bluuebunny/crossref_metadata_2025 huggingface dataset:
SubLocEP: a novel ensemble predictor of subcellular localization of eukaryotic mRNA based on machine learning
Authors: Li Jing , Zhang Lichao , He Shida , Guo Fei , Zou Quan
Published: December 2020

Motivation

mRNA location corresponds to the location of protein translation and contributes to precise spatial and temporal management of the protein function. However, current assignment of subcellular localization of eukaryotic mRNA reveals important limitations: (1) turning multiple classifications into multiple dichotomies makes the training process tedious; (2) the majority of the models trained by classical algorithm are based on the extraction of single sequence information; (3) the existing state-of-the-art models have not reached an ideal level in terms of prediction and generalization ability. To achieve better assignment of subcellular localization of eukaryotic mRNA, a better and more comprehensive model must be developed.

Results

In this paper, SubLocEP is proposed as a two-layer integrated prediction model for accurate prediction of the location of sequence samples. Unlike the existing models based on limited features, SubLocEP comprehensively considers additional feature attributes and is combined with LightGBM to generated single feature classifiers. The initial integration model (single-layer model) is generated according to the categories of a feature. Subsequently, two single-layer integration models are weighted (sequence-based: physicochemical properties = 3:2) to produce the final two-layer model. The performance of SubLocEP on independent datasets is sufficient to indicate that SubLocEP is an accurate and stable prediction model with strong generalization ability. Additionally, an online tool has been developed that contains experimental data and can maximize the user convenience for estimation of subcellular localization of eukaryotic mRNA.
Prediction of RNA-binding protein and alternative splicing event associations during epithelial–mesenchymal transition based on inductive matrix completion
Authors: Qiu Yushan , Ching Wai-Ki , Zou Quan
Published: December 2020

Motivation

The developmental process of epithelial-mesenchymal transition (EMT) is abnormally activated during breast cancer metastasis. Transcriptional regulatory networks that control EMT have been well studied; however, alternative RNA splicing plays a vital regulatory role during this process and the regulating mechanism needs further exploration. Because of the huge cost and complexity of biological experiments, the underlying mechanisms of alternative splicing (AS) and associated RNA-binding proteins (RBPs) that regulate the EMT process remain largely unknown. Thus, there is an urgent need to develop computational methods for predicting potential RBP-AS event associations during EMT.

Results

We developed a novel model for RBP-AS target prediction during EMT that is based on inductive matrix completion (RAIMC). Integrated RBP similarities were calculated based on RBP regulating similarity, and RBP Gaussian interaction profile (GIP) kernel similarity, while integrated AS event similarities were computed based on AS event module similarity and AS event GIP kernel similarity. Our primary objective was to complete missing or unknown RBP-AS event associations based on known associations and on integrated RBP and AS event similarities. In this paper, we identify significant RBPs for AS events during EMT and discuss potential regulating mechanisms. Our computational results confirm the effectiveness and superiority of our model over other state-of-the-art methods. Our RAIMC model achieved AUC values of 0.9587 and 0.9765 based on leave-one-out cross-validation (CV) and 5-fold CV, respectively, which are larger than the AUC values from the previous models. RAIMC is a general matrix completion framework that can be adopted to predict associations between other biological entities. We further validated the prediction performance of RAIMC on the genes CD44 and MAP3K7. RAIMC can identify the related regulating RBPs for isoforms of these two genes.

Availability and implementation

The source code for RAIMC is available at https://github.com/yushanqiu/RAIMC.

Contact

zouquan@nclab.net online.
A hidden fight behind neutrality. Spain’s struggle on exchange rates and gold during the Great War
Authors: Sudrià Carles
Published: December 2020

The aim of this article is to analyse the effects on Spain as a neutral country of the monetary measures adopted by the largest allied nations during the First World War. We will focus on the intervention of exchange rates and on the measures aimed at limiting gold outflows from belligerent countries. The distortions derived from these policies gave rise, in some cases, to additional profits for Spanish exporters and intermediaries, while in others prevented the effective transformation of some benefits from war into valuable assets and pushed them to be dragged down by the economic disturbances of the post-war period.
Metabarcoding reveals hidden species and improves identification of marine zooplankton communities in the North Sea
Authors: Semmouri Ilias , De Schamphelaere Karel A C , Willemse Stijn , Vandegehuchte Michiel B , Janssen Colin R , Asselman Jana
Published: December 2020

Although easily collected in large numbers, the subsequent processing and identification of zooplankton have usually been a barrier to large-scale biodiversity assessments. Therefore, DNA barcoding has been increasingly used by non-taxonomists to identify specimens. Here, we studied the community composition of zooplankton in the Belgian part of the North Sea over the course of 1 year. We identified zooplankton using both a traditional approach based on morphological characteristics and by metabarcoding of a 650 bp fragment of the V4-V5 region of the 18S rRNA gene using nanopore sequencing. Using long rDNA sequences, we were able to identify several taxa at the species level, across a broad taxonomic scale. Using both methods, we compared community composition and obtained diversity metrics. Diversity indices were not significantly correlated. Metabarcoding allowed for comparisons of diversity and community composition, but not all groups were successfully sequenced. Additionally, some disparities existed between relative abundances of the most abundant taxa based on traditional counts and those based on sequence reads. Overall, we conclude that for zooplankton samples, metabarcoding is capable of detecting taxa with a higher resolution, regardless of developmental stage of the organism. Combination of molecular and morphological methods results in the highest detection and identification levels of zooplankton.
Silent information regulator type-1 mediates amelioration of inflammatory response and oxidative stress in lipopolysaccharide-induced acute respiratory distress syndrome
Authors: Zhan Yuan , Yang Chunjian , Zhang Qunhui , Yao Li
Published: December 2020

Silent information regulator type-1 (SIRT1) is crucial during the development of acute respiratory distress syndrome (ARDS). We aimed to explore whether SIRT1 activation could protect against ARDS. SIRT1 was activated by its agonist SRT1720. ARDS was induced by intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS). Lung injuries were determined by the lung wet/dry ratio, inflammatory cells in the broncho-alveolar lavage fluid (BALF) and histological analysis. Inflammatory cytokine release was detected by enzyme-linked immunosorbent assay. The accumulation of neutrophils was detected by myeloperoxidase activity. Oxidative stress was evaluated by malondialdehyde, reduced glutathione, superoxide dismutase and catalase activities. The protein expression levels were detected using western blot. SIRT1 activation, either by SRT1720 administration or recombinant SIRT1, expression eliminated high-dose LPS-induced mortality in mice, attenuated lung injury, influenced cytokine release in BALF and decreased oxidative stress in the lung tissues of ARDS mice. Mechanically, SRT1720 administration inhibited p65 phosphorylation in the lung tissues of ARDS mice. SIRT1 ameliorates inflammatory response and oxidative stress in LPS-induced ARDS.
Discovery of the first AmazonianThomasomys(Rodentia, Cricetidae, Sigmodontinae): a new species from the remote Cordilleras del Cóndor and Kutukú in Ecuador
Authors: Brito Jorge , Vaca-Puente Sarah , Koch Claudia , Tinoco Nicolás
Published: December 2020

A new species of the cricetid rodent genus Thomasomys is described from the montane forests of the Cordilleras del Cóndor and Kutukú, southeastern Ecuador, at elevations between 1,770 and 2,215 m. The species has a large body size (head and body length 137–147 mm) in comparison with other species in the genus, and also is distinguished from its congeners by presenting a tail longer than the head–body length, presence of genal vibrissae 1 and 2, wide presphenoid, first and second lower molars with ectolophid, and third lower molar slightly shorter than the second. A molecular phylogeny based on mitochondrial genes resolved the new species a member of the “aureus” group, most closely related to Thomasomys aureus sensu stricto (genetic distance 8.57%) and as well as an additional undescribed species from southeastern Ecuador. This finding increases the diversity of Thomasomys to 46 species, of which 17 species are present in Ecuador. In addition, the species described herein is the first Thomasomys from the Amazonian basin, a genus that up to now was thought to be restricted to Andean ranges.
An Efficient Alternative to the CDC Gravid Trap for Southern House Mosquito (Diptera: Culicidae) Surveillance
Authors: McNamara Timothy D , O’Shea-Wheller Thomas A , DeLisi Nicholas , Dugas Emily , Caillouet Kevin A , Vaeth Randy , Wallette Dennis , Healy Kristen
Published: December 2020

West Nile virus (WNV) is the most prevalent arbovirus found throughout the United States. Surveillance of surface breeding Culex vectors involved in WNV transmission is primarily conducted using CDC Gravid traps. However, anecdotal claims from mosquito abatement districts in Louisiana assert that other trap types may be more suited to WNV surveillance. To test the validity of these assertions, we conducted a series of trapping trials and WNV surveillance over 3 yr to compare the efficacy of multiple trap types. First, we compared the CDC Gravid trap, CO2-baited New Standard Miniature Blacklight traps, and CO2-baited CDC light traps with either an incandescent light, a red light, or no light. We found that the CDC Gravid trap and CO2-baited no-light CDC Light trap collected the most mosquitoes. Second, we conducted additional, long-term trapping and WNV surveillance to compare these two trap types. We found that CO2-baited no-light CDC traps collected more of the local WNV vector, Culex quinquefasciatus (Say, Diptera, Culicidae), and detected WNV with greater sensitivity. Finally, we conducted trapping to compare the physiological states of Cx. quinquefasciatus and diversity of collected mosquitoes. CO2-baited no-light CDC light traps collected more unfed Cx. quinquefasciatus while Gravid traps collected more blooded Cx. quinquefasciatus; both traps collected the same number of gravid Cx. quinquefasciatus. Additionally, we found that CO2-baited no-light CDC light traps collected a larger diversity of mosquito species than Gravid traps.
Fewer Mistakes and Presumed Consent
Authors: Zambrano Alexander
Published: December 2020

“Opt-out” organ procurement policies based on presumed consent are typically advertised as being superior to “opt-in” policies based on explicit consent at securing organs for transplantation. However, Michael Gill (2004) has argued that presumed consent policies are also better than opt-in policies at respecting patient autonomy. According to Gill’s Fewer Mistakes Argument, we ought to implement the procurement policy that results in the fewest frustrated wishes regarding organ donation. Given that the majority of Americans wish to donate their organs, it is plausible that a presumed consent policy would result in fewer frustrated wishes compared to the current opt-in policy. It follows that we ought to implement a policy of presumed consent. In this paper, I first consider and find wanting an objection to the Fewer Mistakes Argument developed recently by Douglas MacKay (2015). I also consider an objection put forth by James Taylor (2012) but argue that there is a methodological reason to prefer my own argument to Taylor’s. Finally, I argue for two theses: first, that Gill’s major argument in favor of the crucial premise of the Fewer Mistakes Argument is flawed, and second, that the major premise of the Fewer Mistakes Argument is false.
Longitudinal Examination of COVID-19 Public Health Measures on Mental Health for Rural Patients With Serious Mental Illness
Authors: Riblet Natalie B , Stevens Susan P , Shiner Brian , Cornelius Sarah , Forehand Jenna , Scott Robert C , Watts Bradley V
Published: December 2020

Introduction

There is emerging evidence to support that the COVID-19 pandemic and related public health measures may be associated with negative mental health sequelae. Rural populations in particular may fair worse because they share many unique characteristics that may put them at higher risk for adverse outcomes with the pandemic. Yet, rural populations may also be more resilient due to increased sense of community. Little is known about the impact of the pandemic on the mental health and well-being of a rural population pre- and post-pandemic, especially those with serious mental illness.

Material and Methods

We conducted a longitudinal, mixed-methods study with assessments preceding the pandemic (between October 2019 and March 2020) and during the stay-at-home orders (between April 23, 2020, and May 4, 2020). Changes in hopelessness, suicidal ideation, connectedness, and treatment engagement were assessed using a repeated-measures ANOVA or Friedman test.

Results

Among 17 eligible participants, 11 people were interviewed. Overall, there were no notable changes in any symptom scale in the first 3-5 months before the pandemic or during the stay-at-home orders. The few patients who reported worse symptoms were significantly older (mean age: 71.7 years, SD: 4.0). Most patients denied disruptions to treatment, and some perceived telepsychiatry as beneficial.

Conclusions

Rural patients with serious mental illness may be fairly resilient in the face of the COVID-19 pandemic when they have access to treatment and supports. Longer-term outcomes are needed in rural patients with serious mental illness to better understand the impact of the pandemic on this population.
Demonstration of Microsurgical Technique and Nuances for the Resection of a Midbrain Tectal Glioma via the Transcollicular Approach: 3-Dimensional Operative Video
Authors: Sayyahmelli Sima , Ruan Jian , Avci Emel , Başkaya Mustafa K
Published: December 2020

Tectal gliomas are a rare subset of intrinsic brainstem lesions. The microsurgical resection of these lesions remains a major challenge.
1,2
Transcollicular approaches on one side, via the superior or inferior colliculi or both, are neurologically well tolerated without obvious or major auditory or oculomotor consequences. However, any postoperative acute visually triggered saccadic abnormalities caused by iatrogenic superior colliculus damage generally resolve during the postoperative period, as other oculomotor structures compensate for these functions in unilateral lesions.

 In this surgical video, we present a 37-yr-old man with long-standing seizures, new onset headaches, progressive ataxic gait, and imbalance. Magnetic resonance imaging (MRI) showed a circumscribed nonenhancing dorsal midbrain cystic mass with compression on the aqueduct causing hydrocephalus. The lesion had a low signal intensity on T1-weighted images and a high signal intensity on T2-weighted images. The patient first underwent an endoscopic third ventriculostomy. Although his headaches greatly improved after the third ventriculostomy, he remained quite symptomatic in terms of gait imbalance and ataxia. The patient underwent a supracerebellar, infratentorial, transcollicular approach for resection of the tectal tumor. Simultaneously, motor and somatosensory evoked potentials were monitored.

 Both the surgery and the postoperative course were uneventful, with postoperative MRI showing gross total resection of the mass, and histopathology indicating a WHO (World Health Organization) grade I pilocytic astrocytoma. The patient continued to do well without recurrence at 2-yr follow-up.

 In this video, we demonstrate step-by-step microsurgical techniques for resecting these challenging tectal gliomas via the infratentorial-supracerebellar-transcollicular approach.

The patient consented to the procedure and publication of his images.
Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for Palliative Rhizotomy: A Novel Technical Application
Authors: Ravindra Vijay M , Karas Patrick J , Hartnett Sara , Patino Ilana , North Robert , Tatsui Claudio E , Gonda David , Schwabe Aloysia , Curry Daniel J
Published: December 2020

BACKGROUND

Spastic cerebral palsy is caused by an insult to the developing brain. Various medical and surgical procedures are used to reduce tone.

OBJECTIVE

To describe a novel method of magnetic resonance-guided laser interstitial thermal ablation for palliative rhizotomy.

METHODS

Patients treated at a single institution with percutaneous rhizotomy using magnetic resonance–guided laser interstitial thermal therapy were identified. Preoperative and postoperative Modified Ashworth Scale scores were collected as well as procedural information.

RESULTS

Two male children (7.8 and 19 yr, respectively) with spastic quadriparesis were treated using this technique. Neither patient experienced surgical or perioperative complications, and both were discharged from the hospital within 48 h. Each of them demonstrated improvement in his Modified Ashworth Scale score with no need for retreatment for spasticity at last follow-up.

CONCLUSION

These 2 cases illustrate a novel technique for treating spasticity in the setting of cerebral palsy. Further study of this technique in additional patients, and comparison with traditional methods of surgical tone reduction, are warranted.
Role of Surgical Intervention for Intracranial Dural Arteriovenous Fistulas With Cortical Venous Drainage in an Endovascular Era: A Case Series
Authors: Akamatsu Yosuke , Gomez-Paz Santiago , Vergara-Garcia David , Moholkar Viraj M , Kuhn Anna Luisa , Chida Kohei , Singh Jasmeet , Rodrigues Katyucia de Macedo , Massari Francesco , Moore Justin M , Puri Ajit S , Ogilvy Christopher S , Thomas Ajith J
Published: December 2020

BACKGROUND

Intracranial dural arteriovenous fistulae (dAVFs) with cortical venous drainage (CVD) require treatment because of their aggressive clinical presentation and natural history. Although endovascular treatment is effective for the majority of these lesions in the current endovascular era, surgical management has been required if the lesions are not amenable to or fail endovascular treatments.

OBJECTIVE

To demonstrate the angioarchitecture that may necessitate surgical intervention.

METHODS

A retrospective review of the patients with intracranial dAVFs with CVD treated at 2 academic institutions between January 1, 2009, and July 31, 2019 was performed. Patients who required surgical intervention were selected in this study, and angiographic findings were analyzed.

RESULTS

A total of 81 dAVFs in 80 patients were treated during the study period. Endovascular treatments were attempted for 72 (88.9%) dAVFs, resulting in complete obliteration in 55 (76.4%). Surgical interventions were performed in 18 (22.2%) dAVFs, resulting in complete obliteration in all lesions. Overall, complete obliteration was achieved in 74 (93.7%) of 79 dAVFs with follow-up. In the surgically treated dAVFs, curative transarterial embolization was deterred by the angioarchitecture, which included dominant feeding vessels from the ophthalmic artery, meningohypophyseal trunk, posterior meningeal artery, pial artery, or ascending pharyngeal artery. Drainage through tortuous cortical vein, deep venous system, or isolated sinus made transvenous approach challenging.

CONCLUSION

Despite continued improvement in endovascular technology, surgical approaches to dAVFs are still of great value as initial and salvage treatment of dAVFs with angioarchitecture hampering endovascular treatment.
Epidemiology of non-IgE-mediated food allergies: what can we learn from that?
Authors: Barni Simona , Giovannini Mattia , Mori Francesca
Published: December 2020

Purpose of review

To underline the main characteristics of the non-Immunoglobulin E (IgE)-mediated food allergies (food protein-induced allergic proctocolitis food protein-induced enteropathy and food protein-induced enterocolitis syndrome ), which are common diseases in primary care and in allergy and gastroenterology specialty practices evaluating children.

Recent findings

Non-IgE-mediated food allergies comprise a spectrum of diseases with peculiar features affecting infants and young children. The most prominent features of these diseases are symptoms that affect mainly the gastrointestinal tract.

It is of paramount importance to provide the clinicians with the tools for non-IgE-mediated food allergy recognition in clinical practice to avoid the misdiagnosis with unnecessary laboratory tests and detrimental treatments.
Spatiotemporal Trends in Opioid Overdose Deaths by Race for Counties in Ohio
Authors: Kline David , Pan Yuhan , Hepler Staci A.
Published: December 2020

Background:

The opioid epidemic continues to be an ongoing public health crisis in the United States. Initially, large increases in overdose death rates were observed in largely rural, White communities, leading to the initial perception that the opioid epidemic was primarily a problem for the White population. Recent findings have shown increasing rates of overdose death among Blacks. We compare overdose rates between Blacks and Whites and explore county-level spatiotemporal heterogeneity in Ohio.

Methods:

We obtained county-level opioid overdose death counts for Whites and Blacks from 2007 to 2018 in Ohio. We fit a Bayesian multivariate spatial rates model to estimate annual standardized mortality ratios for Whites and Blacks for each county. We accounted for correlation between racial groups in the same county and across space and time. We also estimated differences in the mean trends between urban and rural counties for each racial group.

Results:

The overall overdose death rate in the state was increasing until 2018. County-level death rates for Whites were higher than Blacks throughout the state early in the study period. Death rates for Blacks increased throughout the study period and were comparable to the rates for Whites by the end of the study in many counties.

Conclusions:

County-level opioid overdose death rates increased faster for Blacks than Whites during the study. By 2018, death rates were comparable for Blacks and Whites in many counties. The opioid epidemic spans racial groups in Ohio and trends indicate that overdose is a growing problem among Blacks.
Bounding the Accuracy of Diagnostic Tests, With Application to COVID-19 Antibody Tests
Authors: Manski Charles F.
Published: December 2020

Tests used to diagnose illness commonly have imperfect accuracy, with some false-positive and negative results. For risk assessment and clinical decisions, predictive values are of interest. Positive predictive value (PPV) is the chance that a member of a relevant population who tests positive has been ill. Negative predictive value (NPV) is the chance that someone who tests negative has not been ill. The medical literature regularly reports sensitivity and specificity. Sensitivity is the chance that an ill person receives a positive test result. Specificity is the chance that a nonill person receives a negative result. Knowledge of sensitivity and specificity enables one to predict the test result given a person’s illness status. These predictions are not directly relevant to patient care but, given knowledge of sensitivity and specificity, PPV and NPV can be derived if one knows the prevalence of the disease, the population rate of illness. There is considerable uncertainty about the prevalence of some diseases, a notable case being COVID-19. This paper addresses the problem of identification of PPV and NPV given knowledge of sensitivity and specificity and given bounds on prevalence. I explain the problem and show how to bound PPV and NPV as well as the risk ratio and difference, which are functions thereof. I apply the findings to COVID-19 antibody tests. I question the realism of supposing that sensitivity and specificity are known.
Incidence of Dementia in Patients With Open-angle Glaucoma: A Population-based Study
Authors: Belamkar Aditya V. , Mansukhani Sasha A. , Savica Rodolfo , Spiegel Matthew R. , Hodge David O. , Sit Arthur J.
Published: December 2020

Precis:

In this population-based study of 509 open-angle glaucoma (OAG) patients over a 36-year period, we identified a decreased rate of developing dementia compared with the rate in the general population.

Purpose:

The aim was to determine the incidence of dementia and Alzheimer disease (AD) among patients with OAG.

Patients and Methods:

Retrospective, population-based cohort study. All residents of Olmsted County, Minnesota (≥40 y) who were diagnosed with OAG between January 1, 1965 and December 31, 2000, were eligible for inclusion in this study. A total of 509 patients were included over the 36-year period. The cumulative probability of developing dementia was calculated and compared with the population risk of dementia.

Results:

Of the 509 patients included, 300 (58.9%) were female, the median age was 67.5 years, and 278 patients (54.6%) had primary OAG. Other subgroups were pseudoexfoliation in 15.1%, treated ocular hypertension in 14.1%, normal tension glaucoma in 10.6%, and pigmentary glaucoma in 5.5% of the patients. Respectively, 118 (23.0%) and 99 (19.4%) patients developed dementia and AD. The 10-year cumulative probability of developing dementia and AD was 12.0% and 9.9%, with a 95% confidence interval of 9.3%-15.3% and 7.5%-13%, respectively. The observed 10-year incidence of dementia and AD were significantly lower than the expected population incidence (19.0% and 19.0%; P<0.001). Older age at diagnosis of glaucoma was a strong predictor for the development of dementia by multivariate analysis (hazard ratio: 3.31, 95% confidence interval: 2.61-4.20, P<0.001).

Conclusion:

The risk of developing dementia or AD was decreased in OAG patients compared with the general population. OAG with onset at a later age may present as a different etiopathogenetic entity compared with onset at a younger age, and represent the optic nerve findings of generalized neurodegenerative processes.
Kahook Dual Blade Ab-interno Trabeculectomy Compared With Conventional Goniotomy in the Treatment of Primary Congenital Glaucoma: 1-Year Results
Authors: Elhilali Hala M. , El Sayed Yasmine M. , Elhusseiny Abdelrahman M. , Gawdat Ghada I.
Published: December 2020

Introduction:

Kahook dual blade (KDB) removes a strip of the trabecular meshwork from the angle, which may make it superior to simple goniotomy in treating the angle anomaly in primary congenital glaucoma (PCG). This prospective study compares KDB ab-interno trabeculectomy to conventional goniotomy in PCG.

Methods:

Forty-two eyes of 29 patients with PCG underwent ab-interno trabeculectomy using a KDB or conventional goniotomy using a 25-G irrigating needle, targeting 100 to 120 degrees of the nasal iridocorneal angle. Patients were seen at 1, 3, 6, and 12 months postoperatively. Success was defined as intraocular pressure (IOP) ≤21 mm Hg at 1-year follow-up visit, with no evidence of glaucoma progression.

Results:

The KDB group included 21 eyes of patients with a median age of 6 months (interquartile range: 4 to 8.5 mo) and the goniotomy group included 21 eyes of patients with a median age of 5 months (interquartile range: 3 to 9.5 mo). There was a significant reduction in IOP in both groups at all follow-up visits. The reduction in the number of glaucoma medications was significant at 1, 3, and 6 months postoperatively in the KDB group, and at 1 month in the goniotomy group. There was no significant difference in IOP or glaucoma medications between both groups at any follow-up visit. Success was achieved in 12 eyes (57.1%) in each group, with no eyes developing any serious complications.

Conclusion:

One-year results show that KDB ab-interno trabeculectomy is at least as effective as goniotomy in the treatment of PCG. Eyes with bilateral glaucoma had a tendency to fail both procedures.
The association of impaired lung function and nonalcoholic fatty liver disease: a systematic review
Authors: Wu Yi Chia , Chuang Philip M. , Pinotti Rachel , Nagirimadugu Ankita , Valentin Nelson , Dinani Amreen
Published: December 2020

Background and aims

Nonalcoholic fatty liver disease (NAFLD) and impaired lung function share similar risk factors and phenotypes, such as obesity and type 2 diabetes. The study is an updated meta-analysis to evaluate the association between NAFLD and impaired lung function.

Methods

A total of 696 articles were identified with mention of NAFLD and lung function (or pulmonary function testing) in MEDLINE, EMBASE, and Scopus. After de-duplication, 455 articles were screened, 18 underwent full-text review. Five studies met our review and inclusion criteria with an interrater reliability kappa score of 1.

Results

Five studies with a total of 118 118 subjects (28.4% with NAFLD) were included. The cross-sectional studies supported a statistically significant relationship between decreased pulmonary function tests and NAFLD. There was no association observed with obstructive lung pattern. One of the longitudinal studies revealed an association with increased rate of decline in forced vital capacity in patients with NAFLD and FIB4 score ≥1.30 (−21.7 vs. −27.4 mL/year, P = 0.001 in males, −22.4 vs. −27.9 mL/year, P = 0.016 in females). The second longitudinal study revealed that patients with impaired pulmonary function had an increased hazard ratio of developing NAFLD dependent on the severity of pulmonary impairment.

Conclusions

This is the first systematic review that supports an association of NAFLD with decreased (restrictive) lung function. The estimated severity of liver fibrosis correlates with the rate of progression of restrictive lung function. There are also data showing that patients with impaired lung function have a higher risk of developing NAFLD.
Maternal HIV, antiretroviral timing, and spontaneous preterm birth in an urban Zambian cohort: the role of local and systemic inflammation
Authors: Rittenhouse Katelyn J. , Mwape Humphrey , Nelson Julie A.E. , Mwale John , Chipili Gabriel , Price Joan T. , Hudgens Michael , Stringer Elizabeth M. , De Paris Kristina , Vwalika Bellington , Stringer Jeffrey S.A.
Published: December 2020

Objective:

To assess plasma and vaginal inflammation in three antenatal groups (HIV-uninfected women, HIV-infected women entering care on preconceptional ART, and HIV-infected women not on preconceptional ART) and whether these measures are associated with spontaneous preterm birth (sPTB).

Design:

Case--control study nested within a pregnancy cohort in Lusaka, Zambia.

Methods:

We analyzed 11 pro-inflammatory and two anti-inflammatory markers in 207 women with paired plasma and vaginal specimens collected between 16 and 20 gestational weeks. Among 51 HIV-infected women, we repeated the assays in 24–34-week samples. We used confirmatory factor analysis to create inflammation scores and compared them among the three groups.

Results:

At baseline, HIV-infected women not on ART had higher vaginal pro-inflammatory scores than HIV-uninfected women [mean 0.37 (95% CI −0.06 to 0.80) vs. −0.02 (−0.32 to 0.27), P = 0.02]. In repeat testing, women not on preconceptional ART had an increase in vaginal inflammation between the baseline and 24–34-week visits compared with those continuing preconceptional ART [mean 0.62 (95% CI −0.80 to 4.20) vs. −0.07 (−2.78 to 2.11), P = 0.04]. In multivariate analyses, baseline vaginal inflammation predicted sPTB (aOR 1.5; 95% CI 1.0–2.3; P = 0.02). Plasma inflammation did not differ by HIV or ART exposure and was not associated with sPTB.

Conclusion:

Women not receiving ART at entry into pregnancy care had more vaginal inflammation than women entering on treatment. They also experienced an increase in vaginal inflammation between the two sampling timepoints, possibly as a consequence of ART initiation. Vaginal (but not systemic) inflammation was associated with sPTB and offers a potential mechanistic insight into this important adverse birth outcome.
A Review of Pathophysiology, Clinical Features, and Management Options of COVID-19 Associated Coagulopathy
Authors: Goswami Julie , MacArthur Taleen A. , Sridharan Meera , Pruthi Rajiv K. , McBane Robert D. , Witzig Thomas E. , Park Myung S.
Published: December 2020

There is increasing evidence that novel coronavirus disease 2019 (COVID-19) leads to a significant coagulopathy, a phenomenon termed “COVID-19 associated coagulopathy.” COVID-19 has been associated with increased rates of both venous and arterial thromboembolic events, a source of significant morbidity and mortality in this disease. Further evidence suggests a link between the inflammatory response and coagulopathy associated with COVID-19. This presents a unique set of challenges for diagnosis, prevention, and treatment of thrombotic complications. In this review, we summarize and discuss the current literature on laboratory coagulation disruptions associated with COVID-19 and the clinical effects of thromboembolic events including pulmonary embolism, deep vein thrombosis, peripheral arterial thrombosis, and acute ischemic stroke in COVID-19. Endothelial injury and augmented innate immune response are implicated in the development of diffuse macro- and microvascular thrombosis in COVID-19. The pathophysiology of COVID-19 associated coagulopathy is an important determinant of appropriate treatment and monitoring of these complications. We highlight the importance of diagnosis and management of dysregulated coagulation in COVID-19 to improve outcomes in COVID-19 patients with thromboembolic complications.
The energetic basis for smooth human arm movements
Authors: Wong Jeremy D , Cluff Tyler , Kuo Arthur D
Published: December 2020

The central nervous system plans human reaching movements with stereotypically smooth kinematic trajectories and fairly consistent durations. Smoothness seems to be explained by accuracy as a primary movement objective, whereas duration seems to economize energy expenditure. But the current understanding of energy expenditure does not explain smoothness, so that two aspects of the same movement are governed by seemingly incompatible objectives. Here we show that smoothness is actually economical, because humans expend more metabolic energy for jerkier motions. The proposed mechanism is an underappreciated cost proportional to the rate of muscle force production, for calcium transport to activate muscle. We experimentally tested that energy cost in humans (N=10) performing bimanual reaches cyclically. The empirical cost was then demonstrated to predict smooth, discrete reaches, previously attributed to accuracy alone. A mechanistic, physiologically measurable, energy cost may therefore explain both smoothness and duration in terms of economy, and help resolve motor redundancy in reaching movements.
Quantitative proteome and PTMome analysis ofArabidopsis thalianaroot responses to persistent osmotic and salinity stress
Authors: Rodriguez MC. , Mehta D , Tan M , Uhrig RG
Published: December 2020

Abiotic stresses such as drought result in large annual economic losses around the world. As sessile organisms, plants cannot escape the environmental stresses they encounter, but instead must adapt to survive. Studies investigating plant responses to osmotic and/or salt stress have largely focused on short-term systemic responses, leaving our understanding of intermediate to longer-term adaptation (24 h - days) lacking. In addition to protein abundance and phosphorylation changes, evidence suggests reversible lysine acetylation may also be important for abiotic stress responses. Therefore, to characterize the protein-level effects of osmotic and salt stress, we undertook a label-free proteomic analysis ofArabidopsis thalianaroots exposed to 300 mM Mannitol and 150 mM NaCl for 24 h. We assessed protein phosphorylation, lysine acetylation and changes in protein abundance, detecting significant changes in 245, 35 and 107 total proteins, respectively. Comparison with available transcriptome data indicates that transcriptome- and proteome-level changes occur in parallel, while PTMs do not. Further, we find significant changes in PTMs and protein abundance involve different proteins from the same networks, indicating a multifaceted regulatory approach to prolonged osmotic and salt stress. In particular, we find extensive protein-level changes involving sulphur metabolism under both osmotic and salt conditions as well as changes in protein kinases and transcription factors that may represent new targets for drought stress signaling. Collectively, we find that protein-level changes continue to occur in plant roots 24 h from the onset of osmotic and salt stress and that these changes differ across multiple proteome levels.
Discovery of TMPRSS2 inhibitors from virtual screening
Authors: Hu Xin , Shrimp Jonathan H. , Guo Hui , Xu Miao , Chen Catherine Z. , Zhu Wei , Zakharov Alexey , Jain Sankalp , Shinn Paul , Simeonov Anton , Hall Matthew D. , Shen Min
Published: December 2020

The SARS-CoV-2 pandemic has prompted researchers to pivot their efforts to finding antiviral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received attention for the development of drugs against SARS and MERS. Starting with comparative structural modeling and binding model analysis, we developed an efficient pharmacophore-based approach and applied a large-scalein silicodatabase screening for small molecule inhibitors against TMPRSS2. The hits were evaluated in the TMPRSS2 biochemical assay and the SARS-CoV-2 pseudotyped particle (PP) entry assay. A number of novel inhibitors were identified, providing starting points for further development of drug candidates for the treatment of COVID-19.
Lentiviral vector-based SARS-CoV-2 pseudovirus enables analysis of neutralizing activity in COVID-19 convalescent plasma
Authors: Pamukcu Cevriye , Celik Elif , Ergun Ebru Zeynep , Karahan Zeynep Sena , Turkoz Gozde , Aras Mertkaya , Eren Canan , Sili Uluhan , Bilgin Huseyin , Suder Ilke , Mandaci Baris Can , Dingiloglu Baran , Tatli Ozge , Doganay Gizem Dinler , Baris Safa , Ozoren Nesrin , Sutlu Tolga
Published: December 2020

As the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to spread around the globe, effective vaccination protocols are under deployment. Alternatively, the use of convalescent plasma (CP) therapy relies on the transfer of the immunoglobulin repertoire of a donor that has recovered from the disease as a means of passive vaccination. While the lack of an effective antiviral treatment inadvertently increases the interest in CP products, initial clinical evaluation on COVID-19 patients revealed that critical factors determining the outcome of CP therapy need to be defined clearly if clinical efficacy is to be expected. Measurement of neutralizing activity against SARS-CoV-2 using wildtype virus presents a reliable functional assay but the availability of suitable BSL3 facilities for virus culture restricts its applicability. Instead, the use of pseudovirus particles containing elements from the SARS-CoV-2 virus is widely applied to determine the activity of CP or other neutralizing agents such as monoclonal antibodies.

In this study, we present our approach to optimize GFP-encoding lentiviral particles pseudotyped with the SARS-CoV-2 Spike and Membrane proteins for use in neutralization assays. Our results show the feasibility of pseudovirus production using a C-terminal truncated Spike protein which is greatly enhanced by the incorporation of the D614G mutation. Moreover, we report that the use of Sodium Butyrate during lentiviral vector production dramatically increases pseudovirus titers. Analysis of CP neutralizing activity against particles pseudotyped with wildtype or D614G mutant Spike protein in the presence or absence the M protein revealed differential activity in CP samples that did not necessarily correlate with the amount of anti-SARS-CoV-2 antibodies.

Our results indicate that the extent of neutralizing activity in CP samples depends on the quality rather than the quantity of the humoral immune responses and varies greatly between donors. Functional screening of neutralizing activity using pseudovirus-based neutralization assays must be accepted as a critical tool for choosing CP donors if clinical efficacy is to be maximized.
Modular deep learning enables automated identification of monoclonal cell lines
Authors: Fischbacher Brodie , Hedaya Sarita , Hartley Brigham J. , Wang Zhongwei , Lallos Gregory , Hutson Dillion , Zimmer Matthew , Brammer Jacob ,   The NYSCF Global Stem Cell Array® Team, Paull Daniel
Published: December 2020

Monoclonalization refers to the isolation and expansion of a single cell derived from a cultured population. This is a valuable step in cell culture so as to minimize a cell line’s technical variability downstream of cell-altering events, such as reprogramming or gene editing, as well as for processes such as monoclonal antibody development. However, traditional methods for verifying clonality do not scale well, posing a critical obstacle to studies involving large cohorts. Without automated, standardized methods for assessing clonalitypost-hoc, methods involving monoclonalization cannot be reliably upscaled without exacerbating the technical variability of cell lines. We report the design of a deep learning workflow that automatically detects colony presence and identifies clonality from cellular imaging. The workflow, termed Monoqlo, integrates multiple convolutional neural networks and, critically, leverages the chronological directionality of the cell culturing process. Our algorithm design provides a fully scalable, highly interpretable framework, capable of analyzing industrial data volumes in under an hour using commodity hardware. In the present study, we focus on monoclonalization of human induced pluripotent stem cells (HiPSCs) as a case example. Monoqlo standardizes the monoclonalization process, enabling colony selection protocols to be infinitely upscaled while minimizing technical variability.
Landscapes and dynamic diversifications of B-cell receptor repertoires in COVID-19 patients
Authors: Xiang Haitao , Zhao Yingze , Li Xinyang , Liu Peipei , Wang Longlong , Wang Meiniang , Tian Lei , Sun Haixi , Zhang Wei , Xu Ziqian , Ye Beiwei , Yuan Xiaoju , Wang Pengyan , Zhang Ning , Gong Yuhuan , Bian Chengrong , Wang Zhaohai , Yu Linxiang , Yan Jin , Meng Fanping , Bai Changqing , Wang Xiaoshan , Liu Xiaopan , Gao Kai , Wu Liang , Liu Longqi , Gu Ying , Bi Yuhai , Shi Yi , Zhang Shaogeng , Zhu Chen , Xu Xun , Wu Guizhen , Gao George F. , Yang Naibo , Liu William J. , Yang Penghui
Published: December 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19). Great international efforts have been put into the development of prophylactic vaccines and neutralizing antibodies. However, the knowledge about the B cell immune response induced by the SARS-CoV-2 virus is still limited. Here, we report a comprehensive characterization of the dynamics of immunoglobin heavy chain (IGH) repertoire in COVID-19 patients. By using next-generation sequencing technology, we examined the temporal changes in the landscape of the patient’s immunological status, and found dramatic changes in the IGH within the patients’ immune system after the onset of COVID-19 symptoms. Although different patients have distinct immune responses to SARS-CoV-2 infection, by employing clonotype overlap, lineage expansion and clonotype network analyses, we observed a higher clonotype overlap and substantial lineage expansion of B cell clones during 2-3 weeks of illness, which is of great importance to B-cell immune responses. Meanwhile, for preferences of V gene usage during SARS-CoV-2 infection, IGHV3-74 and IGHV4-34 and IGHV4-39 in COVID-19 patients were more abundant than that of healthy controls. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development as well as mechanistic research.
Serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice
Authors: Lyu Yang , Weaver Kristina J. , Shaukat Humza A. , Plumhoff Marta L. , Tjilos Maria , Promislow Daniel E.L. , Pletcher Scott D.
Published: December 2020

It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan inDrosophilaare affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino acid metabolism, which requires serotonin 2A receptor. Knockdown ofglutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan. Our results reveal a mechanism of aging that applies in natural conditions, including our own, in which organisms continuously perceive and evaluate nutrient availability to promote fitness and well-being.
Structural dynamics of the SARS-CoV-2 frameshift-stimulatory pseudoknot reveal topologically distinct conformers
Authors: Neupane Krishna , Zhao Meng , Lyons Aaron , Munshi Sneha , Ileperuma Sandaru M. , Ritchie Dustin B. , Hoffer Noel Q. , Narayan Abhishek , Woodside Michael T.
Published: December 2020

The RNA pseudoknot that stimulates −1 programmed ribosomal frameshifting in SARS coronavirus-2 (SARS-CoV-2) is a possible drug target. To understand how this 3-stemmed pseudoknot responds to the mechanical tension applied by ribosomes during translation, which is thought to play a key role during frame-shifting, we probed its structural dynamics under tension using optical tweezers. Unfolding curves revealed that the frameshift signal formed multiple different structures: at least two distinct pseudoknotted conformers with different unfolding forces and energy barriers, as well as alternative stem-loop structures. Refolding curves showed that stem 1 formed first in the pseudoknotted conformers, followed by stem 3 and then stem 2. By extending the handle holding the RNA to occlude the 5′ end of stem 1, the proportion of the different pseudoknot conformers could be altered systematically, consistent with structures observed in cryo-EM images and computational simulations that had distinct topologies: the 5′ end of the RNA threaded through the 3-helix junction to form a ring-knot, or unthreaded as in more standard H-type pseudoknots. These results resolve the folding mechanism of the frameshift signal in SARS-CoV-2 and highlight the dynamic conformational heterogeneity of this RNA, with important implications for structure-based drug-discovery efforts.