bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional and Pharmacological Evaluation of a NovelSCN2AVariant Linked to Early-onset Epilepsy
Authors: Adney Scott K. , Millichap John J. , DeKeyser Jean-Marc , Abramova Tatiana , Thompson Christopher H. , George Alfred L. 
Published: April 2020

ABSTRACTObjectiveWe identified a novelde novo SCN2Avariant (M1879T) associated with infantile-onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response.MethodsThe clinical and genetic features of an infant boy with epilepsy are presented. We investigated the effect of the variant using heterologously expressed recombinant human NaV1.2 channels. We performed whole-cell patch clamp recording to determine the functional consequences and response to carbamazepine.ResultsThe M1879T variant caused disturbances in channel inactivation including substantially depolarized voltage-dependence of inactivation, slower time course of inactivation, and enhanced resurgent current that collectively represent a gain-of-function. Carbamazepine partially normalized the voltage-dependence of inactivation and produced use-dependent block of the variant channel at high pulsing frequencies. Carbamazepine also suppresses resurgent current conducted by M1879T channels, but this effect was explained primarily by reducing the peak transient current. Molecular modeling suggests that the M1879T variant disrupts contacts with nearby residues in the C-terminal domain of the channel.InterpretationOur study demonstrates the value of conducting functional analyses ofSCN2Avariants of unknown significance to establish pathogenicity and genotype-phenotype correlations. We also show concordance ofin vitropharmacology using heterologous cells with the drug response observed clinically in a case of SCN2A-associated epilepsy.
The importance of the immunodominant CD8+ T cell epitope ofPlasmodium bergheicircumsporozoite protein in parasite- and vaccine-induced protection
Authors: Gibbins Matthew P. , Müller Katja , Glover Maya , Liu Jasmine , Putrianti Elyzana D. , Bauza Karolis , Reyes-Sandoval Arturo , Matuschewski Kai , Silvie Olivier , Hafalla Julius Clemence R. 
Published: April 2020

ABSTRACTThe circumsporozoite protein (CSP) builds up the surface coat of sporozoites and is the leading malaria pre-erythrocytic-stage vaccine candidate. CSP has been shown to induce robust CD8+ T cell responses that are capable of eliminating developing parasites in hepatocytes resulting in protective immunity. In this study, we characterised the importance of the immunodominant CSP-derived epitope, SYIPSAEKI, ofPlasmodium bergheiin both sporozoite- and vaccine-induced protection in murine infection models. In BALB/c mice, where SYIPSAEKI is efficiently presented in the context of the major histocompatibility complex class I (MHC-I) molecule H-2-Kd, we established that epitope-specific CD8+ T cell responses contribute to parasite killing following sporozoite immunisation. Yet, sterile protection was achieved in the absence of this epitope substantiating the concept that other antigens can be sufficient for parasite-induced protective immunity. Furthermore, we demonstrated that SYIPSAEKI-specific CD8+ T cell responses elicited by viral-vectored CSP-expressing vaccines effectively targeted parasites in hepatocytes. The resulting sterile protection strictly relied on the expression of SYIPSAEKI. In C57BL/6 mice, which are unable to present the immunodominant epitope, CSP-based vaccines did not confer complete protection, despite the induction of high levels of CSP-specific antibodies. These findings underscore the significance of CSP in protection against malaria pre-erythrocytic stages and demonstrate that a significant proportion of the protection against the parasite is mediated by CD8+ T cells specific for the immunodominant CSP-derived epitope.
Factors required for adhesion ofSalmonella entericaserovar Typhimurium to lettuce (Lactuca sativa)
Authors: Elpers Laura , Hensel Michael 
Published: April 2020

AbstractSalmonella entericaserovar Typhimurium (STM) is a major cause of food-borne gastroenteritis. Recent outbreaks of infections by STM are often associated with non-animal related food, i.e. vegetables, fruits, herbs, sprouts and nuts. One main problem related to consumption of fresh produce is the minimal processing, especially for leafy salads such as corn salad, rocket salad, or lettuce. In this study, we focused on lettuce (Lactuca sativa) which is contaminated by STM at higher rates compared to corn salad, resulting in prolonged persistence. We previously described the contribution of Saf fimbriae, type 1 secretion system (T1SS)-secreted BapA, intact LPS, and flagella-mediated motility to adhesion to corn salad leaves. We systematically analyzed factors contributing to adhesion of STM to lettuce leaves. We used the previously established reductionist, synthetic approach to identify factors that contribute to the surface binding of STM to leaves of lettuce by expressing all known adhesive structure by the Tet-on system. The analyses revealed contributions of Lpf fimbriae, Sti fimbriae, autotransported adhesin MisL, T1SS-secreted BapA, intact LPS, and flagella-mediated motility to adhesion of STM to lettuce leaves. In addition, we identified BapA is a potential adhesin involved in binding to corn salad and lettuce leaf surfaces.ImportanceGastrointestinal pathogens can be transmitted by animal products, as well as by fresh produce of non-animal origin. The numbers of outbreaks by fresh produce contaminated with gastrointestinal pathogens are increasing, and underline the relevance to human health. The mechanisms involved in the colonization of, persistence on, and transmission by fresh produce are poorly understood and have to be part of further research. Here, we investigated the contribution of adhesive factors of STM in the initial phase of plant colonization, i.e. the binding to the plant surface. Usage of a reductionist, synthetic approach including the controlled surface expression of specific adhesive structures of STM, one at a time, allowed the determination of relevant fimbrial and non-fimbrial adhesins, the O-antigen of lipopolysaccharide, the flagella, and chemotaxis to binding to lettuce leaves.
No indications for overt innate immune suppression in critically ill COVID-19 patients
Authors: Kox Matthijs , Frenzel Tim , Schouten Jeroen , van de Veerdonk Frank L. , Koenen Hans J.P.M. , Pickkers Peter 
Published: April 2020

AbstractAt the end of March 2020, there were in excess of 800.000 confirmed cases of coronavirus disease 2019 (COVID-19) worldwide. Several reports suggest that, in severe cases, COVID-19 may cause a hyperinflammatory “cytokine storm”. However, unlike SARS-CoV infection, high levels of anti-inflammatory mediators have also been reported in COVID-19 patients. One study reported that 16% of COVID-19 patients who died developed secondary infection, which might indicate an immune-suppressed state. We explored kinetics of mHLA-DR expression, the most widely used marker of innate immune suppression in critically ill patients, in COVID-19 patients admitted to the ICU.Twenty-four confirmed COVID-19 patients were included, of which 75% was male and 79% had comorbidities. All patients were mechanically ventilated and exhibited large high levels of inflammatory parameters such as CRP and PCT. mHLA-DR expression levels were mostly within the normal range of 15000-45000 mAb/cell and showed no change over time. COVID-19 patients displayed notably higher mHLA-DR expression levels compared with bacterial septic shock patients. None of the COVID-19 patients developed a secondary infection.In conclusion, despite a pronounced inflammatory response, mHLA-DR expression kinetics indicate no overt innate immune suppression in COVID-19 patients. These data signify that innate immune suppression as a negative feedback mechanism following PAMP-induced inflammation appears not to be present in COVID-19.
Polygenic score for body mass index is associated with disordered eating in a general population cohort
Authors: Abdulkadir Mohamed , Herle Moritz , De Stavola Bianca , Hübel Christopher , Ferreira Diana Santos , Loos Ruth J F , Bryant-Waugh Rachel , Bulik Cynthia M. , Micali Nadia 
Published: April 2020

AbstractBackgroundDisordered eating (DE) is common and is associated with body mass index (BMI). We aimed to investigate if genetic variants for BMI were associated with DE.MethodsBMI polygenic scores (PGS) were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; N= 8,654) and their association with DE tested. Data on DE behaviors (e.g. binge eating, and compensatory behaviors) were collected at ages 14, 16, 18 years, and DE cognitions (e.g. body dissatisfaction) at 14 years. Mediation analyses determined whether BMI mediated the association between the BMI-PGS and DE.ResultsThe BMI-PGS was positively associated with fasting (OR= 1.42, 95% CI=1.25, 1.61), binge eating (OR=1.28, 95% CI= 1.12, 1.46), purging (OR= 1.20, 95% CI= 1.02, 1.42), body dissatisfaction (Beta= 0.99, 95% CI= 0.77, 1.22), restrained eating (Beta=0.14, 95% CI= 0.10, 1.17), emotional eating (Beta= 0.21, 95% CI= 0.052, 0.38), and negatively associated with thin ideal internalization (Beta= −0.15, 95% CI= −0.23, −0.07) and external eating (Beta= −0.19, 95% CI= −0.30, −0.09). These associations were mainly mediated by BMI.ConclusionsGenetic variants associated with BMI are also associated with DE. This association was mediated through BMI suggesting that weight potentially sits on the pathway from genetic liability to DE.
Risk of aortic aneurysm in patients with psoriasis: a systematic review and meta-analysis
Authors: Yu Xinyu , Feng Xin , Xia Liangtao , Cao Shiyi , Wei Xiang 
Published: April 2020

AbstractObjectivePsoriasis is a chronic inflammatory disease that may play a role in the pathogenesis of atherosclerotic vascular diseases. We conducted this systematic review to investigate the association between psoriasis and the risk of aortic aneurysm.MethodsPubmed, Embase, and Scopus were searched up to July 20, 2019. We included cohort studies if they reported estimate effects assessing the association between having psoriasis and aortic aneurysm. We used Newcastle-Ottawa Scale to evaluate methodology quality of eligible studies. Random-effect meta-analyses were used to pool individual estimates. Subgroup analyses were conducted to find heterogeneity source.ResultsAfter a view of 2207 citations, we included three large cohort studies enrolling 5,706,525 participants in this systematic review. Psoriasis patients have an increased risk of development of aortic aneurysm (hazard ratio [HR]: 1.30, 95%confidence intervals [CI], 1.10 to 1.55,I2= 53.1%). However, the risk of AA was not significantly increased in female psoriasis patients (HR, 1.55, 95%CI, 0.65 to 3.72), patients with hypertension (HR, 1.44, 95%CI, 0.85 to 2.42), patients with hyperlipidemia (HR, 1.69, 95%CI, 1.15 to 2.48) and patients with diabetes (HR, 1.15, 95%CI 0.46 to 2.87).ConclusionsCurrent evidence from observational studies suggests that psoriasis may increase the risk of aortic aneurysm, and screening of aortic aneurysm might be considered among psoriasis patients.Key questionsWhat is already known on this subject?Patients with psoriasis have an increased prevalence of cardiovascular diseases, including ischemic heart disease, heart failure, peripheral vascular disease and stroke. The increased risk of cardiovascular events is believed to be associated with the systematic inflammatory pathophysiological mechanisms of psoriasis.What might this study add?This systematic review and meta-analysis summarized epidemiological evidence investigating the relationship between psoriasis and aortic aneurysm, and we found psoriasis patients have an increased risk of aortic aneurysm.How might this impact on clinical practice?Screening for aortic aneurysm could be conducted among psoriasis patients, and the anti-inflammatory therapy may be helpful for the treatment of aortic aneurysm.
Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
Authors: Fintelman-Rodrigues Natalia , Sacramento Carolina Q. , Lima Carlyle Ribeiro , da Silva Franklin Souza , Ferreira André C. , Mattos Mayara , de Freitas Caroline S. , Soares Vinicius Cardoso , Gomes Dias Suelen da Silva , Temerozo Jairo R. , Miranda Milene , Matos Aline R. , Bozza Fernando A. , Carels Nicolas , Alves Carlos Roberto , Siqueira Marilda M. , Bozza Patrícia T. , Souza Thiago Moreno L. 
Published: April 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors, such as atazanavir (ATV). ATV is of high interest because of its bioavailability within the respiratory tract. Our results show that ATV could dock in the active site of SARS-CoV-2 Mpro, with greater strength than LPV. ATV blocked Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells, human pulmonary epithelial cell line and primary monocytes, impairing virus-induced enhancement of IL-6 and TNF-α levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.
Orthogonal fluorescent chemogenetic reporters for multicolor imaging
Authors: Tebo Alison G. , Moeyaert Benjamien , Thauvin Marion , Carlon-Andres Irene , Böken Dorothea , Volovitch Michel , Padilla-Parra Sergi , Dedecker Peter , Vriz Sophie , Gautier Arnaud 
Published: April 2020

AbstractFluorescence microscopy is an indispensable tool in biological research, allowing sub-second and sub-micrometer mapping of molecules or processes inside living cells. Moreover, using spectrally separated fluorophores, one can observe multiple targets simultaneously, leading to a deeper understanding of the dynamic molecular interplays that regulate cell function and fate. Chemogenetic systems, which combine a protein tag and a synthetic fluorophore, provide certain advantages over fluorescent proteins since there is no requirement for chromophore maturation. However, the fluorophore promiscuity of chemogenetic systems renders two-color applications challenging. Here, we present the engineering of a set of spectrally orthogonal fluorogen activating tags based on the Fluorescence Activating and absorption Shifting Tag (FAST), that are compatible with two-color, live cell imaging. The resulting tags, greenFAST and redFAST, demonstrate orthogonality not only in their fluorogen recognition capabilities, but also in their one- and two-photon absorption profiles. A two-color cell cycle sensor based on greenFAST and redFAST is capable of detecting very short, early cell cycles in zebrafish development which had previously been difficult to image. Furthermore, this pair of orthogonal tags can be developed into split complementation systems that are capable of detecting multiple protein-protein interactions by live cell fluorescence microscopy.
Community assembly as a basis for tropical forest restoration in a global change scenario
Authors: Meira-Neto João Augusto Alves , de Oliveira-Júnior Neil Damas , Silva Nathália , de Oliveira-Filho Ary Teixeira , Bueno Marcelo Leandro , Pontara Vanessa , Gastauer Markus 
Published: April 2020

AbstractNative tropical forests hold high levels of diversity, challenging forest restoration of large areas in a global change scenario. For a site-specific restoration is required the understanding of the main influences ruling the assemblages. We aimed to answer three questions. 1) how do environmental variables influence taxonomic, phylogenetic diversities, and the phylogenetic structure in the of Rio Doce Basin (TFRD)? 2) How do environmental variables, phylogenetic structure and the main types of seed dispersal relate to each other? 3) Which information of the TFRD assemblages can be used for ecological restoration and conservation? We used 78 sites with their checklists to calculate taxonomic, and phylogenetic diversities, phylogenetic structures, and dispersal proportions. Then, we related the diversities of the sites to their bioclimatic variables and built GLM models. Species richness was influenced negatively by water excess duration, by water deficit duration, and positively by maximum temperature, and temperature seasonality. Water regime drives diversity and phylogenetic community structure in the TFRD more than other variables. Annual precipitation and maximum temperature presented the clearer influences on diversity and phylogenetic structure. Zoochory was positively, and anemochory, autochory were negatively related to sesMPD. By choosing the lineages with high fitness for each site, the functioning and the stability of ecosystems should increase. The addition of species with anemochory and autochory increases functional and phylogenetic diversity in areas with extreme water excess or water deficit, important in a global change scenario. A high proportion of zoochory allows the communities to function conserving dispersers, biodiversity, and services.Implications for practiceThe use of objective methods based on community assembly rules enhances the choice of species, and of phylogenetic lineages better fitted to the bioclimatic profiles of the areas to be restored, improving the functioning and stability of the restored forests.The water purification service should be improved through forest restoration as much as possible because ecosystem services and biodiversity conservation are co-benefits of restored forests.The inclusion of species with anemochory, and autochory in forest restoration practices should become usual, as they increase functional, and phylogenetic diversities, and as a consequence, the ecosystem stability.A large proportion of species with zoochory in restored forests co-benefits taxonomic diversity, phylogenetic diversity, and ecosystem stability.
Molecular Basis of Maintaining Circannual Rhythm in the Skin of Cashmere Goat
Authors: Wu Jianghong , li Ying , Gong Husile , Wu Dubala , li Chun , Liu Bin , Ding Lizhong 
Published: April 2020

AbstractThe cashmere goat (Capra hircus) is famous for the fine quality cashmere wool. The cashmere is produced by secondary hair follicle that the growth shows seasonal rhythm. Thus, in this study, the skin of cashmere goat was selected as a model to illustrate the circannual rhythm of skin. The whole length skin transcriptome mixed from selected four months was obtained by PacBio single-molecule long-read sequencing (SMRT) technology. We generated 82,382 high quality non-redundant transcripts belonging to 193,310 genes, including 4,237 novel genes. Other 39 skin transcriptomes sampled from Dec. 2014 to Dec. 2015 were sequenced by Illumina Hi-Seq2500, we found 980 genes were differentially expressed. Of these genes, 403 seasonal rhythm genes (SRGs) were expressed and exhibited a seasonal pattern in skin. The results also showed that miRNAs were differentially expressed as the daylight length changed throughout a year. Some SRG genes related to the hormone secretion and eyes morphogenesis were enriched in skin. These genes gradually increased their expression level under short light, reached the peak near the summer solstice, and then began to decline. We found that the expression of Dio1 gene may be affected by the photoperiod that induces transformation from the inactive T4 to active thyroid hormone T3 in the skin and led to the difference between the skin circannual rhythm and the core circannual rhythm. Furthermore, the skin expressed eye morphogenesis-related genes and miRNAs, which suggested some cells in the skin could have the potential of light sensitivity. These results revealed that SRGs could regulate the downstream gene expression and physiological process in the skin to adapt to the season change.
Neural circuit mechanisms for steering control in walkingDrosophila
Authors: Rayshubskiy Aleksandr , Holtz Stephen L. , Bates Alexander , Vanderbeck Quinn X. , Capdevila Laia Serratosa , Wilson Rachel I. 
Published: April 2020

AbstractOrienting behaviors provide a continuous stream of information about an organism’s sensory experiences and plans. Thus, to study the links between sensation and action, it is useful to identify the neurons in the brain that control orienting behaviors. Here we describe descending neurons in theDrosophilabrain that predict and influence orientation (heading) during walking. We show that these cells have specialized functions: whereas one cell type predicts sustained low-gain steering, the other predicts transient high-gain steering. These latter cells integrate internally-directed steering signals from the head direction system with stimulus-directed steering signals from multimodal sensory pathways. The inputs to these cells are organized to produce “see-saw” steering commands, so that increasing output from one brain hemisphere is accompanied by decreasing output from the other hemisphere. Together, our results show that internal and external drives are integrated to produce descending motor commands with different timescales, for flexible and precise control of an organism’s orientation in space.
Machine Classification of Methylomes in Cancer
Authors: Newsham Isabelle , Sendera Marcin , Jammula SriGanesh , Fitzgerald Rebecca , Massie Charles , Samarajiwa Shamith A. 
Published: April 2020

AbstractCancer remains a leading cause of morbidity and mortality worldwide. Its evolutionary nature and resultant complex interactions with the tumour micro-environment and the host immune system engender heterogeneity, make developing interventions difficult. Usually detected at the advanced stages of disease, metastatic cancer accounts for 90% of cancer-associated deaths. Therefore early detection of cancer, combined with current therapies, would have a significant impact on survival and treatment of this insidious disease. Epigenetic changes such as DNA methylation are some of the early events in carcinogenesis. Here, we report on a machine learning model that can classify 13 types of cancer as well as non-cancer tissue samples using only DNA methylome data, with an accuracy of 98.2%. We utilise the features identified by this model to develop a robust deep neural network that can generalise to independent data sets. We also demonstrate that the methylation associated genomic loci detected by the classifier are associated with genes involved in cancer, providing insights into the epigenomic regulation of carcinogenesis.