s disease is unlikely to prevent the pathological collagen accumulation that is characteristic of fibrosis.
DHX30 coordinates cytoplasmic translation and mitochondrial function contributing to cancer cell survival
Authors: Bosco Bartolomeo , Rossi Annalisa , Rizzotto Dario , Giorgetta Sebastiano , Perzolli Alicia , Bonollo Francesco , Gaucherot Angeline , Catez Frédéric , Diaz Jean-Jacques , Dassi Erik , Inga Alberto
Published: July 2020

DHX30 was recently implicated in the translation control of mRNAs involved in p53-dependent apoptosis. Here we show that DHX30 exhibits a more general function by integrating the activities of its cytoplasmic isoform and of the more abundant mitochondrial one. The depletion of both DHX30 isoforms in HCT116 cells leads to constitutive changes in polysome-associated mRNAs, enhancing the translation of mRNAs coding for cytoplasmic ribosomal proteins while reducing the translational efficiency of the nuclear-encoded mitoribosome mRNAs. Furthermore, depletion of both DHX30 isoforms exhibits higher global translation but slower proliferation, and reduced mitochondrial energy metabolism. Isoform-specific silencing established a role for cytoplasmic DHX30 in modulating global translation. The impact on global translation and proliferation were confirmed in U2OS and MCF7 cells, although the effect of DHX30 depletion on mitochondrial gene expression was observed only in MCF7 cells. Exploiting RIP, eCLIP, and gene expression data, we identified a gene signature comprising DHX30 and fourteen mitoribosome transcripts that we candidate as direct targets: this signature shows prognostic value in several TCGA cancer types, with higher expression associated with reduced overall survival. We propose that DHX30 contributes to cell homeostasis by coordinating ribosome biogenesis, global translation, and mitochondrial metabolism. Targeting DHX30 could, thus, expose a vulnerability in cancer cells.

Author summary

Translation occurs in the cell both through cytoplasmic and mitochondrial ribosomes, respectively translating mRNAs encoded by the nuclear and the mitochondrial genome. Here we found that DHX30, an RNA-binding protein implicated in p53-dependent apoptosis, enhances the translation of mRNAs coding for cytoplasmic ribosomal proteins while reducing that of the mitoribosome mRNAs when silenced. This coordination of the cytoplasmic and mitochondrial translation machineries affected both cell proliferation and energy metabolism, suggesting an important role for this mechanism in determining the fitness of cancer cells. Indeed, the analysis of publicly available cancer datasets led us to define a 15-genes signature that is able to affect the prognosis of a subset of cancer types. In this subset, we found that higher expression of the genes composing the signature is associated with a worse prognosis. We thus propose DHX30 as a potential vulnerability in cancer cells, that could be targeted to develop novel therapeutic strategies.
Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2
Authors: Schmidt Sven H. , Weng Jui-Hung , Aoto Phillip C. , Boassa Daniela , Mathea Sebastian , Silletti Steven , Hu Junru , Wallbott Maximilian , Komives Elizabeth A , Knapp Stefan , Herberg Friedrich W. , Taylor Susan S.
Published: July 2020

In a multi-tiered approach, we explored how Parkinson’s Disease-related mutations hijack the finely tuned activation process of Leucine-Rich Repeat Kinase 2 (LRRK2) using a construct containing the ROC, Cor, Kinase and WD40 domains (LRRK2RCKW). We hypothesized that the N-terminal domains shield the catalytic domains in an inactive state. PD mutations, type-I LRRK2 inhibitors, or physiological Rab GTPases can unleash the catalytic domains while the active kinase conformation, but not kinase activity, is essential for docking onto microtubules. Mapping solvent accessible regions of LRRK2RCKWemploying hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed how inhibitor binding is sensed by the entire protein. Molecular Dynamics simulations of the kinase domain elucidated differences in conformational dynamics between wt and mutants of the DYGψ motif. While all domains contribute to regulating kinase activity and spatial distribution, the kinase domain, driven by the DYGψ motif, coordinates domain crosstalk and serves as an intrinsic hub for LRRK2 regulation.
Vascular Endothelial Growth Factor as an Immediate-Early Activator of UV-induced Skin Injury
Authors: Hartono Stella P. , Bedell Victoria M. , Alam Sk. Kayum , O’Gorman Madelyn , Serres MaKayla , Hall Stephanie R. , Pal Krishnendu , Kudgus Rachel A. , Mukherjee Priyabrata , Seelig Davis M. , Meves Alexander , Mukhopadhyay Debabrata , Ekker Stephen C. , Hoeppner Luke H.
Published: July 2020

The negative health consequences of acute ultraviolet (UV) exposure are evident, with reports of 30,000 emergency room visits annually to treat the effects of sunburn in the United States alone. Acute effects of sunburn include erythema, edema, and severe pain, and chronic overexposure to UV radiation can lead to skin cancer. While the pain associated with the acute effects of sunburn may be relieved by current interventions, existing post-sunburn treatments are not capable of reversing the cumulative and long-term pathological effects of UV exposure, an unmet clinical need. Here we show that activation of the vascular endothelial growth factor (VEGF) pathway is a direct and immediate consequence of acute UV exposure, and activation of VEGF signaling is necessary for the initiating the acute pathological effects of sunburn. In UV-exposed human subjects, VEGF signaling is activated within hours. Topical delivery of VEGF pathway inhibitors, targeted against the ligand VEGF-A (gold nanoparticles conjugated with anti-VEGF antibodies) and small molecule antagonists of VEGF receptor signaling, prevent the development of erythema and edema in UV-exposed mice. Collectively, these findings suggest targeting VEGF signaling may reduce the subsequent inflammation and pathology associated with UV-induced skin damage, which reveals a new post-exposure therapeutic window to potentially inhibit the known detrimental effects of UV on human skin.
Identifying Key Determinants of SARS-CoV-2/ACE2 Tight Interaction
Authors: Ngo Van A. , Jha Ramesh K.
Published: July 2020

SARS-CoV-2 virus, the causative agent of Covid-19, has fired up a global pandemic. The virus interacts with the human receptor angiotensin-converting enzyme 2 (ACE2) for invasion via receptor binding domain (RBD) on its spike protein. To provide a deeper understanding of this interaction, we performed microsecond simulations of the RBD-ACE2 complex for SARS- CoV-2 and compared it with the closely related SARS-CoV discovered in 2003. We show residues in the RBD of SARS-CoV-2 that were mutated from SARS-CoV, collectively help make RBD anchor much stronger to the N-terminal part of ACE2 than the corresponding residues on RBD of SARS-CoV. This would result in reduced dissociation rate of SARS-CoV-2 from human recep- tor protein compared to SARS-CoV. This phenomenon was consistently observed in simulations beyond 500 ns and was reproducible across different force fields. Altogether, our study shed light on the key residues and their dynamics at the virus spike and human receptor binding interface and advance our knowledge for the development of diagnostics and therapeutics to combat the pandemic efficiently.
A highly expressing, soluble, and stable plant-made IgG fusion vaccine strategy enhances antigen immunogenicity in mice without adjuvant
Authors: Diamos Andrew G. , Pardhe Mary D. , Sun Haiyan , Hunter Joseph G. L. , Kilbourne Jacquelyn , Chen Qiang , Mason Hugh S.
Published: July 2020

Therapeutics based on fusing a protein of interest to the IgG Fc domain have been enormously successful, though fewer studies have investigated the vaccine potential of IgG fusions. In this study, we systematically compared the key properties of seven different plant-made human IgG1 fusion vaccine candidates using Zika virus (ZIKV) envelope domain III (ZE3) as a model antigen. Complement protein C1q binding of the IgG fusions was enhanced by: 1) antigen fusion to the IgG N-terminus; 2) removal of the IgG light chain or Fab regions; 3) addition of hexamer-inducing mutations in the IgG Fc; 4) adding a self-binding epitope tag to create recombinant immune complexes (RIC); or 5) producing IgG fusions in plants that lack plant-specific β1,2-linked xylose and α1,3-linked fucose N-linked glycans. We also characterized the expression, solubility, and stability of the IgG fusions. By optimizing immune complex formation, a potently immunogenic vaccine candidate with improved solubility and high stability was produced at 1.5 mg IgG fusion per g leaf fresh weight. In mice, the IgG fusions elicited high titers of Zika-specific antibodies which neutralized ZIKV using only two doses without adjuvant, reaching up to 150-fold higher antibody titers than ZE3 antigen alone. We anticipate these findings will be broadly applicable to the creation of other vaccines and antibody-based therapeutics.

Highlights

A modified immune complex has high expression, solubility, stability, and immunogenicity.

Antigen immunogenicity is improved up to 150-fold by fusion to plant-made IgGs.

High serum IgG titers >1:500,000 were achieved with only two doses without adjuvant.
PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes
Authors: Coulson-Gilmer C. , Morgan R.D. , Nelson L. , Barnes B. , McGrail J.C. , Taylor S.S.
Published: July 2020

The discovery that PARP1/2 inhibitors selectively killBRCAmutant cells has led to a paradigm shift in the treatment of women with homologous recombination (HR)-deficient high-grade serous ovarian cancer (HGSOC), driving unprecedented improvements in progression-free and, more recently, overall survival. However, because most HGSOC cases are not HR-defective, and are therefore unlikely to benefit from PARPi-based therapies, additional strategies will be required to improve outcomes for women with HR-proficient disease. To develop novel therapeutic strategies, considerable attention is now being focused on inhibitors targeting PARG, the poly(ADP ribose) glycohydrolase that counterbalances PARP1/2 activity. Here we characterise ten ovarian cancer cell lines in response to the PARG inhibitor PDD00017273, hereafter PARGi. We demonstrate that six lines are resistant while four are sensitive, and that sensitivity correlates with several markers of persistent DNA replication stress, DNA damage and replication catastrophe, namely the accumulation of asymmetric DNA replication fibres, γH2AX and RPA foci, KAP1 and Chk1 phosphorylation, a pre-mitotic cell cycle block and, following prolonged exposure, a pan-nuclear γH2AX phenotype that indicates RPA exhaustion. We demonstrate that PARGi-sensitive cell lines have down-regulated DNA replication genes, including components of the fork protection complex, namelyTIMELESS,TIPINandCLASPIN. These observations suggest that a subset of HGSOC may respond to PARG inhibitors and that “replication stress” gene expression signature could serve as a predictive biomarker to guide the design of clinical trials.
Oxidations and amino acid substitutions in urinary proteins are the distinguishing characteristics of aging
Authors: Liu Yongtao , Pan Xuanzhen , Hua Yuanrui , Wang Yunlong , Gao Youhe
Published: July 2020

Aging is an inevitable course of life. Additionally, the risk of chronic diseases or cancer increases with age. The comprehensive identification of signs related to aging can be beneficial for the prevention and early diagnosis of geriatric diseases. The comparison of global modifications in the urine proteome is a means of multidimensional information mining. This approach is based on urine, in which changes from whole-body metabolism can accumulate. This study used the urine of healthy people at different ages (22 children, 10 young people, 6 senior people) as the research object and using high-resolution tandem mass spectrometry, label-free quantitation combined with non-limiting modification identification algorithms and random group test, compared the differences in protein chemical modifications among three groups. The results show that multi-sites oxidative modifications and amino acid substitutions are noticeable features that distinguish these three age groups of people. The proportion of multi-site oxidations in urine proteins of senior (29.76%) is significantly higher than the young group (13.71% and 12.97%), which affect the biological processes of various proteins. This study could provide a reference for studies of aging mechanisms and biomarkers of age-related disease.
Dynamics of residual malaria transmission in Central Western Senegal: Mapping the breeding sites ofAnopheles gambiaes. l
Authors: Ndiaye A. , Niang E.A , Niang-Diène A. , Nourdine M. A. , Sarr P C , Konaté L. , Faye O. , Gaye O. , Sy O.
Published: July 2020

Despite the use of several effective control interventions in the central western Senegal, residual malaria transmission still occurring in some hotspots. In order to better understand the factors associated with this situation to better tailor targeted control actions, it is critical to unravel environmental and geographical factors underlying the persistence of the disease in study hotspot villages. Hotspots villages were defined as those reporting more than six indigenous malaria cases during the previous year. A total of ten villages, including seven hotspots and three non-hotspots, were surveyed. All potential mosquito breeding sites identified in and around the tenth study villages were regularly monitored between 2013 and 2017. This monitoring concerned the presence of anophelines larvae and the collection of epidemiological, hydrogeological, topographical and biogeographical data. Throughout the study area, the number of larval breeding sites inventoried and monitored over the study period ranged from 50 to 62. They were higher, with no significant difference, in hotspot sites than in non-hotspot sites for each year of monitoring with 62.3% (56/62) in 2013, 90.9% (50/55) in 2014, 90.3% (56/62) in 2015 and 86% (43/50) in 2017 (Fisher’s exact test; p = 1). The Hotspot villages were mostly characterized by saline or moderately saline hydro-morphic and halomorphic soils allowing water retention and a suitable presence of potential larval breeding sites. Whereas non-hotspot villages are characterized mainly by a high proportion of extremely permeable sandy-textured soils due to their porosity, which reduces water retention. The annual number of confirmed malaria cases was corelated relatively with the frequency and extent of breeding sites. Malaria cases were much more higher in the hamlets located near to the breeding sites ofAn. gambiaes.l then gradually decreases with their remoteness. This study has shown that the dynamics of larval breeding sites by their longevity, stability, proximity to houses and their positiveness rate for the presence ofAnopheleslarvae could be a determining factor in the persistence of malaria hotspots in central western Senegal. The results of this study shed more light on the environmental factors underlying the residual transmission and should make it possible to better organize vector control interventions for malaria elimination in west-central Senegal.
Development of a humanized mouse model to analyze antibodies specific for human leukocyte antigen (HLA)
Authors: Yanagawa Senichiro , Tahara Hiroyuki , Shirouzu Takayuki , Kawai Shintaro , Tanaka Yuka , Ide Kentaro , Akimoto Shuji , Ohdan Hideki
Published: July 2020

In organ transplantation, human leukocyte antigen (HLA)-mismatch grafts not only induce the activation of cellular mediated immune response but also the development of chronic antibody-mediated rejection due to the donor-specific anti-HLA antibody (DSA) produced by B cells and plasma cells interacting with the graft endothelium.

Significant improvement in long-term survival after transplantation can be expected if antibody-mediated rejection due to the DSA can be overcome. However, the mechanism of producing or controlling the DSA remains to be elucidated.

In recent decades, “humanized mouse model” have been widely used for the basic research of human immune systems, but a humanized mouse model to analyze the mechanism of DSA production has not been established yet. Thus, we aimed to create a humanized mouse using a severe immunodeficiency mouse (NSG mouse) administered with human peripheral blood mononuclear cells (PBMCs). Initially, we detected very low level of human total-IgG and no anti-HLA antibodies (Abs) in these mice. The responder PBMCs with antibody-producing B cell activating factors added or regulatory T cells depleted were subsequently co-cultured with the irradiated stimulator PBMCsin vitro, and these whole cells were administered into naïve NSG mice. The humanized model with sufficient human total-IgG and anti-HLA antibody production was consequently established. Interestingly, in all these mouse models, allo-specific anti-HLA Abs production was prominently suppressed, whereas non-allo-specific anti-HLA Abs were sufficiently detectable.

Therefore, this novel humanized mouse model might be useful for analyzing the mechanism of anti-allogeneic human B cell tolerance induction.
Activating a collaborative innate-adaptive immune response to control breast and ovarian cancer metastasis
Authors: Sun Lijuan , Kees Tim , Almeida Ana Santos , Liu Bodu , He Xue-Yan , Ng David , Spector David , McNeish Iain A. , Gimotty Phyllis , Adams Sylvia , Egeblad Mikala
Published: July 2020

Many cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells. Yet, macrophages can also kill cancer cells after polarization bye.g., lipopolysaccharide (LPS, a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFNγ). They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages could therefore be a strategy for controlling cancer. Here, we show that monophosphoryl lipid A (MPLA, a derivative of LPS) with IFNγ activated macrophages isolated from metastatic pleural effusions of breast cancer patients to kill the corresponding patients’ cancer cellsin vitro. Importantly, intratumoral injection of MPLA with IFNγ not only controlled local tumor growth but also reduced metastasis in mouse models of luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA with IFNγ reprogrammed peritoneal macrophages, suppressed metastasis, and enhanced the response to chemotherapy in the ID8-p53−/−ovarian carcinoma mouse model. The combined MPLA+IFNγ treatment reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, decreasing tumor-associated (CD206+) macrophages, increasing tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. MPLA and IFNγ are already used individually in clinical practice, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing.
FEATS: Feature selection based clustering of single-cell RNA-seq data
Authors: Vans Edwin , Patil Ashwini , Sharma Alok
Published: July 2020

Advances in next-generation sequencing (NGS) have made it possible to carry out transcriptomic studies at single-cell resolution and generate vast amounts of single-cell RNA-seq data rapidly. Thus, tools to analyze this data need to evolve as well to improve accuracy and efficiency. We present FEATS, a python software package that performs clustering on single-cell RNA-seq data. FEATS is capable of performing multiple tasks such as estimating the number of clusters, conducting outlier detection, and integrating data from various experiments. We develop a univariate feature selection based approach for clustering, which involves the selection of top informative features to improve clustering performance. This is motivated by the fact that cell types are often manually determined using the expression of only a few known marker genes. On a variety of single-cell RNA-seq datasets, FEATS gives superior performance compared to the current tools, in terms of adjusted rand index (ARI) and estimating the number of clusters. In addition to cluster estimation, FEATS also performs outlier detection and data integration while giving an excellent computational performance. Thus, FEATS is a comprehensive clustering tool capable of addressing the challenges during the clustering of single-cell RNA-seq data. The installation instructions and documentation of FEATS is available athttps://edwinv87.github.io/feats/.
Environmental controls and habitat connectivity of phototrophic microbial mats and bacterioplankton communities in an Antarctic freshwater system
Authors: Ramoneda J. , Hawes I. , Pascual-García A. , Mackey T.J. , Sumner D.Y. , Jungblut A.D.
Published: July 2020

Freshwater ecosystems are considered hotspots of biodiversity in Antarctic polar deserts. Anticipated warming is expected to change the hydrology of these systems due to increased meltwater and reduction of ice cover, with implications for environmental conditions and physical connectivity between habitats. Using 16S rRNA sequencing, we evaluated the structure of microbial mat and planktonic communities within a connected watershed in the McMurdo Wright Valley, Antarctica to determine the roles of connectivity and habitat conditions in controlling microbial assemblage composition. We examined benthic and planktonic samples from glacial Lake Brownworth, the perennially ice-covered Lake Vanda, and the Onyx River, which connects the two. In Lake Vanda, we found distinct microbial assemblages occupying sub-habitats at different lake depths, while the communities from Lake Brownworth and Onyx River were structurally similar between them. Despite the higher connectivity between bacterial communities in the shallow parts of the system, environmental filtering dominated over dispersal in driving bacterial community structure. Functional metagenomics predictions identified genes related to degradation of halogenated aromatic compounds in surface microbial mats exposed to changes in water regimes, which progressively disappeared with increasing depth. Shifting environmental conditions due to increasing connectivity, rather than dispersal, may become the dominant drivers of bacterial diversity and functioning in Antarctic freshwater ecosystems.
Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding
Authors: Wang Jinan , Miao Yinglong
Published: July 2020

Peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes and play an important role in cellular signaling. However, it is challenging to simulate both binding and unbinding of peptides and calculate peptide binding free energies through conventional molecular dynamics, due to long biological timescales and extremely high flexibility of the peptides. Based on the Gaussian accelerated molecular dynamics (GaMD) enhanced sampling technique, we have developed a new computational method “Pep-GaMD”, which selectively boosts essential potential energy of the peptide in order to effectively model its high flexibility. In addition, another boost potential is applied to the remaining potential energy of the entire system in a dual-boost algorithm. Pep-GaMD has been demonstrated on binding of three model peptides to the SH3 domains. Independent 1 μs dual-boost Pep-GaMD simulations have captured repetitive peptide dissociation and binding events, which enable us to calculate peptide binding thermodynamics and kinetics. The calculated binding free energies and kinetic rate constants agreed very well with available experimental data. Furthermore, the all-atom Pep-GaMD simulations have provided important insights into the mechanism of peptide binding to proteins that involves long-range electrostatic interactions and mainly conformational selection. In summary, Pep-GaMD provides a highly efficient, easy-to-use approach for unconstrained enhanced sampling and calculations of peptide binding free energies and kinetics.

Significance Statement

We have developed a new computational method “Pep-GaMD” for enhanced sampling of peptide-protein interactions based on the Gaussian accelerated molecular dynamics (GaMD) technique. Pep-GaMD works by selectively boosting the essential potential energy of the peptide to effectively model its high flexibility. In addition, another boost potential can be applied to the remaining potential energy of the entire system in a dual-boost algorithm. Pep-GaMD has been demonstrated on binding of three model peptides to the SH3 domains. Dual-boost Pep-GaMD has captured repetitive peptide dissociation and binding events within significantly shorter simulation time (microsecond) than conventional molecular dynamics. Compared with previous enhanced sampling methods, Pep-GaMD is easier to use and more efficient for unconstrained enhanced sampling of peptide binding and unbinding, which provides a novel physics-based approach to calculating peptide binding free energies and kinetics.