bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of climate factors on COVID-19 transmission in Malaysia: An autoregressive integrated moving average (ARIMA) model
Authors: Naing Cho , Ni Han , Aung Htar Htar , Chan Elaine , Mak Joon Wah
Published: August 2020

Background

A unique concern pertaining to the spread of COVID-19 across countries is the asymmetry of risk and the irrational fear of a new pandemic and its possible serious consequences. This study aimed to perform a time series analysis on the association between climate factors and daily cases of COVID-19 in Malaysia up to 15 July 2020. The second objective was to predict daily new cases using a forecasting technique. To address within-country variations, the analysis was extended to the state level with Sarawak state as an example.

Methodology/Principal Findings

Datasets on the daily confirmed cases and climate variables in Malaysia and Sarawak state were obtained from publicly accessible official websites. A descriptive analysis was performed to characterize all the important variables over the study period. An autoregressive integrated moving average (ARIMA) model was introduced using daily cases as the dependent variable and climate parameters as the explanatory variables.

For Malaysia, the findings suggest that, ceteris paribus, the number of COVID-19 cases decreased with increasing average temperature (p=0.003) or wind speed (p=0.029). However, none of the climate parameters showed a significant relationship with the number of COVID-19 cases in Sarawak state. Forecasts from the ARIMA models showed that new daily COVID-19 cases had already reached the outbreak level and a decreasing trend in both settings. Holding other parameters constant, a small number of new cases (approximately a single digit) is a probable second wave in Sarawak state,

Conclusions/Significance

The findings suggest that climate parameters and forecasts are helpful for reducing the uncertainty in the severity of future COVID-19 transmission. A highlight is that forecasts will be a useful tool for making decisions and taking the appropriate interventions to contain the spread of the virus in the community.
Utility of gene tumor expression ofVEGF, FOXM1*3andCD-133on diagnosis and prognosis of brain gliomas
Authors: Feria-Romero Iris Angélica , Nettel-Rueda Bárbara , Rodríguez-Florido Marco Antonio , Félix-Espinoza Ignacio , Castellanos-Pallares Luis , Cienfuegos-Meza Jesús , Orozco-Suárez Sandra , Chavez Jesús A. , Escamilla-Nuñez Consuelo , Guinto Gerardo , Márquez-González Horacio , Rodea-Ávila Carlos , Grijalva Israel
Published: August 2020

Objective

This paper seeks to quantify the normalized expression of transcriptsFOXM1*3, VEGF, CD133, andMGMTand their relation with the histopathological and molecular diagnosis and with the probability of estimating tumor progression-free survival of gliomas.

Methods

A cohort of patients was made up of patients aged over 18 years with a histological and molecular diagnosis of gliomas from the year 2011 to 2018. The patients had a complete tumor resection. Patients with high-grade glioma received adjuvant management (temozolamide and radiotherapy). Clinical and imaging follow-up was carried out periodically to identify the time of progression free survival (PFS).

Results

Ninety-one patients (age range, 18–85 years) comprised the study cohort with a predominance of males. The expression ofFOXM1*3, VEGF, andCD133allowed the differentiation of astrocytomas grade II from GBM. ROC curves proved statistically significant in the GBM model (p< 0.05), demonstrating greatest sensitivity withFOXM1*3(91%), and greatest specificity withVEGF(93%). The age-adjusted Cox multivariate model established that a PFS50%of 25 months corresponds to a median value of 5.3 forVEGFand 0.42 for CD133.

Conclusions

The normalized expression of transcripts FOXM1*3, VEGF, andCD133allow us to estimate the probability of PFS, especially in gliomas grades II and IV; likewise, their overexpression defines the diagnosis of GBM.

Authorship

Substantial contributions to conception and design (IAFR, BNR, MARF, GG, IG), acquisition of data (IAFR, BNR, MARF, IFE, LCP, JCM, SOS, JAC, CRA), analysis and interpretation of data (IAFR, BNR, MARF, JCM, SOS, CEN, HMG, IG).

Drafting the article (IAFR, BNR, MARF, IFE, LCP, SOS, JAC, IG), revising it critically for important intellectual content (IAFR, JCM, CEN, GG, HMG, CRA, IG)

Final approval of the version to be published (IAFR, BNR, MARF, IFE, LCP, JCM, SOS, JAC, CEN, GG, HMG, CRA, IG).
Behavioral preventive measures and the use of medicines and herbal products among the public in response to Covid-19 in Bangladesh: A cross-sectional study
Authors: Ahmed Iftekhar , Hasan Maruf , Akter Rahima , Sarkar Bidduth Kumar , Rahman Marufa , Sarker Md Samun , Samad Mohammed A.
Published: August 2020

The present study was conducted to assess the behavioral preventive measures and the use of medicines and herbal foods/products among the public in response to Covid-19. A cross-sectional survey was conducted from 27 June to 20 July 2020, and 1222 people participated. Kruskal-Wallis test was used to identify the differences in behavioral preventive practices across different demographic categories. To identify the factors associated with the use of preventive medicines and herbal foods/products, multivariable logistic regression was performed. Most participants adopted the recommended preventive practices such as washing hands more frequently (87.5%), staying home more often (85.5%), avoiding crowds (86%), and wearing masks (91.6%). About half of the smokers reported a decreased rate of smoking during the pandemic. Also, 14.8% and 57.6% of the participants took medicines and herbal foods/products as preventive measures against Covid-19. Arsenicum album and Zinc supplements were the most commonly used preventive medicines. Gender, age, and fear of Covid-19 were significantly associated with the use of both preventive medicines and herbal products. For the management of Covid-19 related symptoms, Paracetamols, Fexofenadine, and Zinc supplements were used most often. Most participants sought information from non-medical sources while using medicines and herbal products. Moreover, potentially inappropriate and unnecessary use of drugs were identified.
Development and psychometric properties of the Japanese Consumer Assessment of Healthcare Providers and Systems Clinician & Group Survey (CG-CAHPS)
Authors: Aoki Takuya , Taguchi Kuichiro , Hama Eiichi
Published: August 2020

The Consumer Assessment of Healthcare Providers and Systems Clinician & Group Survey (CG-CAHPS) is one of the most widely studied and endorsed patient experience measures for ambulatory care. This study aimed to develop a Japanese CG-CAHPS and examine its psychometric properties. We evaluated the structural validity, criterion-related validity, and internal consistency reliability of the scale. Data were analyzed for 674 outpatients aged 18 years or older in 11 internal medicine clinics. The confirmatory factor analysis supported the scale’s structural validity and the same four composites (Access, Provider Communication, Care Coordination, and Office Staff) as that of the original CG-CAHPS. All provider-level Pearson correlation coefficients between the Japanese CG-CAHPS composites and overall provider rating exceeded the criteria. Results of item-total correlations and Cronbach’s alpha indicated adequate internal consistency reliability. We developed the Japanese CG-CAHPS as a valid and reliable scale to measure the quality of ambulatory care based on patient experience. The results of the Japanese CG-CAHPS survey will provide useful information to providers, organizations, and policy makers for achieving a patient-centered healthcare system in Japan.
COVID-19 Transmission Dynamics in India with Extended SEIR Model
Authors: Reddy Brahmatheja Reddy Mali , Singh Anuj , Srivastava Pradeep
Published: August 2020

India is one of the most harshly affected countries due to COVID epidemic. Early implementation of lockdown protocols were useful to control certain parameters of transmission dynamics, but the numbers are consistently increasing in later months. India’s population is divided into different clusters on the basis of population density and population mobility, even varying resource availability and since the recent cases are coming from throughout the country, it allows us to model an overall average of the country. In this study, we try to prove the efficiency of using the SEIR epidemiological model for different rate study analysis for COVID epidemic in India. Along with it we derived newer components for better forecast of the pandemic in India. We found that there is a decrease in R0 value, but still the epidemic is not under control. The percentage of infected patients being admitted into ICU for critical care is around 9.986%, while the chances of recovery of critical patients being admitted to the ICU seem to be slim at 79.9% of the admitted being dead.
Universal PCR and antibody testing demonstrate little to no transmission of SARS-CoV-2 in a rural community
Authors: Appa Ayesha , Takahashi Saki , Rodriguez-Barraquer Isabel , Chamie Gabriel , Sawyer Aenor ,   CLIAHUB Consortium, Duarte Elias , Hakim Jill , Turcios Keirstinne , Vinden Joanna , Janson Owen , Manglik Aashish , Peluso Michael J. , Deeks Steven G. , Henrich Timothy J. , Torres Leonel , Rodgers Mary , Hackett John , Chiu Charles , Havlir Diane , Greenhouse Bryan
Published: August 2020

Background

The absence of systematic surveillance for SARS-CoV-2 has curtailed accurate appraisal of transmission intensity. Our objective was to perform case detection of an entire rural community to quantify SARS-CoV-2 transmission using PCR and antibody testing.

Methods

We conducted a cross-sectional survey of the prevalence and cumulative incidence of SARSCoV-2 infection in the rural town of Bolinas, California (population 1,620), four weeks following shelter-in-place orders. Residents and county essential workers were tested between April 20th – 24th, 2020. Prevalence by PCR and seroprevalence combining data from two forms of antibody testing were performed in parallel (Abbott ARCHITECT IgG to nucleocapsid protein and in-house IgG ELISA to the receptor binding domain).

Results

Of 1,891 participants, 1,312 were confirmed Bolinas residents (>80% community ascertainment). Zero participants were PCR positive. Assuming 80% sensitivity, it would have been unlikely to observe these results (p< 0.05) if there were > 3 active infections in the community. Based on antibody results, estimated prevalence of prior infection was 0.16% (95% CrI: 0.02%, 0.46%). Seroprevalence estimates using only one of the two tests would have been higher, with greater uncertainty. The positive predictive value (PPV) of a positive result on both tests was 99.11% (95% CrI: 95.75%, 99.94%), compared to PPV 44.19%-63.32% (95% CrI range 3.25%-98.64%) if only one test was utilized.

Conclusions

Four weeks following shelter-in-place, active and prior SARS-CoV-2 infection in a rural Northern California community was extremely rare. In this low prevalence setting, use of two antibody tests increased the PPV and precision of seroprevalence estimates.
Causal Factors of Effective Psychosocial Outcomes in Online Mental Health Communities
Authors: Saha Koustuv , Sharma Amit
Published: August 2020

Online mental health communities enable people to seek and provide support, and growing evidence shows the efficacy of community participation to cope with mental health distress. However, what factors of peer support lead to favorable psychosocial outcomes for individuals is less clear. Using a dataset of over 300K posts by∼39K individuals on an online community TalkLife, we present a study to investigate the effect of several factors, such as adaptability, diversity, immediacy, and the nature of support. Unlike typical causal studies that focus on the effect of each treatment, we focus on the outcome and address thereversecausal question of identifying treatments that may have led to the outcome, drawing on case-control studies in epidemiology. Specifically, we define the outcome as an aggregate of affective, behavioral, and cognitive psychosocial change and identifyCase(most improved) andControl(least improved) cohorts of individuals. Considering responses from peers as treatments, we evaluate the differences in the responses received byCaseandControl, per matched clusters of similar individuals. We find that effective support includes complex language factors such as diversity, adaptability, and style, but simple indicators such as quantity and immediacy are not causally relevant. Our work bears methodological and design implications for online mental health platforms, and has the potential to guide suggestive interventions for peer supporters on these platforms.
Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment immunogen
Authors: Malladi Sameer Kumar , Singh Randhir , Pandey Suman , Gayathri Savitha , Kanjo Kawkab , Ahmed Shahbaz , Khan Mohammad Suhail , Kalita Parismita , Girish Nidhi , Upadhyaya Aditya , Reddy Poorvi , Pramanick Ishika , Bhasin Munmun , Mani Shailendra , Bhattacharyya Sankar , Joseph Jeswin , Thankamani Karthika , Raj V. Stalin , Dutta Somnath , Singh Ramandeep , Nadig Gautham , Varadarajan Raghavan
Published: August 2020

Virtually all SARS-CoV-2 vaccines currently in clinical testing are stored in a refrigerated or frozen state prior to use. This is a major impediment to deployment in resource-poor settings. Several use viral vectors or mRNA. In contrast to protein subunit vaccines, there is limited manufacturing expertise for these novel, nucleic acid based modalities, especially in the developing world. Neutralizing antibodies, the clearest known correlate of protection against SARS-CoV-2, are primarily directed against the Receptor Binding Domain (RBD) of the viral spike protein. We describe a monomeric, glycan engineered RBD protein fragment that is expressed at a purified yield of 214mg/L in unoptimized, mammalian cell culture and in contrast to a stabilized spike ectodomain, is tolerant of exposure to temperatures as high as 100°C when lyophilized, upto 70°C in solution and stable for over four weeks at 37°C. In prime:boost guinea pig immunizations, when formulated with the MF59 like adjuvant AddaVax™, the RBD derivative elicited neutralizing antibodies with an endpoint geometric mean titer of ~415 against replicative virus, comparing favourably with several vaccine formulations currently in the clinic. These features of high yield, extreme thermotolerance and satisfactory immunogenicity suggest that such RBD subunit vaccine formulations hold great promise to combat COVID-19.
Sotagliflozin, a dual SGLT1/2 inhibitor, improves cardiac outcomes in a mouse model of early heart failure without diabetes
Authors: Young Sophia L , Ryan Lydia , Mullins Thomas P , Flint Melanie , Steane Sarah E , Walton Sarah L , Bielefeldt-Ohmann Helle , Carter David A , Reichelt Melissa E , Gallo Linda A
Published: August 2020

Aims

Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in non-diabetic and diabetic mice with cardiac pressure overload.

Methods and Results

Five-week old male C57BL/6J mice were randomized to receive a high fat diet (HFD; 60% of calories from fat) to induce diabetes or remain on normal diet (ND) for 12 weeks. Transverse aortic constriction (TAC) was then employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in features representative of heart failure with preserved ejection fraction. At five weeks into the dietary protocol, mice were treated for seven weeks by oral gavage once daily with sotagliflozin (10mg/kg body weight) or vehicle (0.1% tween 80). In ND non-diabetic mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilisation nor increased cardiac ketolysis. In HFD diabetic mice, sotagliflozin did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound diuresis and glucosuria, which may have compromised drug action and subsequent cardio-protection.

Conclusion

We demonstrate the utility of dual SGLT1/2 inhibition in treating heart failure risk factors in the non-diabetic state. Its efficacy in high fat-induced diabetes with proximal tubular damage requires further study.
Predicting future regional tau accumulation in asymptomatic and early Alzheimer’s disease
Authors: Giorgio Joseph , Jagust William J , Baker Suzanne , Landau Susan M. , Tino Peter , Kourtzi Zoe ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2020

The earliest stages of Alzheimer’s disease (AD) involve interactions between multiple pathophysiological processes. Although these processes are well studied, we still lack robust tools to predict individualised trajectories of disease progression. Here, we employ a robust and interpretable machine learning approach to combine multimodal biological data and predict future tau accumulation, translating predictive information from deep phenotyping cohorts at early stages of AD to cognitively normal individuals. In particular, we use machine learning to quantify interactions between key pathological markers (β-amyloid, medial temporal atrophy, tau and APOE 4) at early and asymptomatic stages of AD. We next derive a predictive index that stratifies individuals based on future pathological tau accumulation, highlighting two critical features for optimal clinical trial design. First, future tau accumulation provides a better outcome measure compared to changes in cognition. Second, stratification based on multimodal data compared to β-amyloid alone reduces the sample size required to detect a clinically meaningful change in tau accumulation. Further, we extend our machine learning approach to derive individualised trajectories of future pathological tau accumulation in early AD patients and accurately predict regional future rate of tau accumulation in an independent sample of cognitively unimpaired individuals. Our results propose a robust approach for fine scale stratification and prognostication with translation impact for clinical trial design at asymptomatic and early stages of AD.

One Sentence Summary

Our machine learning approach combines baseline multimodal data to make individualised predictions of future pathological tau accumulation at prodromal and asymptomatic stages of Alzheimer’s disease with high accuracy and regional specificity.
Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson’s disease heterogeneity
Authors: Hill Emily J. , Grant Mangleburg C. , Alfradique-Dunham Isabel , Ripperger Brittany , Stillwell Amanda , Saade Hiba , Rao Sindhu , Fagbongbe Oluwafunmiso , Coelln Rainer von , Tarakad Arjun , Hunter Christine , Dawe Robert J. , Jankovic Joseph , Shulman Lisa M. , Buchman Aron S. , Shulman Joshua M.
Published: August 2020

Introduction

Emerging technologies show promise for enhanced characterization of Parkinson’s Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS).

Methods

We evaluated 176 subjects with PD (mean age 65, 65% male, 66% H&Y stage 2) at the time of routine clinic visits using the motor MDS-UPDRS and a structured 10-minute motor protocol, which included a 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed, while wearing a body-fixed sensor (DynaPort MT, McRoberts BV). Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS.

Results

Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p< 0.05) and subtype (6 of 12 measures, p< 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for ∼1.5-fold increased variance in either cognition or physical functioning disability. Among minimally-impaired subjects within the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity.

Conclusion

Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.
GIS-based spatial modeling to identify factors affecting COVID-19 incidence rates in Bangladesh
Authors: Rahman Md. Hamidur , Zafri Niaz Mahmud , Ashik Fajle Rabbi , Waliullah Md
Published: August 2020

The outbreak of the COVID-19 pandemic is an unprecedented shock throughout the world which leads to generate a massive social, human, and economic crisis. However, there is a lack of research on geographic modeling of COVID-19 as well as identification of contributory factors affecting the COVID-19 in the context of developing countries. To fulfill the gap, this study aimed to identify the potential factors affecting the COVID-19 incidence rates at the district-level in Bangladesh using spatial regression model (SRM). Therefore, data related to 32 demographic, economic, weather, built environment, health, and facilities related factors were collected and analyzed to explain the spatial variability of this disease incidence. Three global (Ordinary least squares (OLS), spatial lag model (SLM) and spatial error model (SEM)) and one local (geographically weighted regression (GWR)) SRMs were developed in this study. The results of the models showed that four factors significantly affected the COVID-19 incidence rates in Bangladesh. Those four factors are urban population percentage, monthly consumption, number of health workers, and distance from the capital. Among the four developed models, the GWR model performed the best in explaining the variation of COVID-19 incidence rates across Bangladesh with aR2value of 78.6%. Findings from this research offer a better insight into the COVID-19 situation and would help to develop policies aimed to prevent the future epidemic crisis.
Consensus-based somatic variant-calling method correlatesFBXW7mutations with poor prognosis in canine B-cell lymphoma
Authors: White ME , Hayward JJ , Hertafeld SR , Castelhano MG , Leung W , Dave SS , Bhinder BH , Elemento OL , Boyko AR , Richards KL , Suter SE
Published: August 2020

INTRODUCTION

Canine Lymphoma (CL) is the most commonly diagnosed malignancy in the domestic dog, with estimates reaching 80,000 new cases per year in the United States. Understanding of genetic factors involved in development and progression of canine B-Cell Lymphoma (cBCL), the most common of the two major subtypes of CL, can help guide efforts to prevent, diagnose, and treat disease in dogs. Such findings also have implications for human Non-Hodgkin Lymphoma (NHL), as pet dogs have recently emerged as an important translational model due to the many shared histopathological, biological, and clinical characteristics between cBCL and NHL.

OBJECTIVES

We aimed to identify potential driver mutations in cBCL and detect associations between affected genes and differential clinical outcomes.

METHODS

Using exome sequencing of paired normal and tumor tissues from 71 dogs of various breeds with cBCL, we identified somatic variants with a consensus approach: keeping variants called by both MuTect2 and with high-confidence by VarScan 2. We predicted effects of these variants using SnpEff then measured associations between mutated genes and survival times from clinical data available for 62 cohort dogs using a multivariate Cox Proportional Hazards Model.

RESULTS

Mutations inFBXW7, a gene commonly mutated in both human and canine cancers including lymphoma, were associated with shorter overall survival (OS; p=0.01, HR 3.3 [1.4-7.6]). The two most frequently mutated codons ofFBXW7in our cohort correspond to the most frequently mutated codons in human cancers.

CONCLUSIONS

Our findings show that exome sequencing results can be combined with clinical data to identify key mutations associated with prognosis in cBCL. These results may have implications for precision medicine in dogs and also allow subsets of dogs to serve as models for specific subtypes of human lymphoma.

Translational Relevance

Identifying tumor biomarkers associated with clinical outcomes has been a major driver in improved success in treating many types of human cancers, including Non-Hodgkin lymphoma (NHL). Since canine B-cell Lymphoma (cBCL) shares many clinically identifiable characteristics with NHL, our detection of recurring mutations in certain genes in cBCL and their association with clinical outcomes stands to benefit both humans and dogs. If common canine lymphoma subtypes show mutational similarity to certain human subtypes, then therapies found to be effective for a subtype in one species may be more likely to improve treatment response in the analogous subtype in the other.
A comparative study of stress responses elicited by misfolded proteins targeted by bipartite or matrix-targeting signal sequences to yeast mitochondria
Authors: Rao Kannan Boosi Narayana , Pandey Pratima , Sarkar Rajasri , Ghosh Asmita , Mansuri Shemin , Ali Mudassar , Majumder Priyanka , Kumar K. Ranjith , Ray Arjun , Raychaudhuri Swasti , Mapa Koyeli
Published: August 2020

The double-membrane-bound architecture of mitochondria, essential for ATP production, sub-divides the organelle into inter-membrane space (IMS) and matrix. IMS and matrix possess contrasting oxido-reductive environments and distinct protein quality control (PQC) machineries resulting different protein folding environments. To understand the nature of stress response elicited by equivalent proteotoxic stress to sub-mitochondrial compartments, we fused well-described bipartite or matrix-targeting signal sequences to misfolding and aggregation-prone stressor proteins to target and impart stress to yeast mitochondrial IMS or matrix. We show, mitochondrial proteotoxicity leads to growth arrest of yeast cells of varying degrees depending on nature of stressor proteins and the intra-mitochondrial location of stress. Next, using transcriptomics and proteomics, we report a comprehensive stress response elicited by two types of targeting signal-fused stressor proteins. Among global responses by mitochondria-targeted stressors by both types of signal sequences, an adaptive response of abrogated mitochondrial respiration and concomitant upregulation of glycolysis is uncovered. Beyond shared stress responses, specific signatures due to stress within mitochondrial sub-compartments are also revealed. We report that bipartite signal sequence-fused stressor proteins eliciting stress to IMS, leads to specific upregulation of IMS-chaperones and TOM complex components. In contrast, matrix-targeted stressors lead to specific upregulation of matrix-chaperones and cytosolic PQC components. Finally, by systematic genetic interaction using deletion strains of differentially upregulated genes, we found prominent modulatory role of TOM complex components during IMS-stress response. In contrast, VMS1 markedly modulates the stress response originated from matrix.
Cortical volume-to-surface and -to-white matter volume relations are explained by uniform cortical architecture in mammals
Authors: de Lussanet Marc H E , Boström Kim J , Wagner Heiko
Published: August 2020

The size of the mammalian cerebrum spans more than 5 orders of magnitude. The smallest cerebrums have a smooth (lissencephalic) cortical surface, which gets increasingly folded (gyrencephalic) with cerebral size. Further, the proportion of white-to-gray matter volume increases with the total volume. These scaling relations have unusually little variation. Even though a number of theories and models have been proposed, it remains an open question, why this is so. Here, we show that almost all variance is explained by assuming a homogeneous composition of the cortex across mammals. On the basis of this assumption we derive quantitative analytical computational models. The first model predicts the cortical surface area from the gray and white matter volume. A single free parameter, for the height of cortical columns is estimated asλ= 2.9mm (r2= 0.996). The second model predicts the white matter volume as a function of the gray volume and the cerebral size (with parameters for intra- and extra-gyral connectionslint, lext;). The models are validated by predicting the effective cortical thickness and the folding parameterκ. The results accurately predict the human intraspecific variation of the surface relations. As expected, we find a reducedλfor cetaceans, and that preterm human infants do not follow the model. We also find deviations of gray and white matter volume for large cerebrums. Overall, the models thus show how the regular architecture of the cortex shapes the cerebrum. We conclude that the mammalian cerebrum scales in anisomorphic, rather than isometric, manner.
Genomic selection for any dairy breeding program via optimized investment in phenotyping and genotyping
Authors: Obšteter Jana , Jenko Janez , Gorjanc Gregor
Published: August 2020

This paper evaluates the potential of maximizing genetic gain in dairy cattle breeding by optimizing investment into phenotyping and genotyping. Conventional breeding focuses on phenotyping selection candidates or their close relatives to maximize selection accuracy for breeders and quality assurance for producers. Genomic selection decoupled phenotyping and selection and through this increased genetic gain per year compared to the conventional selection. Although genomic selection is established in well-resourced breeding programs, small populations and developing countries still struggle with the implementation. The main issues include the lack of training animals and lack of financial resources. To address this, we simulated a case-study of a small dairy population with a number of scenarios with equal resources yet varied use of resources for phenotyping and genotyping. The conventional progeny testing scenario had 11 phenotype records per lactation. In genomic scenarios, we reduced phenotyping to between 10 and 1 phenotype records per lactation and invested the saved resources into genotyping. We tested these scenarios at different relative prices of phenotyping to genotyping and with or without an initial training population for genomic selection. Reallocating a part of phenotyping resources for repeated milk records to genotyping increased genetic gain compared to the conventional scenario regardless of the amount and relative cost of phenotyping, and the availability of an initial training population. Genetic gain increased by increasing genotyping, despite reduced phenotyping. High-genotyping scenarios even saved resources. Genomic scenarios expectedly increased accuracy for young non-phenotyped male and female candidates, but also cows. This study shows that breeding programs should optimize investment into phenotyping and genotyping to maximise return on investment. Our results suggest that any dairy breeding program using conventional progeny testing with repeated milk records can implement genomic selection without increasing the level of investment.
Bilateral Intracranial Beta Activity during Forced and Spontaneous Movements in a Hemi-PD Rat Model
Authors: Mottaghi Soheil , Kohl Sandra , Biemann Dirk , Liebana Samuel , Montano Ruth , Buchholz Oliver , Wilson Mareike , Klaus Carolin , Uchenik Michelle , Münkel Christian , Schmidt Robert , Hofmann Ulrich G.
Published: August 2020

Cortico-basal ganglia beta oscillations (13-30Hz) are assumed to be involved in motor impairments in Parkinson’s Disease (PD), especially in bradykinesia and rigidity. Various studies have utilized the unilateral 6-OHDA rat PD model to further investigate PD and test novel treatments. However, a detailed behavioral and electrophysiological characterization of the model, including analyses of popular PD treatments such as DBS, has not been documented in the literature. We hence challenged the 6-OHDA rat PD model with a series of experiments (i.e. cylinder test, open field test and rotarod test) aimed at assessing the motor impairments, analyzing the effects of Deep Brain Stimulation (DBS), and identifying under which conditions excessive beta oscillations occur. We found that hemi-PD rats presented an impaired performance in all experiments compared to the sham group, and DBS could improve their overall performance. Across all the experiments and behaviors, the power in the high beta band was observed to be an important biomarker for PD as it showed differences between healthy and lesioned hemispheres and between PD and sham rats. This all shows that the 6-OHDA PD model accurately represents many of the motor and electrophysiological symptoms of PD and makes it a useful tool for the pre-clinical testing of new treatments and further investigations into this disease.
Howµ-Opioid Receptor Recognizes Fentanyl
Authors: Vo Quynh N. , Mahinthichaichan Paween , Shen Jana , Ellis Christopher R.
Published: August 2020

In 2019, drug overdose has claimed over 70,000 lives in the United States. More than half of the deaths are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, the crystal structures of mOR in complex with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like synthetic opioids remains lacking. Exploiting the X-ray structure of mOR bound to a morphinan ligand and several state-of-the-art simulation techniques, including weighted ensemble and continuous constant pH molecular dynamics, we elucidated the detailed binding mechanism of fentanyl with mOR. Surprisingly, in addition to forming a salt-bridge with Asp1473.32in the orthosteric site common to morphinan opiates, fentanyl can move deeper and bind mOR through hydrogen bonding with a conserved histidine His2976.52, which has been shown to modulate mOR’s ligand affinity and pH dependence in mutagenesis experiments, but its precise role remains unclear. Intriguingly, the secondary binding mode is only accessible when His297 adopts a neutral HID tautomer. Alternative binding modes and involvement of tautomer states may represent general mechanisms in G protein-coupled receptor (GPCR)-ligand recognition. Our work provides a starting point for understanding the molecular basis of mOR activation by fentanyl which has many analogs emerging at a rapid pace. The knowledge may also inform the design of safer analgesics to combat the opioid crisis. Current protein simulation studies employ standard protonation and tautomer states; our work demonstrates the need to move beyond the practice to advance our understanding of protein-ligand recognition.
Dissociating the effects of distraction and proactive interference on object memory through tests of novelty preference
Authors: Landreth K. , Simanaviciute U. , Fletcher J. , Grayson B. , Grant R.A. , Harte M.H. , Gigg J.
Published: August 2020

Encoding information into memory is sensitive to distraction whilst retrieving that memory may be compromised by proactive interference from pre-existing memories. These two debilitating effects are common in neuropsychiatric conditions but modelling them preclinically to date is slow as it requires prolonged operant training. A step change would be the validation of functionally equivalent but fast, simple, high-throughput tasks based on spontaneous behaviour. Here, we show that spontaneous object preference testing meets these requirements in the subchronic phencyclidine (scPCP) rat model for cognitive impairments associated with schizophrenia. scPCP rats show clear memory sensitivity to distraction in the standard novel object recognition task (stNOR). However, due to this, stNOR cannot assess proactive interference. Therefore, we compared scPCP performance in stNOR to that using the continuous NOR task (conNOR), which offers minimal distraction, allowing disease-relevant memory deficits to be assessed directly. We first determined that scPCP treatment did not affect whisker movements during object exploration. scPCP rats exhibited the expected distraction stNOR effect but had intact performance on the first conNOR trial, effectively dissociating distraction by using two NOR task variants. In remaining conNOR trials, scPCP rats performed above chance throughout but, importantly, their detection of object novelty was increasingly impaired relative to controls. We attribute this effect to the accumulation of proactive interference. This is the first demonstration that increased sensitivity to distraction and proactive interference, both key cognitive impairments in schizophrenia, can be dissociated in the scPCP rat using two variants of the same fast, simple, spontaneous object memory paradigm.
Targeted mutagenesis of the Arabidopsis GROWTH-REGULATING FACTOR (GRF) gene family suggests competition of multiplexed sgRNAs for Cas9 apoprotein
Authors: Angulo Juan , Astin Christopher P , Bauer Olivia , Blash Kelan J , Bowen Natalee M , Chukwudinma Nneoma J , Dinofrio Austin S , Faletti Donald O , Ghulam Alexa M , Gusinde-Duffy Cloe M , Horace Kamaria J , Ingram Andrew M , Isaack Kylie E , Jeong Geon , Kiser Randolph J , Kobylanski Jason S , Long Madeline R , Manning Grace A , Morales Julie M , Nguyen Kevin H , Pham Robin T , Phillips Monthip H , Reel Tanner W , Seo Jenny E , Vo Hiep D , Wukuson Alexander M , Yeary Kathryn A , Zheng Grace Y , Lukowitz Wolfgang
Published: August 2020

Genome editing in plants typically relies on T-DNA plasmids that are mobilized by Agrobacterium-mediated transformation to deliver the CRISPR/Cas9 machinery. Here, we introduce a series of CRISPR/Cas9 T-DNA vectors for minimal lab settings, such as in the classroom or citizen science projects. Spacer sequences targeting genes of interest can be inserted as annealed short oligonucleotides in a single straightforward cloning step. Fluorescent markers expressed in mature seeds enable reliable selection of transgenic as well as transgene-free individuals using a combination of inexpensive LED lamps and colored-glass alternative filters. Testing these tools on the Arabidopsis GROWTH-REGULATING FACTOR (GRF) gene family, we found that Cas9 expression from an EGG CELL1 (EC1) promoter resulted in tenfold lower mutation rates than expression from a UBIQUITIN10 (UBQ10) promoter. A collection of bona fide null mutations in all nine GRF genes could be established with little effort. Finally, we explored the effects of simultaneously targeting two, four and eight GRF genes on the rate of induced mutations at each target locus. Multiplexing caused strong interference effects: while mutation rates at some loci remained consistently high, mutation rates at other loci dropped dramatically with increasing number of single guide RNA species. Our results suggest potential detrimental genetic interaction between induced mutations as well as competition of CRISPR RNAs for a limiting amount of Cas9 apoprotein.
Sleep-dependent offline performance gain in visual perceptual learning is consistent with a learning-dependent model
Authors: Tamaki Masako , Sasaki Yuka
Published: August 2020

Are the sleep-dependent offline performance gains of visual perceptual learning (VPL) consistent with a use-dependent or learning-dependent model? Here, we found that a use-dependent model is inconsistent with the offline performance gains in VPL. In two training conditions with matched visual usages, one generated VPL (learning condition), while the other did not (interference condition). The use-dependent model predicts that slow-wave activity (SWA) during posttraining NREM sleep in the trained region increases in both conditions, in correlation with offline performance gains. However, compared with those in the interference condition, sigma activity, not SWA, during NREM sleep and theta activity during REM sleep, source-localized to the trained early visual areas, increased in the learning condition. Sigma activity correlated with offline performance gain. These significant differences in spontaneous activity between the conditions suggest that there is a learning-dependent process during posttraining sleep for the offline performance gains in VPL.
Alternative catalytic mechanisms driven by structural plasticity is an emerging theme in HAS-GTPases, Era and FeoB
Authors: Batra Sahil , Kumar Ashok , Prakash Balaji
Published: August 2020

GTP hydrolysis is the underlying basis for functioning of ‘biological switches’ or GTPases. Extensively studied GTPases, Ras and EF-Tu, use a conserved Gln/His that facilitates the activation of attacking water for nucleophilic attack. However, this is insufficient to explain catalysis inHydrophobicAmino acidSubstituted (HAS)-GTPases that naturally possess a hydrophobic residue in lieu of Gln/His. We had previously reported a bridging water-chain mediated catalytic mechanism for HAS-GTPase FeoB; which utilizes two distantly-located but conserved glutamates. Curiously, mutating these does not abolish GTP hydrolysis. Similarly, in this study we report our observations on another HAS-GTPase Era, wherein the mutants of catalytically important residues continue to hydrolyze GTP. We attempt to rationalize these inquisitive observations on GTP hydrolysis by FeoB and Era mutants. We propose a general theory that appears common to at least three classes of GTPases, where ‘alternative mechanisms’ emerge when the primary mechanism is disrupted. Based on the analysis of crystal structures of FeoB and Era mutants, bound to the transition state analogue GDP.AlFx, this work suggests that in the absence of catalytically important residues, the active site waters in both FeoB and Era undergo re-arrangements, which in turn helps in sustaining GTP hydrolysis. Similar employment of alternative mechanisms was also suggested for the catalytic mutants of hGBP1. Importantly, such alternatives underscore the robustness of GTP hydrolysis mechanisms in these systems, and raise important questions regarding the need for persistent GTP hydrolysis and the physiological relevance of structural plasticity seen here.
Flagella Ca2+elevations regulate pausing of retrograde intraflagellar transport trains in adherentChlamydomonasflagella
Authors: Fort Cecile , Collingridge Peter , Brownlee Colin , Wheeler Glen
Published: August 2020

The movement of ciliary membrane proteins is directed by transient interactions with intraflagellar transport (IFT) trains. The green algaChlamydomonashas adapted this process for gliding motility, using IFT to move adhesive glycoproteins (FMG-1B) in the flagella membrane. Although Ca2+signalling contributes directly to the gliding process, uncertainty remains over the mechanisms through which Ca2+acts to influence the movement of IFT trains. Here we show that flagella Ca2+elevations regulate IFT primarily by initiating the movement of paused retrograde IFT trains. Flagella Ca2+elevations exhibit complex spatial and temporal properties, including high frequency repetitive Ca2+elevations that prevent the accumulation of paused retrograde IFT trains. We show that flagella Ca2+elevations disrupt the IFT-dependent movement of microspheres along the flagella membrane. The results suggest that flagella Ca2+elevations directly disrupt the interaction between retrograde IFT particles and flagella membrane glycoproteins to modulate gliding motility and the adhesion of the flagellum to a surface.
Binocular disparity-based learning does not generalize to the other visual hemifield
Authors: Klinzing Jens G. , Nienborg Hendrikje , Rauss Karsten
Published: August 2020

Visual perceptual learning refers to long-lasting performance improvements on a visual skill, an ability presumably supported by plastic changes in early visual brain areas. Visual perceptual learning has been shown to be induced by training and to benefit from consolidation during sleep, presumably via the reactivation of learning-associated neuronal firing patterns. However, previous studies have almost exclusively relied on a single paradigm, the texture discrimination task, on which performance improvements may not rely on strictly perceptual skills. Here, we tested whether sleep has beneficial effects on a visual disparity discrimination task. We confirm previous findings in showing that the ability to discriminate different disparities is unaffected by sleep during a 12-hour retention period after training. Importantly, we extend these results by providing evidence against an effect of sleep on the generalization of improved disparity discrimination across the vertical meridian. We further rule out carry-over effects as a possible confound in our earlier within-subject study by relying on a between-subject design. The combined data from both studies argue against sleep as an important factor in the consolidation of a strictly perceptual skill. This sets important constraints on models of the role of sleep and sleep-associated neural reactivation in the consolidation of non-declarative memories.
Complexome profile ofToxoplasma gondiimitochondria identifies a divergent cytochromebc1complex
Authors: Maclean Andrew E. , Bridges Hannah R. , Silva Mariana F. , Ding Shujing , Hirst Judy , Sheiner Lilach
Published: August 2020

The mitochondrial electron transport chain (mETC) and F1Fo-ATP synthase are of central importance for energy and metabolism in eukaryotic cells. The Apicomplexa, important pathogens of humans causing diseases such as toxoplasmosis and malaria, depend on their mETC in every known stage of their complicated life cycles. Here, using a complexome profiling proteomic approach, we have characterised theToxoplasmamETC complexes and F1Fo-ATP synthase. We identified and assigned 60 proteins to complexes II, IV and F1Fo-ATP synthase ofToxoplasma, of which 16 have not been identified previously. Notably, our complexome profile elucidates the composition of theToxoplasmacomplex III, the target of clinically used drugs such as atovaquone. We identified two new homologous subunits and two new parasite-specific subunits, one of which is broadly conserved in myzozoans. We demonstrate all four proteins are essential for complex III stability and parasite growth, and show their depletion leads to decreased mitochondrial potential, supporting their role as complex III subunits. Our study highlights the divergent subunit composition of the apicomplexan mETC complexes and sets the stage for future structural and drug discovery studies.

Author Summary

Apicomplexan parasites, such asToxoplasmaandPlasmodium, cause diseases of global importance, such as toxoplasmosis and malaria. The mitochondrial electron transport chain (mETC) and F1Fo-ATP synthase, which provide the parasite with energy and important metabolites, are essential for parasite function. Here, using a proteomic technique called complexome profiling, we report the composition of theToxoplasmamETC and F1Fo-ATP synthase. In particular, we reveal the compositions of complexes II and III for the first time. Complex III is an important drug target, yet its full protein composition was unknown. We identify new parasite-specific complex III subunits and demonstrate that they are essential for parasite survival and for proper functioning of the mETC. Our study highlights the divergent nature of the apicomplexan mETC and F1Fo-ATP synthase.