bluuebunny/crossref_metadata_2025 huggingface dataset:
Two year data from a preliminary study of double lesion site MRgFUS treatment of Essential Tremor targeting the thalamus and the posterior subthalamic area
Authors: Jameel Ayesha , Gedroyc Wladyslaw , Nandi Dipankar , Jones Bryn , Kirmi Olga , Molloy Sophie , Tai Yen , Charlesworth Gavin , Bain Peter
Published: January 2021

Background

MR-guided focused ultrasound (MRgFUS) is an effective treatment for essential tremor (ET). However, the optimal intracranial target sites remain to be determined.

Objective

To assess MRgFUS induced sequential lesions in (anterior-VIM/VOP nuclei) the thalamus and then posterior subthalamic area (PSA) performed during the same procedure for alleviating ET.

Methods

14 patients had unilateral MRgFUS lesions placed in anterior-VIM/VOP then PSA. Bain-Findley Spirals were collected during MRgFUS from the treated arm (BFS-TA) and throughout the study from the treated (BFS-TA) and non-treated (BFS-NTA) arms and scored by blinded assessors. Although, the primary outcome was change in the BFS-TA from baseline to 12 months we have highlighted the 24 month data.

Secondary outcomes included the Clinical Rating Scale for Tremor (CRST), Quality of Life for ET (QUEST) and PHQ-9 depression scores.

Results

The mean improvement in the BFS-TA from baseline to 24 months was 41.1% (p<0.001) whilst BFS-NTA worsened by 8.8% (p<0.001). Intra-operative BFS scores from the targeted arm showed a mean 27.9% (p<0.001) decrease after anterior-VIM/VOP ablation and an additional 30.1% (p<0.001) reduction from post anterior-VIM/VOP to post-PSA ablation.

Mean improvements at 24 month follow-up in the CRST-parts A, B and C were 60.7%, 30.4% and 65.6% respectively and 37.8% in QUEST-tremor score (all p<0.05). Unilateral tremor severity scores decreased in the treated arm (UETTS-TA) 72.9% (p=0.001) and non-treated arm (UETTS-NTA) 30.5% (p=0.003). At 24 months residual adverse effects were slight unsteadiness (n=1) and mild hemi-chorea (n=1).

Conclusion

Unilateral anterior-VIM/VOP and PSA MRgFUS significantly diminished contralateral arm tremor with improvements in arm function, tremor related disability and quality of life, with an acceptable adverse event profile.
Improving Polygenic Prediction in Ancestrally Diverse Populations
Authors: Ruan Yunfeng , Lin Yen-Feng , Feng Yen-Chen Anne , Chen Chia-Yen , Lam Max , Guo Zhenglin ,   Stanley Global Asia Initiatives, He Lin , Sawa Akira , Martin Alicia R. , Qin Shengying , Huang Hailiang , Ge Tian
Published: January 2021

Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) were predominantly conducted in individuals of European descent, the limited transferability of PRS reduces its clinical value in non-European populations and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research have expanded the scale of non-European GWAS, although most of them remain under-powered. Here we present a novel PRS construction method, PRS-CSx, which improves cross-population polygenic prediction by integrating GWAS summary statistics from multiple populations. PRS-CSx couples genetic effects across populations via a shared continuous shrinkage prior, enabling more accurate effect size estimation by sharing information between summary statistics and leveraging linkage disequilibrium (LD) diversity across discovery samples, while inheriting computational efficiency and robustness from PRS-CS. We show that PRS-CSx outperforms alternative methods across traits with a wide range of genetic architectures, cross-population genetic overlaps and discovery GWAS sample sizes in simulations, and improves the prediction of quantitative traits and schizophrenia risk in non-European populations.
Comparing the predictive value of suicide risk screening to the detection of suicide risk using electronic health records in an urban pediatric emergency department
Authors: Haroz E.E. , Kitchen C. , Nestadt P.S. , Wilcox H.C. , DeVylder J.E. , Kharrazi H.
Published: January 2021

Objective

To compare the accuracy, sensitivity and utility of brief screening to predictive modeling for identifying suicide-related outcomes in a pediatric emergency department. Our hypothesis was that predictive modeling would be more accurate and useful compared to brief screening.

Methods

This was a retrospective cohort study at an urban pediatric Emergency Department (PED) in the United States. Patients were aged 8 to 18 years old who presented from January 1, 2017 to June 30, 2019. Predictors included positive suicide risk screen and/or demographic, medical and mental health diagnostic Electronic Health Record (EHR) data at the time of visit. The main outcome was subsequent PED visit with suicide-related presenting problem (i.e. ideation or attempt) within a 3-month follow-up period.

Results

Of theN=13420 individuals,n=141 had a subsequent suicide-related ED visit. Approximately 63% identified as Black Non-Hispanic. Results showed that a model based only on EHR data performed only slightly worse than the ASQ alone. Combining ASQ screening and EHR data resulted in a 17.4% improvement in sensitivity and 13.4% increase in AUC compared to the ASQ alone. The LASSO models indicated a diagnosis of major depressive disorder in addition to the ASQ improved the AUC by 9%.

Conclusions, Implications, Future Directions

Our findings show that EHR data is helpful either in the absence or as an addition to brief suicide screening. To our knowledge, this is the first study to compare brief screening to EHR based predictive modeling and adds to our understanding of how best to identify youth at risk of suicidal behaviors in clinical care settings.
Maternity waiting home Utilization and associated factors among women who gave birth in the Digelu and Tijo district of the Arsi Zone, Oromia, Ethiopia
Authors: Teshome Derese , Abera Muluemebet , Nigatu Mamo
Published: January 2021

Background

Maternity Waiting Homes (MWHs) is an intervention designed to reduce maternal and perinatal mortality. Ethiopia has introduced the intervention before three decades however; its utilization is very low. Therefore, this study is aimed to assess MWH utilization and associated factors among women who gave birth in the last 12 months in Digelu and Tijo district Arsi Zone Oromia Region, Ethiopia.

Methods

Community-based cross-sectional study was conducted in April 2019 on 530 randomly selected women. Data were collected by face-to-face interview using structured questionnaire. Descriptive statistics and logistics regressions were used to analyze the results. Adjusted odds ratio and 95% confidence interval were respectively calculated to measure strength of association and its statistical significance.The confidence interval was used to declare statistical significance in the final model.

Results

One hundred twenty-five (23.6%) of the respondents used maternity waiting home. Traveling time less than and equals to 60 minutes from a nearby health facility (AOR=0.16, 95% CI: 0.09, 0.27), women’s decision power (AOR=1.81, 95% CI: 1.10, 2.96), not utilizing antenatal care (AOR=0.6, 95% CI: 0.37, 0.97) and delivering more than three children (AOR=0.56, 95% CI: 0.34, 0.90) were independently associated with utilizing the maternity waiting home.

Conclusion

Even though the MWH was designed to reduce maternal and perinatal mortality, less than a quarter (23.6%) of women delivered in the last 12 months before the study in the Digelu and Tijo District had utilized the services. Increasing availability of the service, promoting antenatal care utilization, empowering women and evolving policy makers are recommended to enhance the current low utilization of the MWH.
Prevalence and clinical profile of SARS-CoV-2 infection among farmworkers in Monterey County, California: June-November, 2020
Authors: Lewnard Joseph A. , Mora Ana M. , Nkwocha Oguchi , Kogut Katherine , Rauch Stephen A. , Morga Norma , Hernandez Samantha , Wong Marcus P. , Huen Karen , Andrejko Kristin , Jewell Nicholas P. , Parra Kimberly L. , Holland Nina , Harris Eva , Cuevas Maximiliano , Eskenazi Brenda
Published: January 2021

As essential personnel, United States farmworkers have continued working in-person throughout the COVID-19 pandemic. We undertook prospective surveillance of SARS-CoV-2 infection and antibody prevalence among farmworkers in California’s Salinas Valley from 15 June to 30 November, 2020. Over this period, we observed 22.1% (1514/6864) positivity for current SARS-CoV-2 by nucleic acid detection among farmworkers tested at federally-qualified migrant and community health clinics, as compared to 17.2% (1255/7305) among other adults from the same communities (risk ratio, 1.29; 95% confidence interval, 1.20-1.37). In a nested study enrolling 1,115 farmworkers, prevalence of current infection was 27.7% among farmworkers reporting ≥1 potential COVID-19 symptom, and 7.2% among farmworkers without symptoms (adjusted odds ratio 4.17; 2.86-6.09). Prevalence of anti-SARS-CoV-2 IgG antibodies increased from 10.5% (6.0-18.4%) between 16 July-31 August to 21.2% (16.6-27.4%) between 1-30 November. The high observed prevalence of infection among farmworkers underscores the need for vaccination and other preventive interventions.
Probability that an infection like Covid-19 stops without reaching herd immunity, calculated with a stochastic agent-based model
Authors: Eissler Manfred
Published: January 2021

The spread of an infection is simulated with a stochastic agent-based model. In a certain range of R0 values, the infection either rapidly comes to halt or a large proportion of the population is infected until herd immunity is achieved. Which of these two possibilities actually occurs is random. The probability of each case is determined ‘quasi-empirically’. This stochastic phenomenon may explain unexpected infection trajectories.
Tumor Suppressor Immune Gene Therapy to Reverse Immunotherapy Resistance
Authors: Chada Sunil , Wiederhold Dora , Menander Kerstin B. , Sellman Beatha , Talbott Max , Nemunaitis John J. , Ahn Hyo Min , Jung Bo-Kyeong , Yun Chae-Ok , Sobol Robert E.
Published: January 2021

Background

While immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required overcome resistance to immunotherapies.

Methods

We investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms action, pre and post Ad-p53 treatment biopsies were evaluated for changes in gene expression profiles by Nanostring IO 360 assays.

Results

Substantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with complete tumor remissions of both primary and contralateral tumors. Interestingly, contralateral tumors which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p<0.001). None of the monotherapies or doublet treatments induced complete tumor regressions. Ad-p53 treatment increased Type I Interferon, CD8+ T cell, immuno-proteosome antigen presentation and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 down regulated genes associated with stromal pathways and IL10 expression identified novel anti-cancer therapeutic applications.

Conclusions

These results imply the ability of Ad-p53 to induce efficacious local and systemic anti-tumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complimentary immune mechanisms of action which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist and immune checkpoint inhibitor combination treatment.
Blood-based host biomarker diagnostics in active case finding for pulmonary tuberculosis: a diagnostic case-control study
Authors: Moreira Flora Martinez Figueira , Verma Renu , dos Santos Paulo Cesar Pereira , Leite Alessandra , da Silva Santos Andrea , de Araujo Rafaele Carla Pivetta , da Silva Bruna Oliveira , de Sá Queiroz Júlio Henrique Ferreira , Persing David H. , Södersten Erik , Gnanashanmugam Devasena , Khatri Purvesh , Croda Julio , Andrews Jason R.
Published: January 2021

Background

There is a need to identify scalable tuberculosis screening strategies among high burden populations. The WHO has identified a non-sputum-based triage test as a development priority.

Methods

We performed a diagnostic case-control study of point-of-care C-reactive protein (CRP) and Xpert-MTB-Host-Response (Xpert-MTB-HR) assays in the context of a mass screening program for tuberculosis in two prisons in Brazil. All incarcerated individuals irrespective of symptoms were screened by sputum Xpert-MTB/RIF and sputum culture. Among consecutive, Xpert-MTB/RIF or culture-confirmed cases and Xpert-MTB/RIF and culture-negative controls, CRP was quantified in serum by a point-of-care assay (iChroma-II) and a 3-gene expression score was quantified from whole blood using the Xpert-MTB-HR cartridge. We evaluated receiver operating characteristic area under the curve (AUC) and assessed specificity at 90% sensitivity and sensitivity at 70% specificity, consistent with WHO target product profile (TPP) benchmarks.

Findings

Two hundred controls and 100 culture- or Xpert-positive tuberculosis cases were included. Half of tuberculosis cases and 11% of controls reported any tuberculosis symptoms. AUC for CRP was 0·79 (95% CI: 0·73-0·84) and for Xpert-MTB-HR was 0·84 (95% CI: 0·79-0·89). At 90% sensitivity, Xpert-MTB-HR had significantly higher specificity (53·0%, 95% CI: 45·0-69·0%) than CRP (28·1%, 95% CI: 20·2-41·8%) (p=0·003), both well below the TPP benchmark of 70%. Among individuals with medium or high sputum Xpert semi-quantitative load, sensitivity (at 70% specificity) of CRP (90·3%, 95% CI: 74·2-98·0) and Xpert-MTB-HR (96·8%, 95% CI: 83·3-99·9%) was higher.

Interpretation

For active case finding in this high tuberculosis-burden setting, CRP and Xpert-MTB-HR did not meet TPP benchmarks for a triage test. However, Xpert-MTB-HR was highly sensitive in detecting individuals with medium or high sputum bacillary burden.

Funding

National Institutes of Health (R01 AI130058 and R01 AI149620) and Brazilian National Council for Scientific and Technological Development (CNPq-404182/2019-4).
Impact of Discoordinated Care on Healthcare Utilization and Survival in Stage IV Non-Small Cell Lung Cancer Patients
Authors: Heilbroner Samuel P , Xanthopoulos Eric P , Hoffman Mark A , Buono Donna , Durkee Ben Y , Corradetti Michael , Wang Tony JC , Wright Jason D , Neugut Alfred I , Hershman Dawn L , Rohs Nicholas C , Cheng Simon K
Published: January 2021

Background

Cancer patients’ treatment is often dispersed across multiple physician communities that may not exchange information. We measured the association between this type of discoordinated care and healthcare utilization, cost, and mortality in stage IV non-small cell lung cancer (NSCLC).

Methods

Stage IV NSCLC patients ≥65 years were identified from the Surveillance, Epidemiology, and End Results database attached to Medicare claims. A discoordinated care subgroup was selected using a novel index that approximated how many physician communities each patient encountered. Communities were defined by (1) using claims data to create a nationwide social network of healthcare providers and then (2) dividing that network into communities using cluster label propagation. Associations between discoordinated care and overall survival (OS), cancer-specific survival (CSS), hospitalizations, the burden of diagnostic imaging, and cost were assessed.

Results

Of the 11,417 patients in our cohort, 5,855 received discoordinated care. Discoordination was associated with younger age, higher socioeconomic status, higher physician density, and lack of a home health aide. Discoordinated care was associated with improved OS and CSS (HR = 0.92, 95% CI 0.88 - 0.95 for OS). However, discoordinated patients also received 32% more MRIs (p = 0.007) and paid $494.02 more for imaging (p = 0.004). There was no association with other kinds of imaging, rates of hospitalization, or other healthcare costs, including total cost.

Conclusions

Discoordinated care was associated with additional MRIs, but also improved survival. The reason is unclear, but discoordinated patients may be seeking the best care at the expense of continuity.

Key Points

Question

How does dispersing healthcare across multiple physician communities impact healthcare utilization and survival in patients with advanced stage non-small cell lung cancer?

Findings

In this retrospective cohort study, we found that discoordinated care was associated with increased utilization of MRIs and total cost of imaging. Surprisingly, it was also associated with improved survival.

Meaning

Cancer patients with dispersed healthcare may be seeking care through a tertiary care center or clinical trial. This may lead to increased healthcare utilization but also improved survival.
Secretome of senescent hepatoma cells modulate macrophage polarization and neutrophil extracellular traps formation
Authors: Sen Bijoya , Aggarwal Savera , Nath Rhisita , Sehgal Rashi , Rastogi Archana , Trehanpati Nirupma , Ramakrishna Gayatri
Published: January 2021

Presence of dysfunctional senescent hepatocyte is a hallmark feature of cirrhosis. We now report the presence of senescent hepatocytes (p21 and p53 positive) in vicinity of infiltrated immune cells in hepatocellular carcinoma. Hence, we checked if senescent cells can alter fate of macrophage polarization and neutrophil extracellular trap (NETs) formation. Using an in vitro assay, senescence was induced in hepatoma cells (HepG2 and Huh7 cells) by doxorubicin treatment and senescent cell showed secretory phenotype with strong expression of cytokines (IL1β, IL6, IL8 and IL13) as evaluated by Flow cytometry. The senescent secretome from hepatoma cells induced macrophage differentiation predominantly with M2 markers (CD80, CD86) while that of non-senescent cell induced M1 phenotype (CD163, CD206) as analysed by flow cytometry. Human hepatocellular carcinoma harbouring senescent hepatocytes showed presence of M2 macrophages, while M1 macrophages were predominant in non-tumorous region. Additionally, the senescent secretome from Huh7 cells (p53mut) enhanced the NETs formation, while HepG2 (p53+/+) secretome had an inhibitory affect In conclusion, the “pro-inflammatory” senescent secretome drives non-inflammatory type M2 macrophage polarization and modulate neutrophil traps thereby modulating the microenvironment towards tumor promotion. Targeting senescent hepatocyte secretome appears a promising therapeutic target in liver cancer in future.

Abstract Figure

Work Highlight (Diagrammatic Representation).
Variability of the Surface Area of the V1, V2, and V3 Maps in a Large Sample of Human Observers
Authors: Benson Noah C. , Yoon Jennifer M. D. , Forenzo Dylan , Engel Stephen A. , Kay Kendrick N. , Winawer Jonathan
Published: January 2021

How variable is the functionally-defined structure of early visual areas in human cortex and how much variability is shared between twins? Here we quantify individual differences in the best understood functionally-defined regions of cortex: V1, V2, V3. The Human Connectome Project 7T Retinotopy Dataset includes retinotopic measurements from 181 subjects, including many twins. We trained four “anatomists” to manually define V1-V3 using retinotopic features. These definitions were more accurate than automated anatomical templates and showed that surface areas for these maps varied more than three-fold across individuals. This three-fold variation was little changed when normalizing visual area size by the surface area of the entire cerebral cortex. In addition to varying in size, we find that visual areas vary in how they sample the visual field. Specifically, the cortical magnification function differed substantially among individuals, with the relative amount of cortex devoted to central vision varying by more than a factor of 2. To complement the variability analysis, we examined the similarity of visual area size and structure across twins. Whereas the twin sample sizes are too small to make precise heritability estimates (50 monozygotic pairs, 34 dizygotic pairs), they nonetheless reveal high correlations, consistent with strong effects of the combination of shared genes and environment on visual area size. Collectively, these results provide the most comprehensive account of individual variability in visual area structure to date, and provide a robust population benchmark against which new individuals and developmental and clinical populations can be compared.

Significance Statement

Areas V1, V2, and V3 are among the best studied functionally-defined regions in human cortex. Using the largest retinotopy dataset to date, we characterized the variability of these regions across individuals and the similarity between twin pairs. We find that the size of visual areas varies dramatically (up to 3.5x) across healthy young adults, far more than the variability of the cerebral cortex size as a whole. Much of this variability appears to arise from inherited factors, as we find very high correlations in visual area size between monozygotic twin-pairs, and lower but still substantial correlations between dizygotic twin pairs. These results provide the most comprehensive assessment of how functionally defined visual cortex varies across the population to date.
Data-driven filtration and segmentation of mesoscale neural dynamics
Authors: Weiser Sydney C. , Mullen Brian R. , Ascencio Desiderio , Ackman James B.
Published: January 2021

Recording neuronal group activity across the cortical hemispheres from awake, behaving mice is essential for understanding information flow across cerebral networks. Video recordings of cerebral function comes with challenges, including optical and movement-associated vessel artifacts, and limited references for time series extraction. Here we present a data-driven workflow that isolates artifacts from calcium activity patterns, and segments independent functional units across the cortical surface. Independent Component Analysis utilizes the statistical interdependence of pixel activation to completely unmix signals from background noise, given sufficient spatial and temporal samples. We also utilize isolated signal components to produce segmentations of the cortical surface, unique to each individual’s functional patterning. Time series extraction from these maps maximally represent the underlying signal in a highly compressed format. These improved techniques for data pre-processing, spatial segmentation, and time series extraction result in optimal signals for further analysis.
Multivariate analysis of strawberry experiments: where are we now and where can we go?
Authors: Olivoto Tiago , Diel Maria Inês , Schmidt Denise , Lúcio Alessandro Dal’Col
Published: January 2021

The multi-trait genotype-ideotype distance index (MGIDI) was used to select superior treatments in experiments with strawberries. Twenty-three productive, qualitative, physiological, and phenological traits with negative and positive desired gains were accessed in 16 treatments, a combination of two cultivars (Albion-neutral days, and Camarosa-short days), two transplants origins (National and Imported), and four organic substrates mixes (Crushed sugarcane bagasse, burnt rice husk, organic substrate, and Carolina commercial substrate). Our results suggest that most of the strawberry traits are influenced by the cultivar, transplant origin, cultivation substrates, as well as by the interaction between cultivar and transplant origin. The MGIDI index indicated that the Albion cultivar originated from imported transplants grown in substrates where the main component (70%) is burnt rice husk provides desired values for 20 of a total of 22 traits, which represents a success rate of ~ 91% in selecting traits with desired values. Thestrengths and weakness viewprovided by the MGIDI index revealed that the looking for an ideal treatment should direct the efforts on improving the water efficiency use and reducing total acidy of fruits. On the other hand, the strengths of selected treatments are mainly related to productive precocity, total soluble solids, and flesh firmness. The MGIDI index provides a unique, robust, and easy-to-handle process, standing out as a powerful tool to develop better treatment recommendations for experiments with strawberries when multiple traits are assessed.
Detecting and Reversing Myocardial Ischemia Using an Artificially Intelligent Bioelectronic Medicine
Authors: Ganzer PD , Loeian MS , Roof SR , Teng B , Lin L , Friedenberg DA , Baumgart IW , Meyers EC , Chun KS , Rich A , Muir WW , Weber DJ , Hamlin RL
Published: January 2021

Myocardial ischemia is spontaneous, usually asymptomatic, and contributes to fatal cardiovascular consequences. Importantly, biological neural networks cannot reliably detect and correct myocardial ischemia on their own. In this study, we demonstrate an artificially intelligent and responsive bioelectronic medicine, where an artificial neural network (ANN) supplements biological neural networks enabling reliable detection and correction of myocardial ischemia. ANNs were first trained to decode spontaneous cardiovascular stress and myocardial ischemia with an overall accuracy of ∼92%. ANN-controlled vagus nerve stimulation (VNS) reversed the major biomarkers of myocardial ischemia with no side effects. In contrast, open-loop VNS or ANN-controlled VNS following a caudal vagotomy essentially failed to reverse correlates of myocardial ischemia. Lastly, variants of ANNs were used to meet clinically relevant needs, including interpretable visualizations and unsupervised detection of emerging cardiovascular stress states. Overall, these results demonstrate that ANNs can supplement deficient biological neural networks via an artificially intelligent bioelectronic medicine system.
Packpred: Predicting the functional effect of missense mutations
Authors: Tan Kuan Pern , Kanitkar Tejashree Rajaram , Keong Kwoh Chee , Madhusudhan M.S.
Published: January 2021

1.

Predicting the functional consequences of single point mutations has relevance to protein function annotation and to clinical analysis/diagnosis. We developed and tested Packpred that makes use of a multi-body clique statistical potential in combination with a depth dependent amino acid substitution matrix (FADHM) and positional Shannon Entropy to predict the functional consequences of point mutations in proteins. Parameters were trained over a saturation mutagenesis data set of T4-lysozyme (1966 mutations). The method was tested over another saturation mutagenesis data set (CcdB; 1534 mutations) and the Missense3D data set (4099 mutations). The performance of Packpred was compared against those of six other contemporary methods. With MCC values of 0.42, 0.47 and 0.36 on the training and testing data sets respectively, Packpred outperforms all method in all data sets, with the exception of marginally underperforming to FADHM in the CcdB data set. On analyzing the results, we could build meta servers that chose best performing methods of wild type amino acids and for wild type-mutant amino acid pairs. This lead to an increase of MCC value of 0.40 and 0.51 for the two meta predictors respectively on the Missense3D data set. We conjecture that it is possible to improve accuracy with better meta predictors as among the 7 methods compared, at the least one method or another is able to correctly predict ∼99% of the data.
Hidden Transcriptome Signature in Autism Spectrum Disorder (ASD) is Attributed to the Interpatient Heterogeneity
Authors: Huang Yimei , Yang Yuqing , Qiu Chuchen , Sun Ting , Han Ruilin , Leung Chi Sum , Xie Songhong , Chen Dongjin
Published: January 2021

Recent studies of ASD have mostly supported the existence of heterogeneity and genomic variation in ASD which have hindered and restrained development of any effective and targetable treatment for a long time. As numerous studies have shown, both genetic and phenotypic heterogeneity is presented in ASD, however, heterogeneity in genetic level is not fully understood which is the key challenges for the further research. Even dozens of ASD susceptibility genes have been discovered which is commonly accounting for 10 to 20 percent of ASD cases, the internal complex combination of mutated genes that determine the epigenetic factors of ASD is still not comprehensively recognized by the recent studies. First by discouraging the traditional method that have been applied in most of the current research of diseases, this research will then focus on dissecting the heterogeneity of polygenic diseases and analyzing with an unconventional approach for acquiring Differently Expressed Genes (DEGs) in Gupta’s Dataset that provided transcriptome of frontal cortex of ASD patients. Divide categories by using unsupervised learning strategy, the results yielded by analyzing within clusters of ASD have supported the feasibility of the attempts to use heterogeneity to reveal its underlying mechanism. This study puts forward the inference that the heterogeneity of polygenic diseases will obscure the molecular signals related to the disease, and at the same time attempts to use heterogeneity to reveal the underlying mechanism.
The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates
Authors: Li Dapeng , Edwards Robert J , Manne Kartik , Martinez David R. , Schäfer Alexandra , Alam S. Munir , Wiehe Kevin , Lu Xiaozhi , Parks Robert , Sutherland Laura L. , Oguin Thomas H. , McDanal Charlene , Perez Lautaro G. , Mansouri Katayoun , Gobeil Sophie M. C. , Janowska Katarzyna , Stalls Victoria , Kopp Megan , Cai Fangping , Lee Esther , Foulger Andrew , Hernandez Giovanna E. , Sanzone Aja , Tilahun Kedamawit , Jiang Chuancang , Tse Longping V. , Bock Kevin W. , Minai Mahnaz , Nagata Bianca M. , Cronin Kenneth , Gee-Lai Victoria , Deyton Margaret , Barr Maggie , Holle Tarra Von , Macintyre Andrew N. , Stover Erica , Feldman Jared , Hauser Blake M. , Caradonna Timothy M. , Scobey Trevor D. , Rountree Wes , Wang Yunfei , Moody M. Anthony , Cain Derek W. , DeMarco C. Todd , Denny ThomasN. , Woods Christopher W. , Petzold Elizabeth W. , Schmidt Aaron G. , Teng I-Ting , Zhou Tongqing , Kwong Peter D. , Mascola John R. , Graham Barney S. , Moore Ian N. , Seder Robert , Andersen Hanne , Lewis Mark G. , Montefiori David C. , Sempowski Gregory D. , Baric Ralph S. , Acharya Priyamvada , Haynes Barton F. , Saunders Kevin O.
Published: January 2021

SARS-CoV-2 neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) and the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV-1 infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infectionin vitro, while five non-neutralizing NTD antibodies mediated FcγR-independentin vitroinfection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Nonetheless, three of 31 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, whilein vitroantibody-enhanced infection does not necessarily herald enhanced infectionin vivo, increased lung inflammation can occur in SARS-CoV-2 antibody-infused macaques.
Cas9-cleavage sequences in minimal plasmids enhance non-viral genome targeting of CARs in primary human T cells
Authors: Jing Ruirui , Jiao Peng , Chen Jiangqing , Meng Xianhui , Wu Xiaoyan , Duan Yanting , Shang Kai , Qian Liling , Huang Yanjie , Liu Junwei , Huang Tao , Jin Jin , Chen Wei , Zeng Xun , Yin Weiwei , Gao Xiaofei , Zhou Chun , Sadelain Michel , Sun Jie
Published: January 2021

T cell genome editing holds great promise to advance a range of immunotherapies but is encumbered by the dependence on difficult-to-produce and expensive viral vectors. Here we have designed small double-stranded plasmid DNA modified to mediate high-efficiency homologous recombination. The resulting chimeric antigen receptor (CAR)-T cells display a similar phenotype, transcriptional profile andin vivopotency as CAR-T cells generated using adeno-associated viral (AAV) vector. This method should simplify and accelerate the use of precision engineering to produce edited T cells for research and clinical purposes.
Comprehensive analysis of the host-virus interactome of SARS-CoV-2
Authors: Chen Zhen , Wang Chao , Feng Xu , Nie Litong , Tang Mengfan , Zhang Huimin , Xiong Yun , Swisher Samuel K. , Srivastava Mrinal , Chen Junjie
Published: January 2021

Host-virus protein-protein interaction is the key component of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle. We conducted a comprehensive interactome study between the virus and host cells using tandem affinity purification and proximity labeling strategies and identified 437 human proteins as the high-confidence interacting proteins. Functional characterization and further validation of these interactions elucidated how distinct SARS-CoV-2 viral proteins participate in its lifecycle, and discovered potential drug targets to the treatment of COVID-19. The interactomes of two key SARS-CoV-2 encoded viral proteins, NSP1 and N protein, were compared with the interactomes of their counterparts in other human coronaviruses. These comparisons not only revealed common host pathways these viruses manipulate for their survival, but also showed divergent protein-protein interactions that may explain differences in disease pathology. This comprehensive interactome of coronavirus disease-2019 provides valuable resources for understanding and treating this disease.
Spatial and temporal dynamics of SAR11 marine bacteria sampled across a nearshore to offshore transect in the tropical Pacific Ocean
Authors: Tucker Sarah J. , Freel Kelle C. , Monaghan Elizabeth A. , Sullivan Clarisse E.S. , Ramfelt Oscar , Rii Yoshimi M. , Rappé Michael S.
Published: January 2021

Time-series surveys of microbial communities coupled with contextual measures of the environment provide a useful approach to dissect the factors determining distributions of microorganisms across ecological niches. Here, monthly time-series samples of surface seawater along a transect spanning the nearshore coastal environment within Kāne‘ohe Bay on the island of O‘ahu, Hawai‘i, and the adjacent offshore environment were collected to investigate the diversity and abundance of SAR11 marine bacteria over a two-year time period. Using 16S ribosomal RNA gene amplicon sequencing, the spatiotemporal distributions of major SAR11 subclades and individual amplicon sequence variants (ASVs) were evaluated. On average, 77% of the SAR11 community was compromised of a small number of ASVs (7 of 106 in total), which were ubiquitously distributed across all samples collected from one or both of the end-member environments sampled in this study (coastal or offshore). SAR11 ASVs were more often restricted spatially to coastal or offshore environments (64 of 106 ASVs) than they were shared among coastal, transition, and offshore environments (39 of 106 ASVs). Overall, offshore SAR11 communities contained a higher diversity of SAR11 ASVs than their nearshore counterparts. This study reveals ecological differentiation of SAR11 marine bacteria across a short physiochemical gradient, further increasing our understanding of how SAR11 genetic diversity partitions into distinct ecological units.
Sequencing of Sars-CoV-2 genome using different Nanopore chemistries
Authors: González-Recio Oscar , Gutiérrez-Rivas Mónica , Peiró-Pastor Ramón , Aguilera-Sepúlveda Pilar , Cano-Gómez Cristina , Jiménez-Clavero Miguel Ángel , Fernández-Pinero Jovita
Published: January 2021

Nanopore sequencing has emerged as a rapid and cost-efficient tool for diagnostic and epidemiological surveillance of SARS-CoV-2 during the COVID-19 pandemic. This study compared results from sequencing the SARS-CoV-2 genome using R9 vs R10 flow cells and Rapid Barcoding Kit (RBK) vs Ligation Sequencing Kit (LSK). The R9 chemistry provided a lower error rate (3.5%) than R10 chemistry (7%). The SARS-CoV-2 genome includes few homopolymeric regions. Longest homopolymers were composed of 7 (TTTTTTT) and 6 (AAAAAA) nucleotides. The R10 chemistry resulted in a lower rate of deletions in timine and adenine homopolymeric regions than R9, at expenses of a larger rate (~10%) of mismatches in these regions.

The LSK had a larger yield than RBK, and provided longer reads than RBK. It also resulted in a larger percentage of aligned reads (99% vs 93%) and also in a complete consensus genome.

The results from this study suggest that the LSK used on a R9 flow cell could maximize the yield and accuracy of the consensus sequence when used in epidemiological surveillance of SARS-CoV-2.

Keypoints

Sequencing SARS-CoV-2 genome is of great importance for the pandemic surveillance

Nanopore offers a low cost and accurate method to sequence SARS-CoV-2 genome

Ligation sequencing is preferred rather than the rapid kit using transposases
An RNAi screen inC. elegansfor genes that play a role in secretion and cleavage of VAPB MSP domain
Authors: Zein-Sabatto Hala , Collawn Jim , Chang Chenbei , Miller Michael A.
Published: January 2021

VAPB (VPR-1 inC. elegans) is a type-II ER transmembrane protein whose N-terminal Major Sperm Protein domain (MSPd) is cleaved and secreted. Mutations in the MSPd of human VAPB cause impaired secretion and are associated with Amyotrophic Lateral Sclerosis (ALS). InC. elegans, the secreted MSPd signals non-cell-autonomously to regulate striated muscle mitochondrial morphology and gonad development. As VAPB/VPR-1 does not have a signal peptide and its MSPd extends into the cytosol, it is unclear how the protein is proteolytically cleaved and secreted. To identify genes that are involved in VPR-1 cleavage and unconventional secretion, we performed an RNA interference (RNAi) screen inC. elegans. Worms null forvpr-1are sterile and have striated muscle mitochondrial abnormalities. These defects can be rescued byvpr-1expression in the neurons, germline, or intestine, implying that these three tissues share a common machinery to cleave and secrete the MSPd. Examination of shared gene expression in these tissues revealed a list of 422 genes, which we targeted with RNAi.vpr-1null worms expressingvpr-1from intestine were used in the screen, and the brood size of these worms after RNAi knockdown was scored. Disruption of factors involved in VPR-1 MSPd processing and/or secretion should revert fertility phenotypes in these worms. We identified many genes that induce compromised fertility when knocked down in these but not wild type worms, including a V-SNARE, several proteasome components, stress response molecules, and mitochondrial genes. Our screen thus identified many potential players involved in MSPd processing and/or secretion.

The MSP domain (MSPd) of a type-II ER transmembrane protein called VAPB is cleaved and secreted to function as a non-cell-autonomous signal. The topology of VAPB positions MSPd in the cytosol. It is thus unclear how MSPd is cleaved from VAPB and released extracellularly. UsingC. elegans, we screened 422 genes by RNAi to identify potential candidates regulating MSPd cleaving and secretion. We identified the Golgi v-SNARE YKT-6 and several components of the 20S and 19S proteasome that may mediate MSPd trafficking and cleaving, respectively. These results have promising implications in advancing our understanding of MSPd signaling.
Translational control of lipogenesis links protein synthesis and phosphoinositide signaling with nuclear division
Authors: Maitra Nairita , Hammer Staci , Kjerfve Clara , Bankaitis Vytas A. , Polymenis Michael
Published: January 2021

Continuously dividing cells coordinate their growth and division. How fast cells grow in mass determines how fast they will multiply. Yet, there are few, if any, examples of a metabolic pathway that actively drives a cell cycle event instead of just being required for it. Here, we show that translational upregulation of lipogenic enzymes in yeast increased the abundance of lipids and accelerated nuclear elongation and division. De-repressing translation of acetyl CoA carboxylase and fatty acid synthase also suppressed cell cycle-related phenotypes, including delayed nuclear division, associated with Sec14p phosphatidylinositol transfer protein deficiencies, and the irregular nuclear morphologies of mutants defective in phosphatidylinositol 4-OH kinase activities. Our results show that increased lipogenesis drives a critical cell cycle landmark and report a phosphoinositide signaling axis in control of nuclear division. The broad conservation of these lipid metabolic and signaling pathways raises the possibility these activities similarly govern nuclear division in mammals.
Current status and perspectives on the role of polyamines in plant immunity
Authors: Gonzalez María E. , Jasso‐Robles Francisco I. , Flores‐Hernández Emmanuel , Rodríguez‐Kessler Margarita , Pieckenstain Fernando L.
Published: January 2021

Polyamines are low molecular weight amines, with versatile and essential functions during the lifespan of prokaryotes and eukaryotes. Modulation of polyamine metabolism under biotic stress has attracted a great deal of interest; however, the precise functions of these amines in plant defence responses to pathogen attack are still poorly understood. Herein we summarise and review important aspects of the regulation of polyamine biosynthesis, catabolism and conjugation under biotic stress that might contribute to improve present‐day knowledge about these compounds in plant immunity. Particular attention is paid to the intracellular localisation of the proteins/enzymes associated to polyamine metabolism, as well as the impact of pathogen effector proteins on the control of plant polyamine metabolism is discussed.
Soil properties and bamboo cover drive the structure of the woody plant community along a forest–savanna gradient
Authors: Gonçalves Lorrayne Aparecida , Abadia Ana Clara , Vilar Cesar Crispim , Silvério Divino Vicente , Colli Guarino Rinaldi , Martins Jhany , Maracahipes‐Santos Leonardo , Ushiwata Silvio Yoshiharu , Lenza Eddie
Published: January 2021

Understanding the role of environmental conditions and geographic space on species distributions is a major goal of ecological studies. Here, we investigate the effects of soil properties, a native bamboo (Actinocladum verticillatum (Nees) McClure ex Soderstr) ground cover and geographic distance on species richness and turnover in the Brazilian Cerrado. We established three transects along a forest–savanna gradient (14°41′S and 52°20′W), from the lowland next to a stream to the top of a hill, where we sampled the woody plant community (DBH ≥ 3 cm), soil properties and ground cover of A. verticillatum. We evaluated changes in species composition with a principal coordinates analysis, and the effects of the environmental predictors on species richness using generalised linear models and on species turnover using generalised dissimilarity modelling. We found that species richness increases with K concentration in the soil and decreases with Zn concentration in the soil and bamboo cover. The predictors explained 62% of species turnover, with environmental parameters (soil properties, bamboo cover and altitude) having the most significant contribution (80%), followed by the spatially structured environmental variation (20%). The most important environmental predictors of woody species turnover were soil concentration of Zn, P and K, altitude, and bamboo cover. Changes in species richness and composition in the studied gradient were strongly associated with plot height, bamboo cover and soil content of K, Zn and P. Our findings indicate that nutrient availability and competition with bamboo explain vegetation structure and composition in this region.
Rethinking third trimester ultrasound measurements and risk of adverse neonatal outcomes in pregnancies complicated by hyperglycaemia: A retrospective study
Authors: McLean Anna , Katz Melissa , Oats Jeremy , Wang Zhiqiang , Barr Elizabeth , Maple‐Brown Louise
Published: January 2021

Background

Antenatal ultrasound is used frequently in pregnancies complicated by hyperglycaemia; however, it is unclear which measurements have the greatest association with adverse neonatal outcomes.

Aim

To assess the association between third trimester ultrasound parameters with adverse neonatal outcomes in pregnancies complicated by hyperglycaemia.

Method

All pregnant women with gestational or type 2 diabetes who birthed in a regional hospital over 12 months were included. A composite adverse neonatal outcome was defined by one or more: admission to special care nursery, acidosis, hypoglycaemia, jaundice, shoulder dystocia, respiratory distress syndrome or 5‐minute Apgar score < 5. Logistic regression was used to determine odds ratios (OR) for an adverse neonatal outcome, according to pre‐specified cut points in both lower and upper percentiles of abdominal circumference (AC) and estimated fetal weight (EFW).

Results

Of 275 births an adverse outcome occurred in 122 (44%). Unadjusted OR (95% CI) for AC ≤30th was 3.2 (1.1–8.8) and >95th percentile was 3.1 (1.5–6.0) compared with the reference group of 31–70th percentile. Unadjusted OR for EFW ≤30th was 1.5 (0.7–3.1) and >95th percentile was 3.0 (1.4–6.3). After adjusting for maternal age, body mass index, diabetes type, ethnicity, gravidity, mode of delivery and gestation at birth the OR (95% CI) were as follows: AC ≤30th percentile, 3.7 (1.1–12.4); AC >95th, 2.2 (1.1–4.8); EFW ≤30th, 2.6 (1.1–6.1); EFW >95th, 2.5 (1.1–6.1).

Conclusion

An AC and EFW up to the 30th percentile may pose just as great a risk to the fetus as an AC or EFW >95th percentile in pregnancies complicated by hyperglycaemia.