bluuebunny/crossref_metadata_2025 huggingface dataset:
An Administrative Data-based Surrogate Definition Identifies Children Evaluated Beyond Physical Examination for Suspected Appendicitis
Authors: Glissmeyer Eric W. , Ryan Sydney , Dudley Nanette C. , Schunk Jeff E. , Nielsen Jeremy , Weng Cindy , Skarda David E.
Published: October 2020

Introduction:

Previous studies have reported on the evaluation of patients diagnosed with appendicitis. Very little is known about all patients evaluated for suspected appendicitis. Patients evaluated beyond physical examination with laboratory and imaging testing, then found not to have appendicitis, are more difficult to identify. Data readily available in administrative databases may be used to identify these patients.

Methods:

A multidisciplinary team developed a surrogate definition for evaluating suspected appendicitis in children based on available administrative data. Appendicitis was “suspected” if the patient underwent ultrasonography of the appendix or had a chief complaint of abdominal pain with both complete blood count performed and the word “appendicitis” in the ED provider note. Performance characteristics described the surrogate definition’s ability to retrospectively identify patients evaluated for suspected appendicitis through comparison to a population identified via chart review.

Results:

Compared with manual chart review of 498 patients from June 2014, the surrogate definition identified patients evaluated beyond physical examination for suspected appendicitis with a sensitivity of 79.8%, a specificity of 96.3%, a positive predictive value of 83.3%, and a negative predictive value of 95.3%. Of the 94 patients evaluated beyond physical examination for suspected appendicitis, 37 (39%) underwent appendectomy.

Conclusions:

Health systems can retrospectively identify children evaluated beyond physical examination for appendicitis using discrete administrative data and a word search of clinical notes. This surrogate definition for evaluation of suspected appendicitis enables research in quality improvement efforts and health care resource utilization.
A Comprehensive, Evidence-Based Literature Review of the Surgical Treatment of Rectus Diastasis
Authors: ElHawary Hassan , Abdelhamid Kenzy , Meng Fanyi , Janis Jeffrey E.
Published: October 2020

Background:

Rectus diastasis is a common condition that can result in a protruding abdomen, causing cosmetic and functional disability. Although it is usually repaired during abdominoplasty or herniorrhaphy, there is a lack of consensus with regard to the repair indications and optimal surgical techniques. The goal of this study is to provide an updated review of the surgical techniques used for rectus diastasis repair and their comparative efficacy.

Methods:

In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the PubMed, Embase, and Cochrane databases were searched for articles that discussed the surgical management of rectus diastasis and reported on either outcomes, complications, or recurrence rates. Data detailing surgical techniques were extracted, and pooled analyses of complication and recurrence rates were performed, controlling for surgical approach, common variations in technique, and an associated herniorrhaphy.

Results:

Thirty-seven studies describing 45 techniques were included. An open rectus diastasis repair was performed in 24 of the studies. After controlling for an associated herniorrhaphy, there was no statistically significant difference in surgical complication and recurrence rates between open and laparoscopic approaches (p = 0.165 and p = 0.133, respectively). Although a double-layer suture closure was associated with a significantly lower rate of complications (p = 0.002), no significant difference was found for suture type absorbability.

Conclusions:

Surgical repair of rectus diastasis is safe and effective through both open and laparoscopic approaches. Although suture type absorbability does not affect complication or recurrence rates, a double-layer suture closure can decrease surgical complications. The pooled analysis of complication and recurrence rates can help improve informed consent and patient education.
Cost-Effectiveness of HRSA's Ryan White HIV/AIDS Program?
Authors: Goyal Ravi , Luca Dara , Klein Pamela W. , Morris Eric , Mandsager Paul , Cohen Stacy M. , Hu Cindy , Hotchkiss John , Gao Jessica , Jones Andrew , Addison West , O'Brien-Strain Margaret , Cheever Laura W. , Gilman Boyd
Published: October 2020

Background:

With an annual budget of more than $2 billion, the Health Resources and Services Administration's Ryan White HIV/AIDS Program (RWHAP) is the third largest source of public funding for HIV care and treatment in the United States, yet little analysis has been done to quantify the long-term public health and economic impacts of the federal program.

Methods:

Using an agent-based, stochastic model, we estimated health care costs and outcomes over a 50-year period in the presence of the RWHAP relative to those expected to prevail if the comprehensive and integrated system of medical and support services funded by the RWHAP were not available. We made a conservative assumption that, in the absence of the RWHAP, only uninsured clients would lose access to these medical and support services.

Results:

The model predicts that the proportion of people with HIV who are virally suppressed would be 25.2 percentage points higher in the presence of the RWHAP (82.6 percent versus 57.4 percent without the RWHAP). The number of new HIV infections would be 18 percent (190,197) lower, the number of deaths among people with HIV would be 31 percent (267,886) lower, the number of quality-adjusted life years would be 2.7 percent (5.6 million) higher, and the cumulative health care costs would be 25 percent ($165 billion) higher in the presence of the RWHAP relative to the counterfactual. Based on these results, the RWHAP has an incremental cost-effectiveness ratio of $29,573 per quality-adjusted life year gained compared with the non-RWHAP scenario. Sensitivity analysis indicates that the probability of transmitting HIV via male-to-male sexual contact and the cost of antiretroviral medications have the largest effect on the cost-effectiveness of the program.

Conclusions:

The RWHAP would be considered very cost-effective when using standard guidelines of less than the per capita gross domestic product of the United States. The results suggest that the RWHAP plays a critical and cost-effective role in the United States' public health response to the HIV epidemic.
Discrete Choice Experiments to Elicit Patient Preferences for Decision Making in Transplantation
Authors: James Laura J. , Wong Germaine , Tong Allison , Craig Jonathan C. , Howard Kirsten , Howell Martin
Published: October 2020

Providing care for transplant recipients is challenging given the need to maintain optimal graft function and survival while managing the debilitating side effects and complications associated with immunosuppression including infection, cancer, new-onset diabetes mellitus, and cardiovascular disease. Given the complexity of treatment options and the uncertainty about long-term benefits and harms of treatment, understanding patient preferences and values are key to ensuring that clinical decisions take into consideration patient priorities to support shared decision making and self-management. Choice experiments are increasingly used to quantify patient and community preferences, including in the field of transplantation. Discrete choice experiments (DCEs) are a well-established, validated methodology used to elicit preferences for decision making in health and other settings. In transplantation, for example, DCEs have been used to elicit patient preferences for outcomes following kidney transplantation, to identify community preferences factors for organ allocation and in establishing core outcomes. This article provides an overview of the concepts and methods used in the design of DCEs and how patients’ preferences can be applied in shared decision making in transplantation.
Liver Transplantation for Propionic Acidemia: Evidence From a Systematic Review and Meta-analysis
Authors: Zhou Guang-Peng , Jiang Yi-Zhou , Wu Shan-Shan , Kong Yuan-Yuan , Sun Li-Ying , Zhu Zhi-Jun
Published: October 2020

Background.

The worldwide experience of liver transplantation (LT) in the treatment of propionic acidemia (PA) remains limited and fragmented. This review aims to provide a comprehensive and quantitative understanding of posttransplant clinical outcomes in PA patients.

Methods.

MEDLINE, Embase, and the Cochrane Library databases were searched for studies focusing on PA patients who underwent LT. The pooled estimate rates and 95% confidence intervals (CIs) were calculated using a random-effects model with Freeman-Tukey double arcsine transformation.

Results.

Twenty-one studies involving 70 individuals were included. The pooled estimate rates were 0.95 (95% CI, 0.80-1.00) for patient survival and 0.91 (95% CI, 0.72-1.00) for allograft survival. The pooled estimate rates were 0.20 (95% CI, 0.05-0.39) for rejection, 0.08 (95% CI, 0.00-0.21) for hepatic artery thrombosis, 0.14 (95% CI, 0.00-0.37) for cytomegalovirus/Epstein-Barr virus infection, and 0.03 (95% CI, 0.00-0.15) for biliary complications. The pooled estimate rates were 0.98 (95% CI, 0.88-1.00) for metabolic stability, 1.00 (95% CI, 0.79-1.00) for reversal of preexisting cardiomyopathy, and 0.97 (95% CI, 0.78-1.00) for improvement of neurodevelopmental delay. A large proportion of patients achieved liberalization of protein intake posttransplant (pooled estimate rate 0.66 [95% CI, 0.35-0.93]).

Conclusions.

Despite the risk of transplant-related complications, LT is a viable therapeutic option in PA patients with satisfactory survival rates and clinical outcomes. Given the diversity in neurological assessment methods and the inconsistency in the achievement of dietary protein liberalization across different studies, consensus on neurological evaluation methods and posttransplant protein intake is necessary. Longer-term clinical outcomes of LT for PA warrants further investigation.
Microbispora clausenae sp. nov., an endophytic actinobacterium isolated from the surface-sterilized stem of a Thai medicinal plant, Clausena excavala Burm. f.
Authors: Kaewkla Onuma , Koomsiri Wilaiwan , Thamchaipenet Arinthip , Franco Christopher Milton Mathew
Published: October 2020

An endophytic actinobacterium, strain CLES2T, was discovered from the surface-sterilized stem of a Thai medicinal plant, Clausena excavala Burm. f., collected from the Phujong-Nayoa National Park, Ubon Ratchathani Province, Thailand. The results of a polyphasic taxonomic study identified this strain as a member of the genus

Microbispora

and a Gram-stain-positive, aerobic actinobacterium. It had well-developed substrate mycelia, which were non-motile and possessed paired spores. A phylogenetic evaluation based on 16S rRNA gene sequence analysis placed this strain in the family

Streptosporangiaceae

, being most closely related to

Microbispora bryophytorum

NEAU-TX2-2T (99.4 %),

Microbispora camponoti

2C-HV3T (99.2 %),

Microbispora catharanthi

CR1-09T (99.2 %) and

Microbispora amethystogenes

JCM 3021T and

Microbispora fusca

NEAU-HEGS1-5T (both at 99.1 %). The major cellular fatty acid of this strain was iso-C16 : 0 and major menaquinone was MK-9(H4). The polar lipid profile of strain CLES2T contained diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylinositol and phosphatidylinositol dimannosides. These chemotaxonomic data confirmed the affiliation of strain CLES2T to the genus

Microbispora

. The DNA G+C content of this strain was 70 mol%. Digital DNA–DNA hybridization and average nucleotide identity blast values between strain CLES2T and

M. catharanthi

CR1-09T were 62.4 and 94.0 %, respectively. The results of the polyphasic study allowed the genotypic and phenotypic differentiation of strain CLES2T from its closest species with valid names. The name proposed for the new species is Microbispora clausenae sp. nov. The type strain is CLES2T (=DSM 101759T=NRRL B-65340T).
A meta-analysis of mesophyll conductance to CO2in relation to major abiotic stresses in poplar species
Authors: Elferjani Raed , Benomar Lahcen , Momayyezi Mina , Tognetti Roberto , Niinemets Ülo , Soolanayakanahally Raju Y. , Théroux-Rancourt Guillaume , Tosens Tiina , Lamara Mebarek , Ripullone Francesco , Bilodeau-Gauthier Simon , Lamhamedi Mohammed S. , Calfapietra Carlo
Published: October 2020

Mesophyll conductance (gm) determines the diffusion of CO2from the substomatal cavities to the site of carboxylation in the chloroplasts and represents a critical limiting factor to photosynthesis. In this study, we evaluated the average effect sizes of different environmental constraints ongminPopulusspp., a forest tree model. We collected raw data of 815A-Ciresponse curves from 26 datasets to estimategm, using a single curve-fitting method to alleviate method-related bias. We performed a meta-analysis to assess the effects of different abiotic stresses ongm. We found a significant increase ingmfrom the bottom to the top of the canopy that was concomitant with the increase of maximum rate of carboxylation and light-saturated photosynthetic rate (Amax).gmwas positively associated with increases in soil moisture and nutrient availability, but insensitive to increasing soil copper concentration, and did not vary with atmospheric CO2concentration. Our results showed thatgmwas strongly related toAmaxand to a lesser extent to stomatal conductance (gs). Also, a negative linear relation was obtained betweengmand specific leaf area, which may be used to scale-upgmwithin the canopy.
Global RNAseq of ocular cells reveals gene dysregulation in both asymptomatic and with Congenital Zika Syndrome infants exposed prenatally to Zika virus
Authors: Rosa-Fernandes Livia , Bedrat Amina , dos Santos Maria Luiza B. , Pinto Ana , Lucena E , Silva Thiago P. , Melo Rossana C. N. , Palmisano Giuseppe , Cardoso Claudete Araújo , Barbosa Raquel Hora
Published: October 2020

In 2015, Brazil reported an outbreak identified as Zika virus (ZIKV) infection associated with congenital abnormalities. To date, a total of 86 countries and territories have described evidence of Zika infection and recently the appearance of the African ZIKV lineage in Brazil highlights the risk of a new epidemic. The spectrum of ZIKV infection-induced alterations at both cellular and molecular levels is not completely elucidated. Here, we present for the first time the gene expression responses associated with prenatal ZIKV infection from ocular cells. We applied a recently developed non-invasive method (impression cytology) which use eye cells as a model for ZIKV studies. The ocular profiling revealed significant differences between exposed and control groups, as well as a different pattern in ocular transcripts from Congenital Zika Syndrome (CZS) compared to ZIKV-exposed but asymptomatic infants. Our data showed pathways related to mismatch repair, cancer, and PI3K/AKT/mTOR signaling and genes probably causative or protective in the modulation of ZIKV infection. Ocular cells revealed the effects of ZIKV infection on primordial neuronal cell genes, evidenced by changes in genes associated with embryonic cells. The changes in gene expression support an association with the gestational period of the infection and provide evidence for the resulting clinical and ophthalmological pathologies. Additionally, the findings of cell death- and cancer-associated deregulated genes raise concerns about the early onset of other potential pathologies including the need for tumor surveillance. Our results thus provide direct evidence that infants exposed prenatally to the Zika virus, not only with CZS but also without clinical signs (asymptomatic) express cellular and molecular changes with potential clinical implications.
Diagnostic utility of a Ferritin-to-Procalcitonin Ratio to differentiate patients with COVID-19 from those with Bacterial Pneumonia: A multicenter study
Authors: Gharamti Amal A. , Mei Fei , Jankousky Katherine C. , Huang Jin , Hyson Peter , Chastain Daniel B. , Fan Jiawei , Osae Sharmon , Zhang Wayne W. , Montoya José G. , Erlandson Kristine M. , Scherger Sias J. , Franco-Paredes Carlos , Henao-Martínez Andrés F. , Shapiro Leland
Published: October 2020

Importance

There is a need to develop tools to differentiate COVID-19 from bacterial pneumonia at the time of clinical presentation before diagnostic testing is available.

Objective

To determine if the Ferritin-to-Procalcitonin ratio (F/P) can be used to differentiate COVID-19 from bacterial pneumonia.

Design

This case-control study compared patients with either COVID-19 or bacterial pneumonia, admitted between March 1 and May 31, 2020. Patients with COVID-19 and bacterial pneumonia co-infection were excluded.

Setting

A multicenter study conducted at three hospitals that included UCHealth and Phoebe Putney Memorial Hospital in the United States, and Yichang Central People’s Hospital in China.

Participants

A total of 242 cases with COVID-19 infection and 34 controls with bacterial pneumonia.

Main Outcomes and Measures

The F/P in patients with COVID-19 or with bacterial pneumonia were compared. Receiver operating characteristic analysis determined the sensitivity and specificity of various cut-off F/P values for the diagnosis of COVID-19 versus bacterial pneumonia.

Results

Patients with COVID-19 pneumonia had a lower mean age (57.11 vs 64.4 years, p=0.02) and a higher BMI (30.74 vs 27.15 kg/m2, p=0.02) compared to patients with bacterial pneumonia. Cases and controls had a similar proportion of women (47% vs 53%, p=0.5) and COVID-19 patients had a higher prevalence of diabetes mellitus (32.6% vs 12%, p=0.01). The median F/P was significantly higher in patients with COVID-19 (4037.5) compared to the F/P in bacterial pneumonia (802, p<0.001). An F/P ≥ 877 used to diagnose COVID-19 resulted in a sensitivity of 85% and a specificity of 56%, with a positive predictive value of 93.2%, and a likelihood ratio of 1.92. In multivariable analyses, an F/P ≥ 877 was associated with greater odds of identifying a COVID-19 case (OR: 11.27, CI: 4-31.2, p<0.001).

Conclusions and Relevance

An F/P ≥ 877 increases the likelihood of COVID-19 pneumonia compared to bacterial pneumonia. Further research is needed to determine if obtaining ferritin and procalcitonin simultaneously at the time of clinical presentation has improved diagnostic value. Additional questions include whether an increased F/P and/or serial F/P associates with COVID-19 disease severity or outcomes.
Maximally selective single cell target for circuit control in epilepsy
Authors: Hadjiabadi Darian , Lovett-Barron Matthew , Raikov Ivan , Sparks Fraser , Liao Zhenrui , Baraban Scott C. , Leskovec Jure , Losonczy Attila , Deisseroth Karl , Soltesz Ivan
Published: October 2020

Neurological and psychiatric disorders are associated with pathological neural dynamics. The fundamental connectivity patterns of cell-cell communication networks that enable pathological dynamics to emerge remain unknown. We studied epileptic circuits using a newly developed integrated computational pipeline applied to cellular resolution functional imaging data. Control and preseizure neural dynamics in larval zebrafish and in chronically epileptic mice were captured using large-scale cellular-resolution calcium imaging. Biologically constrained effective connectivity modeling extracted the underlying cell-cell communication network. Novel analysis of the higher-order network structure revealed the existence of ‘superhub’ cells that are unusually richly connected to the rest of the network through feedforward motifs. Instability in epileptic networks was causally linked to superhubs whose involvement in feedforward motifs critically enhanced downstream excitation. Disconnecting individual superhubs was significantly more effective in stabilizing epileptic networks compared to disconnecting hub cells defined traditionally by connection count. Collectively, these results predict a new, maximally selective and minimally invasive cellular target for seizure control.

Highlights

Higher-order connectivity patterns of large-scale neuronal communication networks were studied in zebrafish and mice

Control and epileptic networks were modeled from in vivo cellular resolution calcium imaging data

Rare ‘superhub’ cells unusually richly connected to the rest of the network through higher-order feedforward motifs were identified

Disconnecting single superhub neurons more effectively stabilized epileptic networks than targeting conventional hub cells defined by high connection count.

These data predict a maximally selective novel single cell target for minimally invasive seizure control
Resolving a Systematic Error in STARR-seq for Quantitative Enhancer Activity Mapping
Authors: Niu Longjian , Wan Jing , Sun Jialei , Huang Yingzhang , He Na , Li Li , Hou Chunhui
Published: October 2020

STARR-seq assesses millions of fragments in parallel measuring enhancer activity quantitatively. Here we show that STARR-seq is critically flawed with a systematic error in the cells ofArabidopsis thaliana (A. thaliana). Large amount of self-transcripts (STs) is lost during reverse transcription because these STs are polyadenylated after alternative polyadenylation sites (APAS) inside the test sequences. We solved this problem by using specially designed primer and recovered self-transcribed sequences independent from the PAS usage. InA. thaliana, we identified active enhancers and also enhancers quiescent in their endogenous genomic loci. Different from traditional STARR-seq identified enhancers, enhancers identified by new method are highly enriched in sequences proximal to the 5’ and 3’ ends of genes, and their epigenetic states correlate with gene expression levels. Our solution applies to methods based on self-transcript quantification. In addition, our results provide an invaluable functional enhancer activity map and insights into the functional complexity of enhancers inA. thaliana.
Leveraging supervised learning for functionally-informed fine-mapping of cis-eQTLs identifies an additional 20,913 putative causal eQTLs
Authors: Wang Qingbo S. , Kelley David R. , Ulirsch Jacob , Kanai Masahiro , Sadhuka Shuvom , Cui Ran , Albors Carlos , Cheng Nathan , Okada Yukinori ,   The Biobank Japan Project, Aguet Francois , Ardlie Kristin G. , MacArthur Daniel G. , Finucane Hilary K.
Published: October 2020

The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants’ effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6,121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.
Apical-root apoplastic acidification affects cell-wall extensibility in wheat under salinity stress
Authors: Shao Yang , Feng Xiaohui , Nakahara Hiroki , Irshad Muhammad , Eneji A. Egrinya , Zheng Yuanrun , An Ping
Published: October 2020

Plant salt tolerance is closely associated with a high rate of root growth. Although root growth is governed by cell-wall and apoplastic pH, the relationship between these factors in the root elongation zone under salinity stress remains unclear. Here, we assess apoplastic pH, pH- and expansin-dependent cell-wall extensibility, and expansin expression in the root elongation zone of salt-sensitive (Yongliang-15) and -tolerant (JS-7) cultivars under salinity stress. A six-day 80 mM NaCl treatment significantly reduced apical-root apoplastic pH, from 6.2 to 5.3, in both cultivars. Using a pH-dependent cell-wall extensibility experiment, we found that, under 0 mM NaCl treatment, the optimal pH for cell-wall loosening was 6.0 in the salinity-tolerant cultivar and 4.6 in the salinity-sensitive cultivar. Under 80 mM treatment, a pH of 5.0 mitigated the cell-wall stiffness caused by salinity stress in the salinity-tolerant cultivar, but promoted cell-wall stiffening in the salinity-sensitive cultivar. These changes in pH-dependent cell-wall extensibility are consistent with differences in the root growth of two cultivars under salinity stress. Exogenous expansin application, and expansin expression experiments, we found that salinity stress altered expansin expression, differentially affecting cell-wall extensibility under pH 5.0 and 6.0.TaEXPA7andTaEXPA8induced cell-wall loosening at pH 5.0, whereasTaEXPA5induced cell-wall loosening at pH 6.0. These results elucidate the relationship between expansin and cell-wall extensibility in the root elongation zone, with important implications for enhancing plant growth under salinity stress.
Mitohormesis reprograms macrophage metabolism to enforce tolerance
Authors: Timblin Greg A. , Tharp Kevin M. , Ford Breanna , Winchenster Janet M. , Wang Jerome , Zhu Stella , Khan Rida I. , Louie Shannon K. , Iavarone Anthony T. , Hoeve Johanna ten , Nomura Daniel K. , Stahl Andreas , Saijo Kaoru
Published: October 2020

Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, pharmacologically-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.

Abstract Figure
PSK signaling controls ABA homeostasis and signaling genes and maintains shoot growth under osmotic stress
Authors: Rajamanickam Komathy , Schönhof Martina D. , Hause Bettina , Sauter Margret
Published: October 2020

Water deficit impairs growth and survival of plants. Many water stress responses are under control of abscisic acid (ABA) but little is known about growth control under osmotic stress. Based on the previously described growth-promoting activity of the peptide hormone phytosulfokine (PSK), we hypothesized that it may contribute to growth regulation under water stress conditions. To test this hypothesis, we analyzed theArabidopsis thalianaPSK receptor (PSKR) null mutantpskr1-3 pskr2-1under mannitol and drought stress. In particular under mild water stress, fresht weight and photosynthetic efficiency were more reduced inpskr1-3 pskr2-1than in wild type. Hydroponic and grafting experiments showed that PSKR signaling was not required for long-distance signaling from mannitol-stressed roots to shoot but rather for cell growth promotion in the shoot. Unlike wild type,pskr1-3 pskr2-1shoots did not accumulate ABA in response to mannitol, showed misregulation of ABA synthesis genes and elevated expression ofABI1andABI2, repressors of ABA signaling whereas application of ABA partially reversed shoot growth inhibition by mannitol inpskr1-3 pskr2-1. In turn, mannitol and ABA induced expression ofPSK3and PSKR1, and ABA promoted expression ofPSK2andPSK4revealing feedback regulatory loops between PSKR and osmotic stress signaling.

Highlight

Phytosulfokine receptor signaling regulates ABA synthesis and signaling genes and promotes ABA accumulation in the shoot of water-stressed plants and maintains leaf growth and photosynthetic efficiency which ensures plant health.
Contribution of noncanonical antigens to virulence and adaptive immunity in human infection with enterotoxigenicE. coli
Authors: Kuhlmann FM , Laine RO , Afrin S , Nakajima R , Akhtar M , Vickers T , Parker K , Nizam NN , Grigura V , Goss CW , Felgner PL , Rasko DA , Qadri F , Fleckenstein JM
Published: October 2020

EnterotoxigenicE. coli(ETEC) contribute significantly to the substantial burden of infectious diarrhea among children living in low and middle income countries. In the absence of a vaccine for ETEC, children succumb to acute dehydration as well as non-diarrheal sequelae related to these infections including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches focused on a subset of antigens known as colonization factors (CFs). To identify additional conserved immunogens, we mined genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (n=118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (n=52), and toxin subunits to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this open-aperture approach, we found that immune responses were largely constrained to a small number of antigens including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children < 2 years of age, both EtpA and a second noncanonical antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing eitheretpA or eatAgenes were significantly more likely to develop symptomatic disease. These studies support a role for more recently discovered noncanonical antigens in virulence and the development of adaptive immune responses during ETEC infections, findings that may inform vaccine design efforts to complement existing approaches.
Patterns of Multimorbidity and Risk of Severe SARS-CoV-2 Infection: an observational study in the U.K
Authors: Chudasama Yogini V , Zaccardi Francesco , Gillies Clare L , Razieh Cameron , Yates Thomas , Kloecker David E , Rowlands Alex V , Davies Melanie J , Islam Nazrul , Seidu Samuel , Forouhi Nita G , Khunti Kamlesh
Published: October 2020

Background

Pre-existing comorbidities have been linked to SARS-CoV-2 infection but evidence is sparse on the importance and pattern of multimorbidity (2 or more conditions) and severity of infection indicated by hospitalisation or mortality. We aimed to use a multimorbidity index developed specifically for COVID-19 to investigate the association between multimorbidity and risk of severe SARS-CoV-2 infection.

Methods

We used data from the UK Biobank linked to laboratory confirmed test results for SARS-CoV-2 infection and mortality data from Public Health England between March 16 and July 26, 2020. By reviewing the current literature on COVID-19 we derived a multimorbidity index including: 1) angina; 2) asthma; 3) atrial fibrillation; 4) cancer; 5) chronic kidney disease; 6) chronic obstructive pulmonary disease; 7) diabetes mellitus; 8) heart failure; 9) hypertension; 10) myocardial infarction; 11) peripheral vascular disease; 12) stroke. Adjusted logistic regression models were used to assess the association between multimorbidity and risk of severe SARS-CoV-2 infection (hospitalisation or death). Potential effect modifiers of the association were assessed: age, sex, ethnicity, deprivation, smoking status, body mass index, air pollution, 25‐hydroxyvitamin D, cardiorespiratory fitness, high sensitivity C-reactive protein.

Results

Among 360,283 participants, the median age was 68 [range, 48-85] years, most were White (94.5%), and 1,706 had severe SARS-CoV-2 infection. The prevalence of multimorbidity was more than double in those with severe SARS-CoV-2 infection (25%) compared to those without (11%), and clusters of several multimorbidities were more common in those with severe SARS-CoV-2 infection. The most common clusters with severe SARS-CoV-2 infection were stroke with hypertension (79% of those with stroke had hypertension); diabetes and hypertension (72%); and chronic kidney disease and hypertension (68%). Multimorbidity was independently associated with a greater risk of severe SARS-CoV-2 infection (adjusted odds ratio 1.91 [95% confidence interval 1.70, 2.15] compared to no multimorbidity). The risk remained consistent across potential effect modifiers, except for greater risk among men.

Conclusion

The risk of severe SARS-CoV-2 infection is higher in individuals with multimorbidity, indicating the need to target research and resources in people with SARS-CoV-2 infection and multimorbidity.
Alpha globin variation in the long-tailed macaque suggests malaria selection
Authors: Faust C.L. , Rangkuti F. , Preston S. G. , Boyd A. , Flammer P. , Bia B. , Rose N. J. , Piel F. B. , Smith A. L. , Dobson A.P. , Gupta S. , Penman B. S.
Published: October 2020

Human haemoglobin variants, such as sickle, confer protection against death from malaria; consequently, frequencies of such variants are often greatly elevated in humans from malaria endemic regions. Among non-human primates, the long-tailed macaque,Macaca fascicularis, also displays substantial haemoglobin variation. Almost allM. fascicularishaemoglobin variation is in the alpha globin chain, encoded by two linked genes:HBA1andHBA2. We demonstrate that alpha globin variation inM. fasciculariscorrelates with the strength of malaria selection. We identify a range of missense mutations inM. fascicularisalpha globin and demonstrate that some of these exhibit a strikingHBA1orHBA2specificity, a pattern consistent with computational simulations of selection on genes exhibiting copy number variation. We propose thatM. fascicularisaccumulated amino acid substitutions in its alpha globin genes under malaria selection, in a process that closely mirrors, but does not entirely converge with, human malaria adaptation.
PEPATAC: An optimized pipeline for ATAC-seq data analysis with serial alignments
Authors: Smith Jason P. , Corces M. Ryan , Xu Jin , Reuter Vincent P. , Chang Howard Y. , Sheffield Nathan C.
Published: October 2020

Motivation

As chromatin accessibility data from ATAC-seq experiments continues to expand, there is continuing need for standardized analysis pipelines. Here, we present PEPATAC, an ATAC-seq pipeline that is easily applied to ATAC-seq projects of any size, from one-off experiments to large-scale sequencing projects.

Results

PEPATAC leverages unique features of ATAC-seq data to optimize for speed and accuracy, and it provides several unique analytical approaches. Output includes convenient quality control plots, summary statistics, and a variety of generally useful data formats to set the groundwork for subsequent project-specific data analysis. Downstream analysis is simplified by a standard definition format, modularity of components, and metadata APIs in R and Python. It is restartable, fault-tolerant, and can be run on local hardware, using any cluster resource manager, or in provided Linux containers. We also demonstrate the advantage of aligning to the mitochondrial genome serially, which improves the accuracy of alignment statistics and quality control metrics. PEPATAC is a robust and portable first step for any ATAC-seq project.

Availability

BSD2-licensed code and documentation athttps://pepatac.databio.org.
Widespread effects of DNA methylation and intra-motif dependencies revealed by novel transcription factor binding models
Authors: Grau Jan , Schmidt Florian , Schulz Marcel H.
Published: October 2020

Several studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that are affected by DNA methylation. Overall, we find that CpG methylation decreases the likelihood of binding for the majority of TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding.
Combination of arsenic trioxide epigallocatechin-3-gallate and Resveratrol synergistically suppresses the growth and invasion in Brain tumor cell lines
Authors: Sajjadi Roshanak S. , Ahmadi Samaneh , Mantashloo Marziye , Layeghi Sepideh Mehrpour , Asgari Yazdan , Ghorbani Mohammad , Mohammadi Seyed Danial , Saffari Mojtaba
Published: October 2020

The glioblastoma multiform has some properties including rapid growth, invasion, treatment resistance, and recurrence. Therefore, new therapies need to be developed that can be approved for using in patients. The previous study showed Arsenic Trioxide inhibits aggressive behavior in glioblastoma cells. Also, (–)-epigallocatechin-3-gallate prevents cellular proliferation, and invasion in multiple glioma cells. Resveratrol decreases cellular proliferation, induces cell death, and impaired the invasiveness of glioma cells. Combination therapy to inhibit cancer cells may have important clinical implications. Therefore, to assess the combination therapy of 2μM Arsenic trioxide, 100μM EGCG, and 100μM Resveratrol, we examined the metabolic activity, colony formation, media pH, cell proliferation, Caspase 3 activity, and gene expression analysis of BCL2, Caspase 3, MMP2, MMP9, CA9, u-PA, u-PAR, and Cathepsin B genes in apoptosis and invasion by both quantitative PCR experiments and Western blot assay. Systems biology tools also were used to obtain, the related network, involved pathways, and identifying the key genes in our selected criteria. The results of the study confirmed that the combined therapy prevents cell proliferation and induces of apoptosis in the Brain tumor cell lines including: U87-MG, A-172, and 1321N1. Furthermore, over-expression of caspase-3 and down-regulation of BCL-2, MMP-2, and MMP-9 confirmed that combination therapy leads to induces apoptosis and decreases invasion. Nevertheless, the lowering of pharmacological doses and improving therapeutic efficacy through combination therapy may provide advantages to treat resistance cancer cells with lower side effects. Finally, the results might suggest new modality for Glioblastoma treatment.
Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction
Authors: Tribble James R , Otmani Amin , Sun Shanshan , Ellis Sevannah A , Cimaglia Gloria , Vohra Rupali , Jöe Melissa , Lardner Emma , Venkataraman Abinaya P , Domínguez-Vicent Alberto , Kokkali Eirini , Rho Seungsoo , Jóhannesson Gauti , Burgess Robert W , Fuerst Peter G , Brautaset Rune , Kolko Miriam , Morgan James E , Crowston Jonathan G , Votruba Marcela , Williams Pete A
Published: October 2020

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse models. Supporting this, short-term oral nicotinamide treatment in human glaucoma patients provides a recovery of retinal ganglion cell function implying a protection of visual function. Despite this, the mechanism of neuroprotection and full effects of nicotinamide on retinal ganglion cells is unclear. Glaucoma is a complex neurodegenerative disease in which a mix of healthy, stressed, and degenerating retinal ganglion cells co-exist, and in which retinal ganglion cells display compartmentalized degeneration across their visual trajectory. Therefore, we assess the effects of nicotinamide on retinal ganglion cells in normal physiological conditions and across a range of glaucoma relevant insults. We confirm neuroprotection afforded by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We define a small molecular weight metabolome for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption that can be prevented by nicotinamide. Nicotinamide provides these neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term NAM treatment as a neuroprotective therapy for human glaucoma.

One Sentence Summary

The NAD precursor nicotinamide has a potent neuroprotective effect in the retina and optic nerve, targeting neuronal function, metabolism, and mitochondrial function.
A stacked ensemble method for forecasting influenza-like illness visit volumes at emergency departments
Authors: de Amorim Arthur Novaes , Deardon Rob , Saini Vineet
Published: October 2020

Accurate and reliable short-term forecasts of influenza-like illness (ILI) visit volumes at the emergency departments can improve staffing and resource allocation decisions in each hospital. In this paper, we developed a stacked ensemble model that averages the predictions from various competing methodologies in the current frontier for ILI-related forecasts. We also constructed a back-of-the-envelope prediction interval for the stacked ensemble, which provides a conservative characterization of the uncertainty in the stacked ensemble predictions. We assessed the reliability and accuracy of our model’s 1 to 4 weeks ahead forecasts using real-time hospital-level data on weekly ILI visit volumes during the 2012-2018 flu seasons in the Alberta Children’s Hospital, located in Calgary, Alberta, Canada. Over this time period, our model’s prediction deviated from the realized ILI visit volume by an average of 12% for 1 week ahead forecasts, with a 90% prediction interval having coverage rates ranging from 90.7 to 97.7%.
PharmaNet: Pharmaceutical discovery with deep recurrent neural networks
Authors: Puentes Paola Ruiz , Valderrama Natalia , González Cristina , Daza Laura , Muñoz-Camargo Carolina , Cruz Juan C. , Arbeláez Pablo
Published: October 2020

The discovery and development of novel pharmaceuticals is an area of active research mainly due to the large investments required and long payback times. As of 2016, the development of a novel drug candidate required up to $ USD 2.6 billion in investment for only 10% rate of approval by the FDA. To help decreasing the costs associated with the process, a number ofin silicoapproaches have been developed with relatively low success due to limited predicting performance. Here, we introduced a machine learning-based algorithm as an alternative for a more accurate search of new pharmacological candidates, which takes advantage of Recurrent Neural Networks (RNN) for active molecule prediction within large databases. Our approach, termed PharmaNet was implemented here to search for ligands against specific cell receptors within 102 targets of the DUD-E database, which contains 22886 active molecules. PharmaNet comprises three main phases. First, a SMILES representation of the molecule is converted into araw molecular image. Second, a convolutional encoder processes the data to obtain afingerprint molecular imagethat is finally analyzed by a Recurrent Neural Network (RNN). This approach enables precise predictions of the molecules’ target on the basis of the feature extraction, the sequence analysis and the relevant information filtered out throughout the process. Molecule Target prediction is a highly unbalanced detection problem and therefore, we propose that an adequate evaluation metric of performance is the area under the Normalized Average Precision (NAP) curve. PharmaNet largely surpasses the previous state-of-the-art method with 97.7% in the Receiver Operating Characteristic curve (ROC-AUC) and 65.5% in the NAP curve. We obtained a perfect performance for human farnesyl pyrophosphate synthase (FPPS), which is a potential target for antimicrobial and anticancer treatments. We decided to test PharmaNet for activity prediction against FPPS by searching in the CHEMBL data set. We obtained three (3) potential inhibitors that were further validated through both molecular docking andin silicotoxicity prediction. Most importantly, one of this candidates, CHEMBL2007613, was predicted as a potential antiviral due to its involvement on thePCDH17pathway, which has been reported to be related to viral infections.
Dorsal anterior cingulate cortex intrinsic functional connectivity linked to electrocortical measures of error-monitoring
Authors: Gilbertson Hayley , Fang Lin , Andrzejewski Jeremy A. , Carlson Joshua M.
Published: October 2020

The error-related negativity (ERN) is a response-locked event-related potential, occurring approximately 50 ms following an erroneous response at frontocentral electrode sites. Source localization and functional magnetic resonance imaging (fMRI) research indicate that the ERN is likely generated by activity in the dorsal anterior cingulate cortex (dACC). The dACC is thought to be a part of a broader network of brain regions that collectively comprise an error-monitoring network. However, little is known about how intrinsic connectivity within the dACC-based error-monitoring network contributes to variability in ERN amplitude. The purpose of this study was to assess the relationship between dACC functional connectivity and ERN amplitude. In a sample of 53 highly trait-anxious individuals, the ERN was elicited in a flanker task and functional connectivity was assessed in a 10-minute resting-state fMRI scan. Results suggest that the strength of dACC seeded functional connectivity with the supplementary motor area is correlated with the ΔERN (i.e., incorrect – correct responses) amplitude such that greater ΔERN amplitude was accompanied by greater functional coupling between these regions. In addition to the dACC, exploratory analyses found that functional connectivity in the caudate, cerebellum, and a number of regions in the error-monitoring network were linked to variability in ΔERN amplitude. In sum, ERN amplitude appears to be related to the strength of functional connectivity between error-monitoring and motor control regions of the brain.