bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tornadic shear stress induces a transient, calcineurin-dependent hyper-virulent phenotype in Mucorales molds
Authors: Wurster Sebastian , Tatara Alexander M. , Albert Nathaniel D. , Ibrahim Ashraf S. , Heitman Joseph , Lee Soo Chan , Shetty Amol C. , McCracken Carrie , Graf Karen T. , Mikos Antonios G. , Bruno Vincent M. , Kontoyiannis Dimitrios P. 
Published: February 2020

AbstractTrauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in victims of combat-related injuries, geo-meteorological disasters, and severe burns. Inspired by the observation that several recent clusters of NMM have been associated with extreme mechanical forces (e.g. during tornados), we studied the impact of mechanical stress on Mucoralean biology and virulence in aDrosophila melanogasterinfection model. In contrast to other experimental procedures to exert mechanical stress, tornadic shear challenge (TSC) by magnetic stirring induced a hyper-virulent phenotype in several clinically relevant Mucorales species but not inAspergillusorFusarium. Whereas fungal growth rates, morphogenesis, and susceptibility to noxious environments or phagocytes were not altered by TSC, soluble factors released in the supernatant of shear-challengedR. arrhizusspores rendered static spores hyper-virulent. Consistent with a rapid decay of TSC-induced hyper-virulence, minimal transcriptional changes were revealed by comparative RNA sequencing analysis of static and shear-challengedRhizopus arrhizus. However, inhibition of the calcineurin/heat shock protein 90 (hsp90) stress response circuitry by cyclosporine A (CsA) and tanespimycin abrogated the increased pathogenicity ofR. arrhizusspores following TSC. Similarly, calcineurin loss-of-function mutants ofMucor circinelloidesdisplayed no increased virulence capacity in flies after undergoing TSC. Collectively, these results establish that TSC induces hyper-virulence specifically in Mucorales and point out the calcineurin/hsp90 pathway as a key orchestrator of this phenotype. Our findings invite future studies of topical calcineurin inhibitor treatment of wounds as an adjunct mitigation strategy for NMM following high-energy trauma.SignificanceGiven the limited efficacy of current medical treatments in trauma-related necrotizing mucormycosis, there is a dire need to better understand the Mucoralean pathophysiology in order to develop novel strategies to counteract fungal tissue invasion following severe trauma. Here, we describe that tornadic shear stress challenge transiently induces a hyper-virulent phenotype in various pathogenic Mucorales species but not in other molds known to cause wound infections. Our data support a model whereby shear stress-induced hyper-virulence is primarily driven by soluble factors and orchestrated by the calcineurin/hsp90 pathway. Importantly, pharmacological and genetic inhibition of calcineurin signaling abrogated hyper-virulence in shear stress-challenged Mucorales, encouraging further evaluation of (topical) calcineurin inhibitors to improve therapeutic outcomes of NMM after combat-related blast injuries or violent storms.
Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser
Authors: Gnanapradeepan Keerthana , Basu Subhasree , Barnoud Thibaut , Leu Julia I-Ju , Good Madeline , Lee Joyce V. , Quinn William J. , Kung Che-Pei , Ahima Rexford S. , Baur Joseph A. , Wellen Kathryn E. , Liu Qin , Schug Zachary T. , George Donna L. , Murphy Maureen E. 
Published: February 2020

AbstractThe Pro47Ser variant of p53 exists in African-descent populations, and is associated with increased cancer risk in humans and mice. This variant, hereafter S47, shows altered regulation of the cystine importerSlc7a11, and S47 cells possess increased cysteine and glutathione (GSH) accumulation compared to cells with wild type p53. In this study we show that mice containing the S47 variant have increased mTOR activity, increased oxidative metabolism, larger size, and improved metabolic efficiency. Mechanistically, we show that there is increased association between mTOR and its positive regulator Rheb in S47 cells, due to altered redox state of GAPDH, which normally binds and sequesters Rheb. Compounds that decrease glutathione in S47 cells normalize GAPDH-Rheb complex formation and mTOR activity. The enhanced metabolic efficiency may have been selected for in early Africa, making the S47 variant one of a growing number of cancer-predisposing genetic variants that possesses other positive, potentially selectable attributes.
GPU accelerated partial order multiple sequence alignment for long reads self-correction
Authors: Peverelli Francesco , Tucci Lorenzo Di , Santambrogio Marco D. , Ding Nan , Hofmeyr Steven , Buluç Aydın , Oliker Leonid , Yelick Katherine 
Published: February 2020

AbstractAs third generation sequencing technologies become more reliable and widely used to solve several genome-related problems, self-correction of long reads is becoming the preferred method to reduce the error rate of Pacific Biosciences and Oxford Nanopore long reads, that is now around 10-12%. Several of these self-correction methods rely on some form of Multiple Sequence Alignment (MSA) to obtain a consensus sequence for the original reads. In particular, error-correction tools such as RACON and CONSENT use Partial Order (PO) graph alignment to accomplish this task. PO graph alignment, which is computationally more expensive than optimal global pairwise alignment between two sequences, needs to be performed several times for each read during the error correction process. GPUs have proven very effective in accelerating several compute-intensive tasks in different scientific fields. We harnessed the power of these architectures to accelerate the error correction process of existing self-correction tools, to improve the efficiency of this step of genome analysis.In this paper, we introduce a GPU-accelerated version of the PO alignment presented in the POA v2 software library, implemented on an NVIDIA Tesla V100 GPU. We obtain up to 6.5x speedup compared to 64 CPU threads run on two 2.3 GHz 16-core Intel Xeon Processors E5-2698 v3. In our implementation we focused on the alignment of smaller sequences, as the CONSENT segmentation strategy based on k-mer chaining provides an optimal opportunity to exploit the parallel-processing power of GPUs. To demonstrate this, we have integrated our kernel in the CONSENT software. This accelerated version of CONSENT provides a speedup for the whole error correction step that ranges from 1.95x to 8.5x depending on the input reads.
Temporal discounting in adolescents and adults with Tourette syndrome
Authors: Schüller Canan Beate , Wagner Ben Jonathan , Schüller Thomas , Baldermann Juan Carlos , Huys Daniel , auch Koerner Julia Kerner , Niessen Eva , Münchau Alexander , Brandt Valerie , Peters Jan , Kuhn Jens 
Published: February 2020

AbstractBackgroundTourette syndrome is a neurodevelopmental disorder with the clinical hallmarks of motor and phonic tics which are associated with hyperactivity in dopaminergic networks. Dopaminergic hyperactivity in the basal ganglia has previously been linked to increased sensitivity to positive reinforcement and increases in choice impulsivity.ObjectiveWe address whether this extends to changes in temporal discounting, where impulsivity is operationalized as an increased preference to choose smaller-but-sooner over larger-but-later rewards. Results are discussed with respect to neural models of temporal discounting, dopaminergic alterations in Tourette syndrome and the developmental trajectory of temporal discounting.MethodsIn the first study we included nineteen adolescent patients with Tourette syndrome and nineteen age- and education matched controls. In the second study, we compared twenty-five adult patients with Tourette syndrome and twenty-five age- and education-matched controls.ResultsIn the light of the dopaminergic hyperactivity model, we predicted differences in temporal discounting in patients with Tourette syndrome. However, computational modeling of choice behavior using hierarchical Bayesian parameter estimation revealed reduced impulsive choice in adolescent patients, and no group differences in adults.ConclusionWe speculate that adolescents might show reduced discounting due to improved inhibitory functions that also affect choice impulsivity and/or the developmental trajectory of executive control functions. The absence of an effect in adults might be due to differences in the clinical population (e.g. patients who acquired successful tic inhibition during adolescence might have gone into remission). Future studies would benefit from adopting longitudinal approaches to further elucidate the developmental trajectory of these effects.
Disulfide bridge formation prevents CaMKII/Calmodulin interaction in Parkinson’s disease
Authors: Di Maio Roberto , General Ignacio J. , Furbee Emily , Ayoob Joseph C. , Castro Sandra L. , Bahar Ivet , Greenamyre J. Timothy , Pullara Filippo 
Published: February 2020

AbstractThere is increasing evidence for disordered Ca2+signaling in dopamine neurons in Parkinson’s disease (PD), and this likely involves altered Ca2+/calmodulin-dependent protein kinase II (CaMKII) function. Previous work suggests that oxidative stress - a major feature in PD pathogenesis - affects regulatory methionine residues that sustain CaMKII activity in a Ca2+/CaM-independent manner. Here, applying computational modeling, we predicted formation of a defined disulfide bridge close to the CaMKII docking site for Ca2+/CaM binding.In vitroandin vivoinvestigations using PD models revealed formation of a disulfide bridge and loss of the CaMKII–calmodulin interaction. Mutagenesis of the relevant cysteine residues abrogated disulfide bridge formation and recovered the CaMKII–calmodulin interaction. Importantly, dopamine neurons from post-mortem PD brain specimens also lost this regulatory protein-protein interaction, providing relevance in the human disease. This study provides novel insights into oxidative CaMKII-CaM dysfunction, which may contribute to the pathophysiology of PD.
In Silicoidentification of potential drug targets by subtractive genome analysis ofEnterococcus faecium DO
Authors: Karim Marwah , Islam MD Nazrul , Azad Jewel G. M. Nurnabi 
Published: February 2020

AbstractOnce believed to be a commensal bacteria,Enterococcus faeciumhas recently emerged as an important nosocomial pathogen worldwide. A recent outbreak ofE. faeciumunrevealed natural andin vitroresistance against a myriad of antibiotics namely ampicillin, gentamicin and vancomycin due to over-exposure of the pathogen to these antibiotics. This fact combined with the ongoing threat demands the identification of new therapeutic targets to combatE. faecium infections.In this present study, comparative proteome analysis, subtractive genomic approach, metabolic pathway analysis and additional drug prioritizing parameters were used to propose a potential novel drug targets forE. faecium strainDO. Comparative genomic analysis of Kyoto Encyclopedia of Genes and Genomes annotated metabolic pathways identified a total of 207 putative target proteins inE. faecium DOthat showed no similarity to human proteins. Among them 105 proteins were identified as essential novel proteins that could serve as potential drug targets through further bioinformatic approaches; such as-prediction of subcellular localization, calculation of molecular weight, and web-based investigation of 3D structural characterization. Eventually 19 non-homologous essential proteins ofE. faecium DOwere prioritized and proved to have the eligibility to become novel broad-spectrum antibiotic targets. Among these targets aldehyde-alcohol dehydrogenase was found to be involved in maximum pathways, and therefore, was chosen as novel drug target. Interestingly, aldehyde-alcohol dehydrogenase enzyme contains two domains namely acetaldehyde dehydrogenase and alcohol dehydrogenase, on which a 3D structure homology modeling andin silicomolecular docking were performed. Finally, eight molecules were confirmed as the most suitable ligands for aldehyde-alcohol dehydrogenase and hence proposed as the potential inhibitors of this target.In conclusion, being human non-homologous, aldehyde-alcohol dehydrogenase protein can be targeted for potential therapeutic drug development in future. However, laboratory based experimental research should be performed to validate our findingsin vivo.
Central vestibular tuning arises from patterned convergence of otolith afferents
Authors: Liu Zhikai , Kimura Yukiko , Higashijima Shin-ichi , Hildebrand David G. , Morgan Joshua L. , Holy Timothy E. , Bagnall Martha W. 
Published: February 2020

AbstractAs sensory information moves through the brain, higher-order areas exhibit more complex tuning than lower areas. Though models predict this complexity is due to convergent inputs from neurons with diverse response properties, in most vertebrate systems convergence has only been inferred rather than tested directly. Here we measure sensory computations in zebrafish vestibular neurons across multiple axesin vivo. We establish that whole-cell physiological recordings reveal tuning of individual vestibular afferent inputs and their postsynaptic targets. An independent approach, serial section electron microscopy, supports the inferred connectivity. We find that afferents with similar or differing preferred directions converge on central vestibular neurons, conferring more simple or complex tuning, respectively. Our data also resolve a long-standing contradiction between anatomical and physiological analyses by revealing that sensory responses are produced by sparse but powerful inputs from vestibular afferents. Together these results provide a direct, quantifiable demonstration of feedforward input convergencein vivo.
Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations
Authors: Panyard Daniel J. , Kim Kyeong M. , Darst Burcu F. , Deming Yuetiva K. , Zhong Xiaoyuan , Wu Yuchang , Kang Hyunseung , Carlsson Cynthia M. , Johnson Sterling C. , Asthana Sanjay , Engelman Corinne D. , Lu Qiongshi 
Published: February 2020

SummaryAdvances in technology have allowed for the study of metabolomics in the context of disease, enabling the discovery of new potential risk factors, diagnostic markers, and drug targets. For neurological and psychiatric phenotypes, the cerebrospinal fluid (CSF) is of particular biomedical importance as it is in direct contact with the brain and spinal cord. However, the CSF metabolome is difficult to study on a large scale due to the relative complexity of the procedure needed to collect the fluid compared to blood or urine studies. Here, we present a metabolome-wide association study (MWAS), an analysis using individual-level genetic and metabolomic data from two cohorts to impute metabolites into large samples with genome-wide association summary statistics. We conducted a metabolome-wide genome-wide association analysis with 338 CSF metabolites, identifying 16 genotype-metabolite associations, 6 of which were novel. Using these results, we then built prediction models for all available CSF metabolites and tested for associations with 27 neurological and psychiatric phenotypes in large cohorts, identifying 19 significant CSF metabolite-phenotype associations. Our results demonstrate the potential of MWAS to overcome the logistic challenges inherent in cerebrospinal fluid research to study the role of metabolomics in brain-related phenotypes and the feasibility of this framework for similar studies of omic data in scarce sample types.
Effects of Sodium tanshinone IIA sulfonate on H9C2 cardiomyocyte injury induced by sodium arsenite
Authors: Xu Heli , Zhang Xinsheng , Liu Mengyao , Li Jiayu , Dou Wenjing , Wang Xiyan , Tan Hongyou , Ding Jian , Xie Juhua , Zhang Yue 
Published: February 2020

AbstractArsenic is a grade I human carcinogen that can cause kinds of damage to the body. The heart is one of the main target organs of arsenic damage, but the preventive and curative measures underlying arsenic poisoning are not clear. To investigate the effect of tanshinone IIA sulfonate (STS) on the injury of H9C2 cardiomyocytes induced by NaAsO2,H9C2 cardiomyocyteswere divided into four groups where control group with general medium, arsenic (As) group received sodium arsenite (NaAsO2)-containing general medium, STS pretreatment+As group and finally the STS alone group. Compared with the control group, different concentrations of STS had no significant effect on the cell viability (n = 6, P > 0.05); Compared with the control group, there was no significant change in the viability of cells treated with arsenic for 12 h after STS pretreatment for 6 h (n = 6, P > 0.05),the viability of cells treated with NaAsO2 alone was decreased(n = 6, P < 0.05);Compared with the control group, the cell viability was decreased after STS pretreatment for 12h and arsenic for 24h, the cell viability of NaAsO2 group was also decreased, the viability of NaAsO2 cells was lower than that of STS pretreated for 12h with NaAsO2 for 24h(n=6,p<0.05).The content of Caspase 3/7 in the NaAsO2 group was higher than that in the STS and NaAsO2 group and the Control group and STS group after 12h, the differences were statistically significant(n=6,p<0.05).After STS pretreatment for 12h and NaAsO2 for 24 h, there was no significant difference in Caspase 8 content between NaAsO2 group and other groups(n=6,P>0.05) As a result, Sodium tanshinone IIA sulfonate can attenuate the injury of H9C2 cardiomyocytes induced by sodium arsenite.
SPRTN protease and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability
Authors: Vaz Bruno , Ruggiano Annamaria , Popovic Marta , Rodriguez-Berriguete Gonzalo , Kilgas Susan , Singh Abhay N. , Higgins Geoffrey S. , Kiltie Anne E. , Ramadan Kristijan 
Published: February 2020

AbstractDNA-protein crosslinks (DPCs) are a specific type of DNA lesions where proteins are covalently attached to DNA. Unrepaired DPCs lead to genomic instability, cancer, neurodegeneration and accelerated ageing. DPC proteolysis was recently discovered as a specialised pathway for DPC repair. The DNA-dependent SPRTN protease and 26S proteasome emerged as as two independent proteolytic systems for DPC repair. DPCs are also repaired by homologous recombination (HR), a canonical DNA repair pathway. While studying the role of ubiquitin and SUMO in DPC repair, we identified mutually exclusive signalling mechanisms associated with DPC repair pathway choice. DPC modification by SUMO-1 favours SPRTN proteolysis as the preferred pathway for DPC repair. DPC SUMOylation counteracts DPC ubiquitination, which promotes DNA breaks and the switch to HR. We propose that modification of DPCs by SUMO-1 promotes SPRTN proteolysis, which is essential for DPC removal to prevent DNA replication defects, chromosomal recombination and genomic instability.
Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria
Authors: Halloy François , Iyer Pavithra S. , Ćwiek Paulina , Ghidini Alice , Barman-Aksözen Jasmin , van Wijk Nicole Wildner-Verhey , Theocharides Alexandre , Minder Elisabeth I. , Schneider-Yin Xiaoye , Schümperli Daniel , Hall Jonathan 
Published: February 2020

ABSTRACTErythropoietic protoporphyria (EPP) is a rare genetic disease in which patients experience acute phototoxic reactions after sunlight exposure. It is caused by a deficiency in ferrochelatase (FECH) in the heme biosynthesis pathway. Most patients exhibit a loss-of-function mutation intransto an allele bearing a SNP that favours aberrant splicing of transcripts. One viable strategy for EPP is to deploy splice-switching oligonucleotides (SSOs) to increase FECH synthesis, whereby an increase of a few percent would provide therapeutic benefit. However, successful application of SSOs in bone marrow cells is not described. Here, we show that SSOs comprising methoxyethyl-chemistry increase FECH levels in cells. We conjugated one SSO to three prototypical targeting groups and administered them to a mouse model of EPP in order to study their biodistribution, their metabolic stability and their FECH splice-switching ability. The SSOs exhibited distinct distribution profiles, with increased accumulation in liver, kidney, bone marrow and lung. However, they also underwent substantial metabolism, mainly at their linker groups. An SSO bearing a cholesteryl group increased levels of correctly spliced FECH transcript by 80% in the bone marrow. The results provide a promising approach to treat EPP and other disorders originating from splicing dysregulation in the bone marrow.
Long-term implicit memory for sequential auditory patterns in humans
Authors: Bianco Roberta , Harrison Peter M. C. , Hu Mingyue , Bolger Cora , Picken Samantha , Pearce Marcus T. , Chait Maria 
Published: February 2020

AbstractTo understand auditory scenes, listeners track and retain the statistics of sensory inputs as they unfold over time. We combined behavioural manipulation and modelling to investigate how sequence statistics are encoded into long-term memory and used to interpret incoming sensory signals. In a series of experiments, participants detected the emergence of regularly repeating patterns in novel rapid sound sequences. Unbeknownst to them, a few regular patterns reoccurred sparsely (every ∼3 minutes). Reoccurring sequences showed a rapidly growing detection time advantage over novel sequences. This effect was implicit, robust to interference, and persisted up to 7 weeks. Human performance was reproduced by a memory-constrained probabilistic model, where sequences are stored as n-grams and are subject to memory decay. Results suggest that similar psychological mechanisms may underlie integration processes over different-time scales in memory formation and flexible retrieval.
Diversity of culturable actinobacteria producing protease inhibitors isolated from the intertidal zones of Maharashtra, India
Authors: Shintre Neha , Baig Ulfat , Pund Anagha , Patwardhan Rajashree , Tamhane Vaijayanti , Deshpande Neelima 
Published: February 2020

ABSTRACTPhylogenetic diversity of culturable actinobacteria isolated from the intertidal regions of west coast of Maharashtra, India was studied using 16S rRNA gene sequencing. Total of 140 actinobacterial isolates were obtained, which belonged to 14 genera, 10 families and 65 putative species withStreptomycesbeing the most dominant (63%) genus followed byNocardiopsisandMicromonospora. They were screened for production of extracellular protease inhibitors (PI) against three pure proteases viz. chymotrypsin, trypsin, subtilisin and one crude extracellular protease fromPseudomonas aeruginosa. Eighty percent of the isolates showed PI activity against at least one of the four proteases, majority of them belonged to genusStreptomyes. Actinobacterial diversity from two sites Ade (17°52′ N, 73°04′ E) and Harnai (17°48′ N, 73°05′ E) with varying degree of anthropological pressure showed that more putative species diversity was obtained from site with lower human intervention i.e Ade (Shannon’s H 3.45) than from Harnai (Shannon’s H 2.83), a site with more human intervention. Further, in Ade percentage of isolates not showing PI activity against any of the proteases was close to 21% and that in Harnai was close to 9%. Considering human activities in the coastal region might be contributing to increasing the organic load and in turn increasing the presence of extracellular enzymes in the intertidal environments it would be interesting to look at the association of PI production and organic load in these habitats.