bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrasonographic Measurement of Talar Cartilage Thickness in Patients With Cerebral Palsy
Authors: Aras Berke , Kesikburun Serdar , Yilmaz Volkan , Demirtaş Emine Yeliz Gümüş , Yaşar Evren
Published: June 2020

Objective

Foot deformities are one of the most common musculoskeletal problems in children with cerebral palsy (CP). These deformities affect the walking ability and function of the patients. Talar cartilage is the hyaline joint cartilage of the tibiotalar joint that plantarflexes and dorsiflexes of the ankle. The aim of this study was to determine whether talar cartilage thickness was affected in children with ambulant diplegic CP.

Design

Forty patients with diplegic CP (19 boys, 21 girls) and 40 age-, sex-, and weight-matched healthy control subjects (20 boys, 20 girls) were included in the study. The demographic and clinical characteristics of the patients, including age, sex, and body mass index, were recorded. Patients were classified using the Gross Motor Function Classification System. A 12-MHz linear probe was used for ultrasonographic cartilage measurements at the tibiotalar joint according to European Musculoskeletal Ultrasound Study Group (EURO-MUSCULUS) and the Ultrasound Study Group in Physical and Rehabilitation Medicine (USPRM) scanning protocols.

Results

Mean talar cartilage thickness was significantly decreased in the CP group compared with the healthy control group (P< 0.001). There was a significant negative correlation between Gross Motor Function Classification System levels and talar cartilage thickness measurements (P< 0.001, Tb = −0.695).

Conclusion

This study demonstrates that patients with CP have a thinner talar cartilage compared with healthy control subjects.
Physical Medicine and Rehabilitation and Pulmonary Rehabilitation for COVID-19
Authors: Wang Tina J. , Chau Brian , Lui Mickey , Lam Giang-Tuyet , Lin Nancy , Humbert Sarah
Published: June 2020

This analysis extrapolates information from previous studies and experiences to bring physical medicine and rehabilitation perspective and intervention to the multidisciplinary treatment of COVID-19. The purpose of pulmonary rehabilitation in COVID-19 patients is to improve symptoms of dyspnea, relieve anxiety, reduce complications, minimize disability, preserve function, and improve quality of life. Pulmonary rehabilitation during the acute management of COVID-19 should be considered when possible and safe and may include nutrition, airway, posture, clearance technique, oxygen supplementation, breathing exercises, stretching, manual therapy, and physical activity. Given the possibility of long-term disability, outpatient posthospitalization pulmonary rehabilitation may be considered in all patients hospitalized with COVID-19.
Association of Arthritis and Antihypertensive Medication Use Among Individuals With Hypertension
Authors: Liew Jean W. , Cannon Chase A. , Ji Yuekai , Littman Alyson J. , Hawes Stephen E.
Published: June 2020

Background

The aim of this study was to assess whether arthritis is associated with lower antihypertensive medication (AHM) use among those with hypertension and whether this relationship differs by age or cardiovascular (CV) comorbidity.

Methods

The data were from the 2017 Behavioral Risk Factor Surveillance System. We employed survey weights to account for the complex sampling design and nonresponse bias. We used generalized linear models to estimate unadjusted and adjusted prevalence ratios (PRs) and 95% confidence intervals comparing AHM use among those with severe or mild arthritis to those without arthritis, stratified by age, sex, and CV comorbidity.

Results

Among 173,098 adults with hypertension, 26.0% had severe arthritis and 22.3% had mild arthritis. Compared with those without arthritis, individuals with mild or severe arthritis were older, predominantly female, with lower income and more comorbidities. After adjustment for sex, race, inability to afford medications, and CV comorbidity, the prevalence ratios for AHM use were stronger for younger versus older age groups. Associations did not differ significantly by sex or CV comorbidity. Associations were similar for mild and severe arthritis, compared with no arthritis.

Conclusions

Among individuals with hypertension, those with arthritis had significantly higher prevalences of AHM use compared with those without arthritis. Higher prevalences of AHM use were seen with older age categories, although a stronger association of arthritis and AHM use was found in younger age groups. Future studies on hypertension management in arthritis should examine these relationships more closely.
Thirty Years of Tacrolimus in Clinical Practice
Authors: Ong Song C. , Gaston Robert S.
Published: June 2020

Tacrolimus was discovered in 1984 and entered clinical use shortly thereafter, contributing to successful solid organ transplantation across the globe. In this review, we cover development of tacrolimus, its evolving clinical utility, and issues affecting its current usage. Since earliest use of this class of immunosuppressant, concerns for calcineurin-inhibitor toxicity have led to efforts to minimize or eliminate these agents in clinical regimens but with limited success. Current understanding of the role of tacrolimus focuses more on its efficacy in preventing graft rejection and graft loss. As we enter the fourth decade of tacrolimus use, newer studies utilizing novel combinations (as with the mammalian target of rapamycin inhibitor, everolimus, and T-cell costimulation blockade with belatacept) offer potential for enhanced benefits.
Topiramate-Associated Movement Disorder: Case Series and Literature Review
Authors: Rissardo Jamir Pitton , Caprara Ana Letícia Fornari
Published: June 2020

Background

Topiramate (TPM) is a fructose derivative, which was originally developed as an antiepileptic. In this context, movement disorders (MDs) are possible adverse events secondary to TPM.

Case reports

Two patients (cases 1 and 2) developed myoclonus, and the other 2 had restless leg syndrome (RLS, cases 3 and 4). The mean age of the individuals (3 female patients) was 45.75 ± 21.28 years. All the individuals had a negative family history for movement and psychiatry disorders. Topiramate was started at 25 mg with a gradual increase of 25 mg every week. The mean time of onset and recovery of the MD were 1.37 ± 1.10 and 1.02 ± 0.77 months, respectively. The mean TPM dose was 87.5 ± 47.87 mg. Individual 1 presented with upper and lower limb jerks; individual 2 only with upper limb involvement. Individuals 3 and 4 experienced insomnia and nocturnal leg discomfort during inactivity with an urge to move the legs, which they denied having previously; the RLS symptoms occurred within approximately 1 to 3 hours of TPM evening dose. On neurological examination, no tremor or bradykinesia was observed; deep tendon reflexes, sensory examination, and strength were normal and preserved. Laboratory tests, neuroimaging, and electromyography were within normal. Topiramate was discontinued in all of the subjects. Full recovery was obtained in all cases.

Conclusions

To the authors' knowledge, there are 6 cases of myoclonus, 5 RLS, 2 dystonia, 1 dyskinesia, and 1 periodic limb MD. The best management is probably the discontinuation of TPM, but in RLS patients, the addition of a dopaminergic agonist can be beneficial.
Genotypic and antigenic study of SARS-CoV-2 from an Indian isolate
Authors: Dhar Ruby , Sinha Akhauri Yash , Seethy Ashikh , Matta Sri Anusha , Pethusamy Karthikeyan , Srivastava Trymbak , Singh Sunil , Mukherjee Indrani , Sarkar Sajib , Minocha Rashmi , Purkayastha Kakali , Sharma Jai Bhagwan , Paine Suman , Karmakar Subhradip
Published: June 2020

Coronaviruses (CoVs) are one of the largest groups of positive-sense RNA virus families within the Nidovirales order, which are further classified into four genera: alpha, beta, gamma, and delta. Coronaviruses have an extensive range of natural hosts and are known to be responsible for a broad spectrum of diseases in multiple species. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) that has unleashed a global threat to public health and the economy. Coronaviruses are extensively present in birds and mammals, with horseshoe bats (Rhinolophus affinis), being the reservoir for the ongoing SARS-CoV-2 that seems to have resulted from a zoonotic spillover to the human host, causing respiratory infections, lung injury and Acute Respiratory Distress Syndrome(ARDS). About six coronavirus serotypes are linked with the disease in humans, namely HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, SARS-CoV-2, and MERS-CoV. SARS-CoV-2 is the seventh CoV to infect humans. We analyzed the genome sequence of CoV-2 from isolates derived from China as well from India and encountered minute variations in their sequence. A cladogram analysis revealed the predominant strain circulating in India belongs to the A2a clad. We took one such strain (MT012098) and performed a rigorousin-silicogenotypic and antigenic analysis to identify its relatedness to other strains. Further, we also performed a detailed prediction for B and T cell epitopes using BepiPred 2.0 server and NetCTL 1.2 server (DTU Bioinformatics), respectively. We hope this information may assist in an effective vaccine designing program against SARS-CoV-2.
Integrated gut–liver-on-a-chip platform as anin vitrohuman model of non-alcoholic fatty liver disease
Authors: Yang Jiandong , Hirai Yoshikazu , Iida Kei , Ito Shinji , Trumm Marika , Terada Shiho , Sakai Risako , Tsuchiya Toshiyuki , Tabata Osamu , Kamei Ken-ichiro
Published: June 2020

Non-alcoholic fatty liver disease (NAFLD) afflicts a large percentage of the population, but no effective treatments have been established so far because of the unsuitability ofin vitroassays and experimental models using animals. By co-culturing human gut and liver cell lines interconnected via microfluidics for a closed circulation loop, we created a gut–liver-on-a-chip (iGLC) platform as anin vitrohuman model of the gut–liver axis (GLA) for the initiation and progression of NAFLD. Microscopic high-content analysis followed by mRNA sequencing showed that co-culturing the gut and liver cells significantly affected each cell type compared to culturing them separately. NAFLD-inducing free fatty acids (FFAs) accumulated in the gut cells and elevated gene expressions associated with retinol metabolism and glucuronidation. The FFA-treated liver cells accumulated intracellular lipid droplets and showed an increase in gene expressions associated with a cellular response to copper ions and endoplasmic reticulum stress. As anin vitrohuman GLA model, the iGLC platform may serve as an alternative to animal experiments for investigating NAFLD mechanisms.
Structural and Functional Analyses of Hub MicroRNAs in an Integrated Gene Regulatory Network ofArabidopsis
Authors: Gao Zhaoxu , Li Jun , Li Li , Yang Yanzhi , Li Jian , Fu Chunxiang , Zhu Danmeng , He Hang , Cai Huaqing , Li Lei
Published: June 2020

MicroRNAs (miRNAs) are trans-acting small regulatory RNAs that work coordinately with transcription factors (TFs) to shape the repertoires of cellular mRNA available for translation. Despite our growing knowledge of individual plant miRNAs, their global roles in gene regulatory networks remain mostly unassessed. Based on interactions reanalyzed from public databases and curated from the literature, we reconstructed an integrated miRNA network inArabidopsisthat includes 66 core TFs, 318 miRNAs, and 1712 downstream genes. We found that miRNAs occupy distinct niches and enrich miRNA-containing feed-forward loops (FFLs), particularly those in which the miRNAs are intermediate nodes. Further analyses revealed that miRNA-containing FFLs coordinate TFs located in different hierarchical layers and that intertwined miRNA-containing FFLs are associated with party and date miRNA hubs. Using the date hubMIR858Aas an example, we performed detailed molecular and genetic analyses of three interconnected miRNA-containing FFLs. These analyses revealed individual functions of the selected miRNA-containing FFLs and elucidated how the date hub miRNA fulfills multiple regulatory roles. Collectively, our findings highlighted the prevalence and importance of miRNA-containing FFLs to provide new insights into the design principles and control logic of miRNA regulatory networks governing gene expression programs in plants.
Brain networks subserving functional core processes of emotions identified with componential modelling
Authors: Mohammadi Gelareh , Van De Ville Dimitri , Vuilleumier Patrik
Published: June 2020

Emotions have powerful effects on the mind, body, and behavior. Although psychology theories emphasized multi-componential characteristics of emotions, little is known about the nature and neural architecture of such components in the brain. We used a multivariate data-driven approach to decompose a wide range of emotions into functional core processes and identify their neural organization. Twenty participants watched 40 emotional clips and rated 119 emotional moments in terms of 32 component features defined by a previously validated componential model. Results show how different emotions emerge from coordinated activity across a set of brain networks coding for component processes associated with valuation appraisal, hedonic experience, novelty, goal-relevance, approach/avoidance tendencies, and social concerns. Our study goes beyond previous research that focused on either categorical or dimensional emotions and highlighting how novel methodology combined with componential modelling may allow emotion neuroscience to move forward and unveil the functional architecture of human affective experiences.
The genetic origin of evolidine, the first cyclopeptide discovered in plants, and related orbitides
Authors: Fisher Mark F. , Payne Colton , Chetty Thaveshini , Crayn Darren , Berkowitz Oliver , Whelan James , Rosengren K. Johan , Mylne Joshua S.
Published: June 2020

Cyclic peptides are reported to have antibacterial, antifungal and other bioactivities. Several genera of the Rutaceae family are known to produce orbitides, which are small head-to-tail cyclic peptides composed of proteinogenic amino acids and lacking disulfide bonds.Melicope xanthoxyloidesis an Australian rain forest tree of the Rutaceae family in which evolidine - the first plant cyclic peptide - was discovered. Evolidine (cyclo-SFLPVNL) has subsequently been all but forgotten in the academic literature, but here we use tandem mass spectrometry to rediscover evolidine and usingde novotranscriptomics we show its biosynthetic origin to be from a short precursor just 48 residues in length. In all, sevenM. xanthoxyloidesorbitides were found and they had atypically diverse C-termini consisting of residues not recognized by either of the known proteases plants use to macrocyclize peptides. Two of the novel orbitides were studied by nuclear magnetic resonance spectroscopy and although one had definable structure, the other did not. By mining RNA-seq and whole genome sequencing data from other species, it was apparent that a large and diverse family of peptides is encoded by sequences like these across the Rutaceae.
Binding ofLeishmania infantumLPG to the midgut is not sufficient to define vector competence inLutzomyia longipalpissand flies
Authors: Coutinho-Abreu Iliano V. , Oristian James , de Castro Waldionê , Wilson Timothy R. , Meneses Claudio , Soares Rodrigo P. , Borges Valéria M. , Descoteaux Albert , Kamhawi Shaden , Valenzuela Jesus G.
Published: June 2020

The major surface lipophosphoglycan (LPG) ofLeishmaniaparasites is critical to vector competence in restrictive sand fly vectors by mediatingLeishmaniaattachment to the midgut epithelium, considered essential to parasite survival and development. However, the relevance of LPG for sand flies that harbor multiple species ofLeishmaniaremains elusive. We tested binding ofLeishmania infantumwild type (WT), LPG-defective (Δlpg1mutants) and add-back lines (Δlpg1+LPG1) to sand fly midgutsin vitroand their survival inLutzomyia longipalpissand fliesin vivo. Le. infantumWT parasites attached to theLu. longipalpismidgutin vitrowith late-stage parasites binding to midguts in significantly higher numbers compared to early-stage stage promastigotes. Δlpg1mutants did not bind toLu. longipalpismidguts, and this was rescued in the Δlpg1+LPG1lines, indicating that midgut binding is mediated by LPG. WhenLu. longipalpissand flies were infected with eitherLe. infantumWT, Δlpg1, or Δlpg1+LPG1of the BH46 or BA262 strains, the BH46 Δlpg1mutant, but not the BA262 Δlpg1mutant, survived and grew to similar numbers as the WT and Δlpg1+LPG1lines. Exposure of BH46 and BA262 Δlpg1mutants to blood engorged midgut extracts led to the mortality of the BA262 Δlpg1but not the BH46 Δlpg1parasites. These findings suggest thatLe. infantumLPG protects parasites on a strain-specific basis early in infection, likely against toxic components of blood digestion, however, it is not necessary to preventLe. infantumevacuation along with the feces in the permissive vectorLu. longipalpis.

IMPORTANCE

It is well established that LPG is sufficient to define the vector competence of restrictive sand fly vectors toLeishmaniaparasites. However, the permissiveness of other sand flies to multipleLeishmaniaspecies suggests that other factors might define vector competence for these vectors. In this study, we investigated the underpinnings ofLeishmania infantumsurvival and development in its natural vectorLutzomyia longipalpis. We found out that LPG-mediated midgut binding persists in late-stage parasites. This observation is paradigm-changing and suggests that only a subset of infective metacyclics lose their ability to attach to the midgut with implications for parasite transmission dynamics. However, our data also demonstrate that LPG is not a determining factor inLeishmania infantumretention in the midgut ofLutzomyia longipalpis, a permissive vector. Rather, LPG appears to be more important in protecting some parasite strains from the toxic environment generated during blood meal digestion in the insect gut. Thus, the relevance of LPG in parasite development in permissive vectors appears to be complex and should be investigated on a strain-specific basis.
Comparative metabolic profile of maize genotypes reveals the tolerance mechanism associated under combined stresses
Authors: Rafique Suphia
Published: June 2020

Drought, heat, high temperature, waterlogging, low-N stress, and salinity are the major environmental constraints that limit plant productivity. In tropical regions maize grown during the summer rainy season, and often faces irregular rains patterns, which causes drought, and waterlogging simultaneously along with low-N stress and thus affects crop growth and development. The two maize genotypes CML49 and CML100 were subjected to combination of abiotic stresses concurrently (drought and low-N / waterlogging and low-N). Metabolic profiling of leaf and roots of two genotypes was completed using GC-MS technique. The aim of study to reveal the differential response of metabolites in two maize genotypes under combination of stresses and to understand the tolerance mechanism. The results of un-targeted metabolites analysis show, the accumulated metabolites of tolerant genotype (CML49) in response to combined abiotic stresses were related to defense, antioxidants, signaling and some metabolites indirectly involved in nitrogen restoration of the maize plant. Alternatively, some metabolites of sensitive genotype (CML100) were regulated in response to defense, while other metabolites were involved in membrane disruption and also as the signaling antagonist. Therefore, the present study provides insight into the molecular mechanisms of tolerance under various stresses of maize plants, that governed on the regulation of cell wall remodeling, maintain metabolic homeostasis, defense against the pathogen, proper signaling, and restore growth under stress conditions.
Both HIV and Tat Expression Decrease Prepulse Inhibition with Further Impairment by Methamphetamine
Authors: Walter T. Jordan , Young Jared W. , Milienne-Petiot Morgane , Deben D. S. , Heaton Robert K. , Letendre Scott , Grelotti David J. , Perry William , Grant Igor , Minassian Arpi ,   Translational Methamphetamine AIDS Research Center (TMARC)
Published: June 2020

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.

HIGHLIGHTS

HIV decreased PPI in men and women

PPI was most decreased in people with HIV and a history of METH dependence

Chronic METH treatment decreased PPI in male but not female mice

Tat expression decreased PPI in male but not female mice

Chronic METH treatment and Tat expression did not interact to affect PPI in mice
Genome-Wide High Resolution Expression Map and Functions of Key Cell Fate Determinants Reveal the Dynamics of Crown Root Development in Rice
Authors: Garg Tushar , Singh Zeenu , Chennakesavulu Kunchapu , Dwivedi Anuj K. , Varapparambathu Vijina , Singh Raj Suryan , Mushahary Khrang Khrang Khunggur , Yadav Manoj , Sircar Debabrata , Chandran Divya , Prasad Kalika , Jain Mukesh , Yadav Shri Ram
Published: June 2020

Shoot borne adventitious/crown roots (AR/CR) shape up the root architecture in grasses. Mechanisms underlying initiation and subsequent outgrowth of CR remain largely unknown. Here, we provide genome-wide modulation in the landscape of transcriptional signatures during distinct developmental stages of CR formation in highly derived grass species, rice. Our studies implicate the role of potential epigenetic modifiers, transcription factors and cell division regulators in priming the initiation of CR primordia followed by progressive activation of conserved transcription regulatory modules to ensure their outgrowth. In depth analysis of spatio-temporal expression patterns of key cell fate determinants and functional analyses of riceWUSCHEL RELATED HOMEOBOX10(OsWOX10) andPLETHORA(OsPLT1) genes reveal their unprecedented role in controlling root architecture. We further show thatOsPLT1activates local auxin biosynthesis and forms an integral part ofERF3-OsWOX11-OsRR2regulatory module during CR primordia development. Interestingly,OsPLTgenes, when expressed in the transcriptional domain of root-borne lateral root primordia ofArabidopsis pltmutant, rescued their outgrowth demonstrating the conserved role ofPLTgenes in root primordia outgrowth irrespective of their developmental origin. Together, these findings unveil the molecular framework of cellular reprogramming during trans-differentiation of shoot tissue to root leading to culmination of robust root architecture in grass species which got evolutionary diverged from dicots.
Parabrachial neuron types categorically encode thermoregulation variables during heat defense
Authors: Yang Wen Z. , Du Xiaosa , Zhang Wen , Gao Cuicui , Xie Hengchang , Xiao Yan , Jia Xiaoning , Liu Jiashu , Xu Jianhui , Fu Xin , Tu Hongqing , Fu Xiaoyu , Ni Xinyan , He Miao , Yang Jiajun , Wang Hong , Yang Haitao , Xu Xiao-hong , Shen Wei L.
Published: June 2020

Heat defense is crucial for survival and fitness, and its dysregulation may result in deaths due to poor management. Transmission of thermosensory signals into hypothalamic thermoregulation centers represent a key layer of regulation in heat defense. However, the mechanism by which these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that glutamatergic prodynorphin and cholecystokinin neuron populations in the lateral parabrachial (LPB) are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuitries with downstream preoptic hypothalamic neurons to inhibit BAT thermogenesis and activate tail vasodilation, respectively. Both circuitries are selectively activated by warm temperatures and are required for fever limiting. The prodynorphin circuitry is further required for regulation of energy expenditure and weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, which may provide targets for treating thermoregulation disorders.
Cardiac toxicity predictions: Safety pharmacologists correlate with the CiPA model
Authors: Mistry Hitesh B. , Parikh Jaimit
Published: June 2020

There has been a lot of interest and publicity regarding the use of a complex biophysical model within drug development for predicting the TdeP risk of new compounds. Throughout the development of the complex model numerous groups have shown that a simple linear mechanistic model explains the predictive behaviour of complex mechanistic models. That is the input-output relationship is almost linear even when complex kinetic assays are used. We hypothesized that given this linear relationship that scientist would be able to predict the outcome of the biophysical model. The objective of this pilot study was to assess the feasibility of such an analysis but also assess the initial degree of correlation. A set of 15 compounds with diverse ion-channel blocking against 4 ion-channel currents, IKr, ICaL, INa and INaL, was generated. Safety pharmacologists across numerous companies were approached and asked to categorize the TdeP risk of these compounds using only the % block depicted via a bar chart into one of 3 categories: Risk, No-risk or Unsure. 12 scientists participated in the study, of which 11 correlated strongly with the model (11 person ROC AUC range: 0.86-1, 7 scientists had a value >0.9). The combined prediction of all scientists also correlated strongly with the model. These results highlight that the linear input-output relationship can indeed be predicted by the scientist. A future study exploring the degree of correlation with a wider group of scientists and wider set of compounds would be required to get a more precise estimate of the correlation. We hope this initial exploratory study will encourage the community to pursue this idea.
Human cerebral tissues created via active cellular reaggregation produce functionally interconnected 3D neuronal network to mimic pathological circuit disturbance
Authors: Saberi Aref , Aldenkamp Albert P. , Kurniawan Nicholas A. , Bouten Carlijn V.C.
Published: June 2020

Various characteristics of a developing central nervous system, including sensory input-output1,2, neuronal migration3,4, and regionalization3,5, have been recapitulated through recent advances in the culture of brain organoids. These organoids can model the fundamental processes in brain development and disease. A remaining critical challenge, however, is to achieve complex neuronal networks with functional interconnectivity as in native brain tissue. Generation of current organoid models originates from classic dissociation-reaggregation paradigms6, often relying on mechanically-enforced quick reaggregation of pluripotent stem cells7. Here we describe an alternative method that promotes matrix-supported active (migrative) reaggregation of cells (MARC), reminiscent of in vivo developmental morphing processes, to engineer multi-regional brain tissues in vitro. Measurements of neuronal activity in intact 3D tissues revealed functional interconnectivity, characteristic of cerebral neuronal networks. As a proof of concept, we show that interconnected cerebral tissues produced using this approach can mimic propagation of epileptiform discharges in a custom-built in-vitro platform.
Structural correlates of human muscle nicotinic acetylcholine receptor subunit assembly mediated by δ(+) interface residues
Authors: Epstein Max , Maxwell Susan , Piggot Thomas J. , Beeson David , Bermudez Isabel , Biggin Philip C.
Published: June 2020

Muscle nicotinic acetylcholine receptors are a class of heteropentameric ligand-gated cation channels with constituent subunits adopting a fixed stoichiometric arrangement. The specific amino acid residues that govern subunit ordering are however, only partially understood. By integrating all-atom molecular dynamics simulations, bioinformatics, two-electrode voltage clamp electrophysiology and125I-α-bungarotoxin assays of chimeric nAChR subunits, we identify residues across the extracellular, transmembrane and extended M4 helix of the δ subunit that make structural signatures that contribute to intransigent assembly rules. Furthermore, functional differences observed in α2δ2β receptors can be rationalized by changes in dynamical behavior that manifest themselves at the agonist binding site.
UTMOST, A Novel Single And Cross-Tissue TWAS (Transcriptome Wide Association Study), Reveals New ASD (Autism Spectrum Disorder) Associated Genes
Authors: Rodriguez-Fontenla Cristina , Carracedo Angel
Published: June 2020

Background

ASD is a complex neurodevelopmental disorder which may significantly impact on the affected individual’s life. Common variation (SNPs) could explain about 50% of ASD heritability. Despite this fact and the large size of the last GWAS meta-analysis, it is believed that hundreds of risk genes in ASD have yet to be discovered. New tools such as TWAS which integrate tissue-expression and genetic data, are a great approach to identify new ASD susceptibility genes.

Methods

The main goal of this study is to use UTMOST with the public available summary statistics from the largest ASD GWAS meta-analysis as genetic input. In addition, anin silicobiological characterization for the novel associated loci was performed.

Results

Our results have demonstrated the association of 4 genes at the brain level (CIPC, PINX1, NKX2-2andPTPRE) and highlight the association ofNKX2-2, MANBA, ERI1andMITFat the gastrointestinal level. This last finding is quite relevant given the well-established but unexplored relationship between ASD and gastrointestinal symptoms. Cross-tissue analysis has shown the association ofNKX2-2andBLK.

Conclusions

UTMOST associated genes together with theirin silicobiological characterization seems to point to different biological mechanisms underlying ASD etiology not only restricted to brain tissue and involving other body tissues such as the gastrointestinal tissue.
Reproducible, portable, and efficient ancient genome reconstruction with nf-core/eager
Authors: Yates James A. Fellows , Lamnidis Thiseas C. , Borry Maxime , Valtueña Aida Andrades , Fagernäs Zandra , Clayton Stephen , Garcia Maxime U. , Neukamm Judith , Peltzer Alexander
Published: June 2020

The broadening utilisation of ancient DNA to address archaeological, palaeontological, and biological questions is resulting in a rising diversity in the size of laboratories and scale of analyses being performed. In the context of this heterogeneous landscape, we present nf-core/eager, an advanced and entirely redesigned and extended version of the EAGER pipeline for the analysis of ancient genomic data. This Nextflow pipeline aims to address three main themes: accessibility and adaptability to different computing configurations, reproducibility to ensure robust analytical standards, and updating the pipeline to the latest routine ancient genomic practises. This new version of EAGER has been developed within the nf-core initiative to ensure high-quality software development and maintenance support; contributing to a long-term lifecycle for the pipeline. nf-core/eager will assist in ensuring that ancient DNA sequencing data can be used by a diverse range of research groups and fields.
Dentate gyrus development requires a cortical hem-derived astrocytic scaffold
Authors: Caramello Alessia , Galichet Christophe , Rizzoti Karine , Lovell-Badge Robin
Published: June 2020

During embryonic development, radial glial cells give rise to neurons, then to astrocytes following the gliogenic switch. Timely regulation of the switch, operated by several transcription factors, is fundamental for allowing coordinated interactions between neurons and glia. We deleted the gene for one such factor, SOX9, early during mouse brain development and observed a significantly compromised dentate gyrus (DG). We dissected the origin of the defect, targeting embryonicSox9deletion to either the DG neuronal progenitor domain or the adjacent cortical hem (CH). We identified in the latter previously uncharacterized ALDH1L1+ astrocytic progenitors, which form a fimbrial-specific glial scaffold necessary for neuronal progenitor migration towards the developing DG. Our results highlight an early crucial role of SOX9 for DG development through regulation of astroglial potential acquisition in the CH. Moreover, we illustrate how formation of a local network, amidst astrocytic and neuronal progenitors originating from adjacent domains, underlays brain morphogenesis.
Light-dependent translation change of Arabidopsis psbA correlates with RNA structure alterations at the translation initiation region
Authors: Gawroński Piotr , Enroth Christel , Kindgren Peter , Marquardt Sebastian , Karpiński Stanisław , Leister Dario , Jensen Poul Erik , Vinther Jeppe , Scharff Lars B.
Published: June 2020

mRNA secondary structure influences translation. Proteins that modulate the mRNA secondary structure around the translation initiation region may regulate translation in plastids. To test this hypothesis, we exposed Arabidopsis thaliana to high light, which induces translation of psbA mRNA encoding the D1 subunit of photosystem II. We assayed translation by ribosome profiling and applied two complementary methods to analyze in vivo RNA secondary structure: DMS-MaPseq and SHAPE-seq. We detected increased accessibility of the translation initiation region of psbA after high light treatment, likely contributing to the observed increase in translation by facilitating translation initiation. Furthermore, we identified the footprint of a putative regulatory protein in the 5’ UTR of psbA at a position where occlusion of the nucleotide sequence would cause the structure of the translation initiation region to open up, thereby facilitating ribosome access. Moreover, we show that other plastid genes with weak Shine-Dalgarno sequences (SD) are likely to exhibit psbA-like regulation, while those with strong SDs do not. This supports the idea that changes in mRNA secondary structure might represent a general mechanism for translational regulation of psbA and other plastid genes.

SIGNIFICANCE

RNA structure changes in the translation initiation region, most likely as a result of protein binding, affect the translation of psbA and possibly other plastid genes with weak Shine-Dalgarno sequences.
Multiple linear regression allows weighted burden analysis of rare coding variants in an ethnically heterogeneous population
Authors: Curtis David
Published: June 2020

Weighted burden analysis has been used in exome-sequenced case-control studies to identify genes in which there is an excess of rare and/or functional variants associated with phenotype. Implementation in a ridge regression framework allows simultaneous analysis of all variants along with relevant covariates such as population principal components. In order to apply the approach to a quantitative phenotype, a weighted burden score is derived for each subject and included in a linear regression analysis. The weighting scheme is adjusted in order to apply differential weights to rare and very rare variants and a score is derived based on both the frequency and predicted effect of each variant. When applied to an ethnically heterogeneous dataset consisting of 49,790 exome-sequenced UK Biobank subjects and using BMI as the phenotype the method produces a very inflated test statistic. However this is almost completely corrected by including 20 population principal components as covariates. When this is done the top 30 genes include a few which are quite plausibly associated with the phenotype, includingLYPLAL1andNSDHL. This approach offers a way to carry out gene-based analyses of rare variants identified by exome sequencing in heterogeneous datasets without requiring that data from ethnic minority subjects be discarded. This research has been conducted using the UK Biobank Resource.
Bio-informed Protein Sequence Generation for Multi-class Virus Mutation Prediction
Authors: Wang Yuyang , Yadav Prakarsh , Magar Rishikesh , Farimani Amir Barati
Published: June 2020

Viral pandemics are emerging as a serious global threat to public health, like the recent outbreak of COVID-19. Viruses, especially those belonging to a large family of +ssRNA viruses, have a high possibility of mutating by inserting, deleting, or substituting one or multiple genome segments. It is of great importance for human health worldwide to predict the possible virus mutations, which can effectively avoid the potential second outbreak. In this work, we develop a GAN-based multi-class protein sequence generative model, named ProteinSeqGAN. Given the viral species, the generator is modeled on RNNs to predict the corresponding antigen epitope sequences synthesized by viral genomes. Additionally, a Graphical Protein Autoencoder (GProAE) built upon VAE is proposed to featurize proteins bioinformatically. GProAE, as a multi-class discriminator, also learns to evaluate the goodness of protein sequences and predict the corresponding viral species. Further experiments show that our ProteinSeqGAN model can generate valid antigen protein sequences from both bioinformatics and statistics perspectives, which can be promising predictions of virus mutations.
Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations
Authors: Ershova Anna S. , Eliseeva Irina A. , Nikonov Oleg S. , Fedorova Alla D. , Vorontsov Ilya E. , Papatsenko Dmitry , Kulakovskiy Ivan V.
Published: June 2020

Knowledge of mechanisms responsible for mutagenesis of adult stem cells is crucial to track genomic alterations that may affect cell renovation and provoke malignant cell transformation. Mutations in regulatory regions are widely studied nowadays, though mostly in cancer. In this study, we decomposed the mutation signature of adult stem cells, mapped the corresponding mutations into transcription factor binding regions, and assessed mutation frequency in sequence motif occurrences. We found binding sites of C/EBP transcription factors strongly enriched with [C>T]G mutations within the core CG dinucleotide related to deamination of the methylated cytosine. This effect was also exhibited in related cancer samples. Structural modeling predicted enhanced CEBPB binding to the consensus sequence with the [C>T]G mismatch, which was then confirmed in the direct experiment. We propose that it is the enhanced binding of C/EBPs that shields C>T transitions from DNA repair and leads to selective accumulation of the [C>T]G mutations within binding sites.
LRRC8A regulates hypotonicity-induced NLRP3 inflammasome activation
Authors: Green Jack P. , Swanton Tessa , Morris Lucy V. , El-Sharkawy Lina Y. , Cook James , Yu Shi , Beswick James , Adamson Antony , Humphreys Neil , Bryce Richard A. , Freeman Sally , Lawrence Catherine , Brough David
Published: June 2020

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered a therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown. Chloride efflux is suggested as an important step in NLRP3 activation, but the identity of which chloride channels are involved is still unknown. We used chemical, biochemical, and genetic approaches to establish the importance of Cl-channels in the regulation of NLRP3 activation. Specifically we identify LRRC8A, an essential component of volume-regulated anion channels (VRAC), as a vital regulator of hypotonicity-induced, but not DAMP-induced, NLRP3 inflammasome activation. Although LRRC8A was dispensable for canonical DAMP-dependent NLRP3 activation, this was still sensitive to Cl-channel inhibitors, suggesting there are additional and specific Cl-sensing and regulating mechanisms controlling NLRP3.
Artificial light at nigh drives early dawn chorus onset times of the Saffron Finch (Sicalis flaveola) in an Andean city
Authors: Marín Gómez Oscar Humberto
Published: June 2020

Urban birds around the world have to cope with dominant city stressors as anthropogenic noise and artificial light at night by adjusting the temporal and spectral traits of their acoustic signals. It is widely known that higher anthropogenic noise and artificial light levels can disrupt the morning singing routines, but its influence in tropical urban birds remains poorly explored. Here, I assessed the association between light and noise pollution with the dawn chorus onset of the Saffron Finch (Sicalis flaveola) in an Andean city of Colombia. I studied 32 urban sites distributed in the north of the city, which comprise different conditions of urban development based on the built cover. I annotated the time when the first individual of the Saffron Finch was heard at each site and then I obtained anthropogenic noise and artificial light at night measurements using a smartphone. Findings of this study show that Saffron Finches living in highly developed sites sang earlier at dawn than those occupying less urbanized sites. Unexpectedly this timing difference was related to artificial lighting instead of anthropogenic noise, suggesting that artificial light could drive earlier dawn chorus in a tropical urban bird. Saffron Finches could take advantage of earlier singing for signaling territorial ownership among neighbors, as expected by the social dynamic hypothesis. However, findings of this study should be interpreted carefully because the dawn chorus is a complex phenomenon influenced by many multiple factors. Future studies need to assess the influence of ALAN on the dawn chorus timing of Neotropical urban birds by taking into account the influence of confounding factors related to urbanization as well as meteorological, ecological, and social drivers.
Validation and performance of a quantitative IgG assay for the screening of SARS-CoV-2 antibodies
Authors: Espino Ana M. , Pantoja Petraleigh , Sariol Carlos A.
Published: June 2020

The current COVID-19 epidemic imposed an unpreceded challenge to the scientific community in terms of treatment, epidemiology, diagnosis, social interaction, fiscal policies and many other areas. The development of accurate and reliable diagnostic tools (high specificity and sensitivity) is crucial in the current period, the near future and in the long term. These assays should provide guidance to identify immune presumptive protected persons, potential plasma, and/or B cell donors and vaccine development among others. Also, such assays will be contributory in supporting prospective and retrospective studies to identify the prevalence and incidence of COVID-19 and to characterize the dynamics of the immune response. As of today, only thirteen serological assays have received the Emergency Use Authorization (EUA) by the U.S. Federal Drug Administration (FDA). In this work we describe the development and validation of a quantitative IgG enzyme-linked immunoassay (ELISA) using the recombinant SARS-CoV-2 Spike Protein S1 domain, containing the receptor-binding domain (RBD), showing 98% sensitivity, 98.9% specificity and positive and negative predictive values of 100% and 99.2%, respectively. The assay showed to be useful to test for SARS-CoV-2 IgG antibodies in plasma samples from COVID-19-recovered subjects as potential donors for plasmapheresis. This assay is currently under review by the Federal Drug Administration for an Emergency Use Authorization request (Submission Number EUA201115).
Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Saker channel
Authors: Silverå Ejneby Malin , Gromova Arina , Ottosson Nina E , Borg Stina , Estrada-Mondragón Argel , Yazdi Samira , Apostolakis Panagiotis , Elinder Fredrik , Delemotte Lucie
Published: June 2020

Voltage-gated potassium (KV) channels can be opened by negatively charged resin acids and their derivatives. These resin acids have been proposed to attract the positively charged voltage-sensor helix (S4) toward the extracellular side of the membrane by binding to a pocket located between the lipid-facing extracellular ends of the transmembrane segments S3 and S4. By contrast to this proposed mechanism, neutralization of the top gating charge of the Shaker KVchannel increased resin-acid induced opening, suggesting other mechanisms and sites of action. Here we explored the binding of two resin-acid derivatives, Wu50 and Wu161, to the activated/open state of the Shaker KVchannel by a combination of in-silico docking, molecular dynamics simulations, and electrophysiology of mutated channels. We identified three potential resin-acid binding sites around S4: (1) The S3/S4 site previously suggested, in which positively charged residues introduced at the top of S4 are critical to keep the compound bound, (2) a site in the cleft between S4 and the pore domain (S4/pore site), in which a tryptophan at the top of S6 and the top gating charge of S4 keeps the compound bound, and (3) a site located on the extracellular side of the voltage-sensor domain, in a cleft formed by S1-S4 (the top-VSD site). The multiple binding sites around S4 and the anticipated helical-screw motion of the helix during activation make the effect of resin-acid derivatives on channel function intricate. The propensity of a specific resin acid to activate and open a voltage-gated channel likely depends on its exact binding dynamics and the types of interactions it can form with the protein in a state-specific manner.

eTOC Summary

Silverå Ejneby et al use molecular dynamics simulations and electrophysiology to show that the voltage-gated Shaker potassium channel has multiple binding sites for resin-acid derivatives that can regulate its opening.