bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Nrp1 in controlling cortical interhemispheric circuits
Authors: Martín-Fernández F , Briz C. G. , Nieto M. 
Published: May 2021

AbstractCallosal projections establish topographically organized maps between cortical areas. Neuropilin-1 (Nrp1) cortical gradient induces an early segregation of developing callosal axons. We investigated later roles of Nrp1 on the development of callosal projections from layer (L) 2/3 of the primary (S1) and secondary (S2) somatosensory (SS) areas, which express higher and lower levels of Nrp1, respectively. We used in utero electroporation to knock down or overexpress Nrp1 combined with retrograde tracers, to map connections at postnatal day 16 and 30. High levels of Nrp1 blocked contralateral S2 innervation while promoted the late postnatal growth of homotopic S1L2/3 and heterotopic S2L2/3 branches into S1. Conversely, knocking down Nrp1 increased the growth of heterotopic S1L2/3 projections into S2, and the overall refinement of S2L2/3 branches, thereby diminishing the number of P30 S2L2/3 callosally projecting neurons. Thus, the Nrp1 gradient determines homotopic SSL2/3 callosal connectivity by regulating late postnatal branching and refinement in a topographic manner.
Vitrifying multiple embryos in different arrangements does not alter the cooling rate⋆
Authors: Ostler Timothy , Woolley Thomas E. , Swann Karl , Thomson Andrew , Priddle Helen , Palmer Giles , Kaouri Katerina 
Published: May 2021

AbstractVitrification is the most common method of cryopreservation of gametes in fertility clinics due to its improved survival rates compared to slow freezing techniques. For the Open Cryotop® vitrification device, the number of oocytes, or embryos, mounted onto a single device can vary.In this work, a mathematical model is developed for the cooling of oocytes and embryos (samples). The model is solved computationally, to investigate whether varying the number of samples mounted onto the Open Cryotop® affects the cooling rates, and consequently the survival rates, of vitrified samples. Several realistic spatial arrangements of samples are examined, determining their temperature over time. In this way we quantify the effect of spatial arrangement on the cooling rate.Our results indicate that neither the spatial arrangement nor the number of mounted samples has a large effect on cooling rates, so long as the volume of the cryoprotectant remains minimal. The time taken for cooling is found to be on the order of half a second, or less, regardless of the spatial arrangement or number of mounted samples. Hence, rapid cooling can be achieved for any number or arrangement of samples, as long as device manufacturer guidelines are adhered to.
Residue-specific insights into (2x)72 kDa tryptophan synthase obtained from fast-MAS 1H-detected solid-state NMR
Authors: Klein Alexander , Rovó Petra , Sakhrani Varun V. , Wang Yangyang , Holmes Jacob , Liu Viktoriia , Skowronek Patricia , Kukuk Laura , Vasa Suresh K. , Güntert Peter , Mueller Leonard J. , Linser Rasmus 
Published: May 2021

AbstractSolid-state NMR has emerged as a potent technique in structural biology, suitable for the study of fibrillar, micro-crystalline, and membrane proteins. Recent developments in fast-magic-angle-spinning and proton-detected methods have enabled detailed insights into structure and dynamics, but molecular-weight limitations for the asymmetric part of target proteins have remained at ~30-40 kDa. Here we employ solid-state NMR for atom-specific characterization of the 72 kDa (asymmetric unit) microcrystalline protein tryptophan synthase, an important target in pharmacology and biotechnology, chemical-shift assignments of which we obtain via higher-dimensionality, 4D and 5D solid-state NMR experiments. The assignments for the first time provide comprehensive data for assessment of side chain chemical properties involved in the catalytic turnover, and, in conjunction with first-principles calculations, precise determination of thermodynamic and kinetic parameters is demonstrated for the essential acid-base catalytic residue βK87. The insights provided by this study expand by nearly a factor of two the size limitations widely accepted for NMR today, demonstrating the applicability of solid-state NMR to systems that have been thought to be out of reach due to their complexity.
The amino acid substitution affects cellular response to mistranslation
Authors: Berg Matthew D. , Zhu Yanrui , Ruiz Bianca Y. , Loll-Krippleber Raphaël , Isaacson Joshua , Luis Bryan-Joseph San , Genereaux Julie , Boone Charles , Villén Judit , Brown Grant W. , Brandl Christopher J. 
Published: May 2021

ABSTRACTMistranslation, the mis-incorporation of an amino acid not specified by the “standard” genetic code, occurs in all organisms. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. Interestingly, human genomes contain tRNA variants with the potential to mistranslate. Cells cope with increased mistranslation through multiple mechanisms, though high levels cause proteotoxic stress. The goal of this study was to compare the genetic interactions and the impact on transcriptome and cellular growth of two tRNA variants that mistranslate at a similar frequency but create different amino acid substitutions inSaccharomyces cerevisiae.One tRNA variant inserts alanine at proline codons whereas the other inserts serine for arginine. Both tRNAs decreased growth rate, with the effect being greater for arginine to serine than for proline to alanine. The tRNA that substituted serine for arginine resulted in a heat shock response. In contrast, heat shock response was minimal for proline to alanine substitution. Further demonstrating the significance of the amino acid substitution, transcriptome analysis identified unique up- and downregulated genes in response to each mistranslating tRNA. Number and extent of negative synthetic genetic interactions also differed depending upon type of mistranslation. Based on the unique responses observed for these mistranslating tRNAs, we predict that the potential of mistranslation to exacerbate diseases caused by proteotoxic stress depends on the tRNA variant. Furthermore, based on their unique transcriptomes and genetic interactions, different naturally occurring mistranslating tRNAs have the potential to negatively influence specific diseases.
Phenotypic distribution and selection response for linear-product gene-environment interaction in quantitative traits
Authors: Smith Reginald D. 
Published: May 2021

AbstractGene-environment interaction is often described by linear phenotypic plasticity but has recently also been expressed as function of the product of genotype and environmental variables. While this model can be fitted in a multiple regression scenario, little has been written on the distribution of the product of breeding values and environment, GE, its expected moments, and the theoretical impact on phenotypic selection. Here we will explore these topics introducing the distribution for GE, its mean and variance, and its expected impact of lowering realized heritability due to is increasing the phenotypic variance.
Assessing antibiotic tolerance ofStaphylococcus aureusderived directly from patients by the Replica Plating Tolerance Isolation System - REPTIS
Authors: Herren Sebastian C. , Huemer Markus , Acevedo Claudio T. , Andreoni Federica , Gómez-Mejia Alejandro , Shambat Srikanth Mairpady , Hasse Barbara , Zbinden Reinhard , Brugger Silvio D. , Zinkernagel Annelies S. 
Published: May 2021

AbstractAntibiotic tolerantStaphylococcus aureuspose a great challenge to clinicians as well as to microbiological laboratories and are one reason for treatment failure. Antibiotic tolerant strains survive transient antibiotic exposure despite being fully susceptiblein vitro. Thus, fast and reliable methods to detect tolerance in the routine microbiology laboratory are urgently required.We therefore evaluated the feasibility of the replica plating tolerance isolation system (REPTIS) to detect antibiotic tolerance inS. aureusisolates derived directly from patients suffering from different types of infections and investigated possible connections to clinical presentations and patient characteristics.One hundred twenty-fiveS. aureusisolates were included. Replica plating of the original resistance testing plate was used to assess regrowth in the zones of inhibition, indicating antibiotic tolerance. Bacterial regrowth was assessed after 24 and 48 hours of incubation and an overall regrowth score (ORS) was assigned. Regrowth scores were compared to the clinical presentation.Bacterial regrowth was high for most antibiotics targeting protein synthesis and relatively low for antibiotics targeting other cellular functions such as DNA-replication, transcription and cell wall synthesis, with the exception of rifampicin. Isolates with a blaZ penicillinase had lower regrowth in penicillin and ampicillin. Low ORSs were more prevalent among isolates recovered from patients with immunosuppression or methicillin-resistantS. aureus(MRSA) isolates.In conclusion, REPTIS is useful to detect antibiotic tolerance in clinical microbiological routine diagnostics. Rapid detection of antibiotic tolerance offers a new diagnostic readout that might allow more tailored treatments in the future.
Occupation, Work-Related Contact, and SARS-CoV-2 Anti-Nucleocapsid Serological Status: Findings from the Virus Watch prospective cohort study
Authors: Beale Sarah , Patel Parth , Rodger Alison , Braithwaite Isobel , Byrne Thomas , Erica Fong Wing Lam , Fragaszy Ellen , Geismar Cyril , Kovar Jana , Navaratnam Annalan MD , Nguyen Vincent , Shrotri Madhumita , Aldridge Robert W , Hayward Andrew C 
Published: May 2021

AbstractBackgroundWorkers differ in their risk of acquiring SARS-CoV-2 infection according to their occupation; however, few studies have been able to control for multiple confounders or investigate the work-related factors that drive differences in occupational risk. Using data from the Virus Watch community cohort study in England and Wales, we set out to estimate the total effect of occupation on SARS-CoV-2 serological status, whether this is mediated by frequency of close contact within the workplace, and how exposure to poorly ventilated workplaces varied across occupations.MethodsWe used data from a sub-cohort (n =3761) of adults (≥18) tested for SARS-CoV-2 anti-nucleocapsid antibodies between 01 February-28 April 2021 and responded to a questionnaire about work during the pandemic. Anti-nucleocapsid antibodies were used as a proxy of prior natural infection with COVID-19. We used logistic decomposition to estimate the total and direct effect of occupation and indirect effect of workplace contact frequency on odds of seropositivity, adjusting for age, sex, household income and region. We investigated the relationship between occupation and exposure to poorly-ventilated workplace environments using ordinal logistic regression.ResultsSeropositivity was 16.0% (113/707) amongst workers with daily close contact, compared to 12.9% (120/933) for those with intermediate-frequency contact and 9.6% (203/2121) for those with no work-related close contact. Healthcare (OR= 2.14, 95% CI 1.47,3.12), indoor trade, process and plant (2.09, 1.31,3.33), leisure and personal service (1.96, 1.004,3.84), and transport and mobile machine (2.17, 1.12,4.18) workers had elevated total odds of SARS-CoV-2 seropositivity compared to other professional and associate occupations. Frequency of workplace contact accounted for a variable part of the increased odds in different occupational groups (OR range 1.04 [1.0004,1.07] - 1.22 [1.07, 1.38]). Healthcare workers and indoor trades and process plant workers continued to have raised odds of infection after accounting for work-related contact, and also had had greater odds of frequent exposure to poorly-ventilated workplaces (respectively 2.15 [1.66, 2.79] and (1.51, [1.12, 2.04]).DiscussionMarked variations in occupational odds of seropositivity remain after accounting for age, sex, region, and household income. Close contact in the workplace appears to contribute substantially to this variation. Reducing frequency of workplace contact is a critical part of COVID-19 control measures.
The cyclic dinucleotide 2’3’-cGAMP induces a broad anti-bacterial and anti-viral response in the sea anemone Nematostella vectensis
Authors: Margolis Shally R. , Dietzen Peter A. , Hayes Beth M. , Wilson Stephen C. , Remick Brenna C. , Chou Seemay , Vance Russell E. 
Published: May 2021

AbstractIn mammals, cyclic dinucleotides (CDNs) bind and activate STING to initiate an anti-viral type I interferon response. CDNs and STING originated in bacteria and are present in most animals. By contrast, interferons are believed to have emerged in vertebrates; thus, the function of CDN signaling in invertebrates is unclear. Here, we use a CDN, 2’3’-cGAMP, to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA-Seq, we found that 2’3’-cGAMP induces robust transcription of both anti-viral and anti-bacterial genes in N. vectensis. Many of the anti-viral genes induced by 2’3’-cGAMP are homologs of vertebrate interferon stimulated genes, implying that the interferon response predates the evolution of interferons. Knockdown experiments identified a role for NF-κB in specifically inducing anti-bacterial genes downstream of 2’3’-cGAMP. Some of these putative anti-bacterial genes were also found to be induced during Pseudomonas aeruginosa infection. We characterized the protein product of one of the putative anti-bacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved anti-bacterial activity. This work suggests that a broad anti-bacterial and anti-viral transcriptional response is an evolutionarily ancestral output of 2’3’-cGAMP signaling in animals.Significance statementCyclic dinucleotides are signaling molecules that originated in bacteria and were subsequently acquired and co-opted by animals for immune signaling. The major cyclic dinucleotide signaling pathway in mammals results in the production of anti-viral molecules called interferons. Invertebrates such as sea anemones lack interferons, and thus it was unclear whether cyclic dinucleotide signaling would play a role in immunity in these animals. Here we report that in the anemone Nematostella vectensis, cyclic dinucleotides activate both anti-viral and anti-bacterial immune responses, and do so through a conserved pathway. These results provide insights into the evolutionary origins of innate immunity, and suggest a broader ancestral role for cyclic dinucleotide signaling that evolved toward more specialized anti-viral functions in mammals.
High-Efficiency Pharmacogenetic Ablation of Oligodendrocyte Progenitor Cells in the Adult Mouse CNS
Authors: Xing Yao Lulu , Poh Jasmine , Chuang Bernard H.A. , Moradi Kaveh , Mitew Stanislaw , Richardson William D. , Kilpatrick Trevor J. , Osanai Yasuyuki , Merson Tobias D. 
Published: May 2021

AbstractApproaches to investigate adult oligodendrocyte progenitor cells (OPCs) by targeted cell ablation in the rodent central nervous system have been limited by methodological challenges resulting in only partial and transient OPC depletion. We have developed a novel pharmacogenetic model of conditional OPC ablation, eliminating 98.6% of all OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and ventricular-subventricular zone (V-SVZ)-derived neural precursor cells (NPCs), we found new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+NG2+cells with the capacity to migrate and proliferate extensively throughout the dorsal anterior forebrain. Further application of this novel approach to ablate OPCs will advance knowledge of the function of both OPCs and oligodendrogenic NPCs in health and disease.
Host transcriptional response to SARS-CoV-2 infection in COVID-19 patients
Authors: Singh Nitesh Kumar , Srivastava Surabhi , Zaveri Lamuk , Bingi Thrilok Chander , Mesipogu Rajarao , Kumar Santosh , Gaur Namami , Hajirnis Nikhil , Maccha Pratheusa , Shambhavi Sakshi , Khan Shagufta , Soujanya Mamilla , Nagabandi Tulasi , Mishra Rakesh K. , Tallapaka Karthik Bharadwaj , Sowpati Divya Tej 
Published: May 2021

ABSTRACTBackgroundOne of the most perplexing aspects of infection with the SARS-CoV-2 virus has been the variable response elicited in its human hosts. Investigating the transcriptional changes in individuals affected by COVID-19 can help understand and predict the degree of illness and guide clinical outcomes in diverse backgrounds.MethodsAnalysis of host transcriptome variations via RNA sequencing from naso/oropharyngeal swabs of COVID-19 patients.ResultsWe report strong upregulation of the innate immune response, especially type I interferon pathway, upon SARS-CoV-2 infection. Upregulated genes were subjected to a comparative meta-analysis using global datasets to identify a common network of interferon stimulated and viral response genes that mediate the host response and resolution of infection. A large proportion of mis-regulated genes showed a reduction in expression level, suggesting an overall decrease in host mRNA production. Significantly downregulated genes included those encoding olfactory, taste and neuro-sensory receptors. Many pro-inflammatory markers and cytokines were also downregulated or remained unchanged in the COVID-19 patients. Finally, a large number of non-coding RNAs were identified as down-regulated, with a few of the lncRNAs associated with functional roles in directing the response to viral infection.ConclusionsSARS-CoV-2 infection results in the robust activation of the body’s innate immunity. Reduction of gene expression is well correlated with the clinical manifestations and symptoms of COVID-19 such as the loss of smell and taste, and myocardial and neurological complications. This study provides a critical dataset of genes that will enhance our understanding of the nature and prognosis of COVID-19.
Altered cerebellar response to somatosensory stimuli in the Cntnap2 mouse model of autism
Authors: Fernández Marta , Sánchez-León Carlos A. , Llorente Javier , Sierra-Arregui Teresa , Knafo Shira , Márquez-Ruiz Javier , Peñagarikano Olga 
Published: May 2021

AbstractAtypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied cerebellar integration of sensory information in a mouse model of autism, knockout for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice and found striking differences between WT and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These changes were accompanied by altered intrinsic properties and morphological features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of ASD core sensory deficits.
A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart
Authors: Ranea-Robles Pablo , Pavlova Natalya N. , Bender Aaron , Pereyra Andrea S. , Ellis Jessica M. , Stauffer Brandon , Yu Chunli , Thompson Craig B. , Argmann Carmen , Puchowicz Michelle , Houten Sander M. 
Published: May 2021

AbstractThe heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. Cardiomyopathy and arrhythmias can be severe complications in patients with inherited defects in mitochondrial long-chain FAO, reinforcing the importance of FAO for cardiac health. However, the pathophysiological mechanisms that underlie the cardiac abnormalities in long-chain FAO disorders remain largely unknown. Here, we investigated the cardiac transcriptional adaptations to the FAO defect in the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse. We found a prominent activation of the integrated stress response (ISR) mediated by the eIF2α/ATF4 axis in both fed and fasted states, accompanied by a reduction in cardiac protein synthesis during a short period of food withdrawal. Notably, we found an accumulation of uncharged tRNAs in LCAD KO hearts, consistent with a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the cardiac ISR in hearts of mice with a muscle-specific deletion of carnitine palmitoyltransferase 2 deletion (Cpt2M-/-). Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact cardiac metabolic signaling, in particular the ISR, and may play a role in the associated cardiac pathology.
The First High-Quality Reference Genome of Sika Deer Provides Insights for High-Tannin Adaptation
Authors: Xing Xiumei , Ai Cheng , Wang Tianjiao , Li Yang , Liu Huitao , Hu Pengfei , Wang Guiwu , Liu Huamiao , Wang Hongliang , Zhang Ranran , Zheng Junjun , Wang Xiaobo , Wang Lei , Chang Yuxiao , Qian Qian , Yu Jinghua , Tang Lixin , Wu Shigang , Shao Xiujuan , Li Alun , Cui Peng , Zhan Wei , Zhao Sheng , Wu Zhichao , Shao Xiqun , Dong Yimeng , Rong Min , Tan Yihong , Cui Xuezhe , Chang Shuzhuo , Song Xingchao , Yang Tongao , Sun Limin , Ju Yan , Zhao Pei , Fan Huanhuan , Liu Ying , Wang Xinhui , Yang Wanyun , Yang Min , Wei Tao , Song Shanshan , Xu Jiaping , Yue Zhigang , Liang Qiqi , Li Chunyi , Ruan Jue , Yang Fuhe 
Published: May 2021

AbstractSika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement in the elucidation of the genomics of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of UGT genes in a subfamily. The first chromosome-level assembly and genetic characterization of the tolerance toa highly toxic diet suggest that the sika deer genome will serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.