bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-culturingHyphomicrobium nitrativoransstrain NL23 andMethylophaga nitratireducenticrescensstrain JAM1 allows sustainable denitrifying activities under marine conditions
Authors: Alexandra Cucaita , Marianne Piochon , Richard Villemur 
Published: February 2021

ABSTRACTHyphomicrobium nitrativoransstrain NL23 andMethylophaga nitratireducenticrescensstrain JAM1 were the principal bacteria involved in the denitrifying activities of a methanol-fed, fluidized marine denitrification reactor. We believe that a tight relationship has developed between these two strains to achieve denitrification in the reactor under marine conditions. To characterize the potential synergy between strain JAM1 and strain NL23, we compared some of their physiological traits, and performed co-cultures. Pure cultures of strain JAM1 had a readiness to reduce nitrate (NO3−) with no lag phase for growth contrary to pure cultures of strain NL23, which has a 2-3 days lag phase before NO3− starts to be consumed and growth to occur. Compared to strain NL23, strain JAM1 has a higher μmax for growth and higher specific NO3− reduction rates. Antagonist assays showed no sign of exclusion by both strains. Planktonic co-cultures could only be performed on low NaCl concentrations for strain NL23 to survive. Denitrification rates were twice higher in the planktonic co-cultures than those measured in strain NL23 pure cultures. Biofilm co-cultures were performed for several months in a 500-mL bioreactor filled with Bioflow supports, and operated under fed-batch mode with increasing concentrations of NaCl for strain NL23 to acclimate to marine conditions. Under these conditions, the biofilm co-cultures showed sustained denitrifying activities and surface colonization by both strains. Increase in ectoine concentrations produced by strain JAM1 was observed in the biofilm with increasing NaCl concentrations. These results illustrate the capacity of both strains to act together in performing denitrification under marine environments. Although strain JAM1 did not contribute in better specific denitrifying activities in the biofilm co-cultures, its presence was essential for strain NL23 to survive in a medium with NaCl concentrations > 1.0%. We believe that ectoine is an important factor for the survival of strain NL23 in these environments.
“Single-subject studies”-derived analyses unveil altered biomechanisms between very small cohorts: implications for rare diseases
Authors: Aberasturi Dillon , Pouladi Nima , Zaim Samir Rachid , Kenost Colleen , Berghout Joanne , Piegorsch Walter W. , Lussier Yves A. 
Published: February 2021

AbstractMotivationIdentifying altered transcripts between very small human cohorts is particularly challenging and is compounded by the low accrual rate of human subjects in rare diseases or sub-stratified common disorders. Yet,single-subjectstudies (S3) can compare paired transcriptome samples drawn from the same patient under two conditions (e.g., treated vs pre-treatment) and suggest patient-specific responsive biomechanisms based on the overrepresentation of functionally defined gene sets. These improve statistical power by: (i) reducing the total features tested and (ii) relaxing the requirement of within-cohort uniformity at the transcript level. We proposeInter-N-of-1, a novel method, to identify meaningful biomechanism differences between very small cohorts by using the effect size of “single-subject-study”-derived responsive biomechanisms.ResultsIn each subject,Inter-N-of-1requires applying previously published S3-typeN-of-1-pathways MixEnrichto two paired samples (e.g., diseased vs unaffected tissues) for determining patient-specificenrichedgenessets: Odds Ratios (S3-OR) and S3-variance using Gene Ontology Biological Processes. To evaluate small cohorts, we calculated the precision and recall ofInter-N-of-1and that of a control method (GLM+EGS) when comparing two cohorts of decreasing sizes (from 20 vs 20 to 2 vs 2) in a comprehensive six-parameter simulation and in a proof-of-concept clinical dataset. In simulations, theInter-N-of-1median precision and recall are > 90% and >75% in cohorts of 3 vs 3 distinct subjects (regardless of the parameter values), whereas conventional methods outperformInter-N-of-1at sample sizes 9 vs 9 and larger. Similar results were obtained in the clinical proof-of-concept dataset.AvailabilityR software is available at Lussierlab.net/BSSD.ContactLussier.y@gmail.com,Piegorsch@math.arizona.edu
Mitochondrial Fission Regulates Transcription of Ribosomal Protein Genes in Embryonic Hearts
Authors: Zhao Qiancong , Yan Shun , Lu Jin , Parker Danitra J. , Wu Huiying , Sun Qianchuang , Crossman David K. , Liu Shanrun , Wang Qin , Sesaki Hiromi , Mitra Kasturi , Liu Kexiang , Jiao Kai 
Published: February 2021

AbstractMitochondrial dysfunction causes severe congenital heart diseases and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target inborn heart defects due to mitochondrial deficiency. Mitochondrial morphology, which is regulated by fission and fusion, plays key roles in determining mitochondrial activity.Drp1encodes a dynamin-related GTPase required for mitochondrial fission. To investigate the role of mitochondrial fission on cardiogenesis during the embryonic metabolic shift period, we specifically inactivatedDrp1in second heart field derived structures. Deletion ofDrp1in embryonic cardiomyocytes led to severe defects in mitochondrial morphology, ultrastructure, and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes, and embryonic lethality. Through characterizing this model, we reveal a novel AMPK-SIRT7-GABPB axis that relays the mitochondrial fission anomaly to reduced transcription of ribosomal protein genes in mutant cardiomyocytes. We therefore provide the first mouse genetic evidence to show that mitochondrial fission is essential for embryonic heart development. Furthermore, we uncovered a novel signaling cascade that mediates the crosstalk between mitochondrial dysfunction and protein synthesis. Our research provides further mechanistic insight regarding how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.
Succinate metabolism uncouples retinal pigment epithelium mitochondria
Authors: Hass Daniel T. , Bisbach Celia M. , Robbings Brian M. , Kamat Varun S , Sadilek Martin , Sweet Ian R. , Hurley James B. 
Published: February 2021

AbstractSuccinate is central in energy metabolism. It is thought to be made and consumed within mitochondria, and not to cross the plasma membrane. Contrary to the canonical role of succinate, it is produced in the retina and released into the extracellular milleau. It is unknown how this affects adjacent retinal pigment epithelium, within eyecup tissue. By measuring consumption of13C4-succinate and O2we probe metabolism of the eyecup, we find robust succinate consumption by eyecup but not retina tissue. Succinate-dependant stimulation of eyecup respiration is oligomycin resistant; indicating that in eyecup tissue succinate uncouples mitochondrial ATP synthesis from respiration.
Protomer alignment modulates specificity of RNA substrate recognition by Ire1
Authors: Li Weihan , Crotty Kelly , Ruiz Diego Garrido , Voorhies Mark , Rivera Carlos , Sil Anita , Mullins R. Dyche , Jacobson Matthew P. , Peschek Jirka , Walter Peter 
Published: February 2021

AbstractThe unfolded protein response (UPR) maintains protein folding homeostasis in the endoplasmic reticulum (ER). In metazoan cells, the Ire1 branch of the UPR initiates two functional outputs— non-conventional mRNA splicing and selective mRNA decay (RIDD). By contrast, Ire1 orthologs fromSaccharomyces cerevisiaeandSchizosaccharomyces pombeare specialized for only splicing or RIDD, respectively. The functional specialization lies in Ire1’s RNase activity, which is either stringently splice-site specific (as inS. cerevisiae) or promiscuous (as inS. pombe). Here, we developed an assay that reports on Ire1’s RNase promiscuity. We found that conversion of two amino acids within the RNase domain ofS. cerevisiaeIre1 to theirS. pombecounterparts rendered it promiscuous. Using biochemical assays and computational modeling, we show that the mutations rewired a pair of salt bridges at Ire1 RNase domain’s dimer interface, changing its protomer alignment. Thus, Ire1 protomer alignment affects its substrates specificity.
A like-for-like comparison of lightweight-mapping pipelines for single-cell RNA-seq data pre-processing
Authors: Zakeri Mohsen , Srivastava Avi , Sarkar Hirak , Patro Rob 
Published: February 2021

AbstractRecently, Booeshaghi and Pachter (1) published a benchmark comparing the kallisto-bustools pipeline (2) for single-cell data pre-processing to the alevin-fry pipeline (3). Their benchmarking adopted drastically dissimilar configurations for these two tools, and overlooked the time- and space-frugal configurations of alevin-fry previously benchmarked by Sarkar et al. (3). In this manuscript, we provide a small set of modifications to the benchmarking scripts of Booeshaghi and Pachter that are necessary to perform a like-for-like comparison between kallisto-bustools and alevin-fry. We also address some misuses of the alevin-fry commands and include important data on the exact reference transcriptomes used for processing1. Using the same benchmarking scripts of Booeshaghi and Pachter (1), we demonstrate that, when configured to match the computational com-plexity of kallisto-bustools as closely as possible, alevin-fry processes data faster (~2.08 times as fast on average) and uses less peak memory (~ 0.34 times as much on average) compared to kallisto-bustools, while producing results that are similar when assessed in the manner done by Booeshaghi and Pachter (1). This is a notable inversion of the performance characteristics presented in the previous benchmark.
An endogenous opioid circuit determines state-dependent appetitive behavior
Authors: Castro Daniel C. , Oswell Corinna S. , Zhang Eric T. , Pedersen Christian E. , Piantadosi Sean C. , Rossi Mark A. , Hunker Avery , Guglin Anthony , Morón Jose A. , Zweifel Larry S. , Stuber Garret D. , Bruchas Michael R. 
Published: February 2021

AbstractMu-opioid peptide receptor (MOPR) stimulation alters respiration, analgesia, and reward behavior, and can induce addiction and drug overdose. Despite its evident importance, the endogenous mechanisms for MOPR regulation of appetitive behavior have remained unknown. Here we report that endogenous MOPR regulation of appetitive behavior in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine appetitive behavioral state while select enkephalin-containing NAc ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of endogenous MOPR ligand. Selective modulation of NAc enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent appetitive behavior and suggest alternative mechanisms for opiate modulation of reward.
Modelling spinal locomotor circuits for movements in developing zebrafish
Authors: Roussel Yann , Gaudreau Stephanie F. , Kacer Emily R. , Sengupta Mohini , Bui Tuan V. 
Published: February 2021

ABSTRACTMany spinal circuits dedicated to locomotor control have been identified in the developing zebrafish. How these circuits operate together to generate the various swimming movements during development remains to be clarified. In this study, we iteratively built models of developing zebrafish spinal circuits coupled to simplified musculoskeletal models that reproduce coiling and swimming movements. The neurons of the models were based upon morphologically or genetically identified populations in the developing zebrafish spinal cord. We simulated intact spinal circuits as well as circuits with silenced neurons or altered synaptic transmission to better understand the role of specific spinal neurons. Analysis of firing patterns and phase relationships helped identify possible mechanisms underlying the locomotor movements of developing zebrafish. Notably, our simulations demonstrated how the site and the operation of rhythm generation could transition between coiling and swimming. The simulations also underlined the importance of contralateral excitation to multiple tail beats. They allowed us to estimate the sensitivity of spinal locomotor networks to motor command amplitude, synaptic weights, length of ascending and descending axons, and firing behaviour. These models will serve as valuable tools to test and further understand the operation of spinal circuits for locomotion.
Suppressing evolution through environmental switching
Authors: Morsky Bryce , Vural Dervis Can 
Published: February 2021

AbstractEcology and evolution under changing environments are important in many subfields of biology with implications for medicine. Here, we explore an example: the consequences of fluctuating environments on the emergence of antibiotic resistance, which is an immense and growing problem. Typically, high doses of antibiotics are employed to eliminate the infection quickly and minimize the time under which resistance may emerge. However, this strategy may not be optimal. Since competition can reduce fitness and resistance typically has a reproductive cost, resistant mutants’ fitness can depend on their environment. Here we show conditions under which environmental varying fitness can be exploited to prevent the emergence of resistance. We develop a stochastic Lotka-Volterra model of a microbial system with competing phenotypes: a wild strain susceptible to the antibiotic, and a mutant strain that is resistant. We investigate the impact of various pulsed applications of antibiotics on population suppression. Leveraging competition, we show how a strategy of environmental switching can suppress the infection while avoiding resistant mutants. We discuss limitations of the procedure depending on the microbe and pharmacodynamics and methods to ameliorate them.
ZC3H4 restricts non-coding transcription in human cells
Authors: Estell Chris , Davidson Lee , Steketee Pieter C. , Monier Adam , West Steven 
Published: February 2021

SUMMARYThe human genome encodes thousands of non-coding RNAs. Many of these terminate early and are then rapidly degraded, but how their transcription is restricted is poorly understood. In a screen for protein-coding gene termination factors, we identified ZC3H4. However, its depletion causes upregulation and extension of hundreds of unstable transcripts, particularly antisense RNAs and those transcribed from so-called super-enhancers. These loci are occupied by ZC3H4, suggesting that it directly functions in their transcription. Consistently, engineered tethering of ZC3H4 to reporter RNA promotes its degradation by the exosome. ZC3H4 is metazoan-specific - interesting when considering its impact on enhancer RNAs that are less prominent in single-celled organisms. Finally, ZC3H4 loss causes a substantial reduction in cell proliferation, highlighting its overall importance. In summary, we identify ZC3H4 as a factor that plays an important role in restricting non-coding transcription in multi-cellular organisms.
HotspotESR1mutations are multimodal and contextual drivers of breast cancer metastasis
Authors: Li Zheqi , Wu Yang , Yates Megan E. , Tasdemir Nilgun , Bahreini Amir , Chen Jian , Levine Kevin M. , Priedigkeit Nolan M. , Ali Simak , Buluwela Laki , Arnesen Spencer , Gertz Jason , Richer Jennifer K. , Troness Benjamin , El-Ashry Dorraya , Zhang Qiang , Gerratana Lorenzo , Zhang Youbin , Cristofanilli Massimo , Montanez Maritza A. , Sundd Prithu , Wallace Callen T. , Watkins Simon C. , Zhu Li , Tseng George C. , Wagle Nikhil , Carroll Jason S. , Jank Paul , Denkert Carsten , Karsten Maria M , Blohmer Jens-Uwe , Park Ben H. , Lucas Peter C. , Atkinson Jennifer M. , Lee Adrian V. , Oesterreich Steffi 
Published: February 2021

AbstractConstitutively active estrogen receptor-α (ER/ESR1) mutations have been identified in approximately one third of ER+ metastatic breast cancer. Although these mutations are known mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence ofESR1mutations exclusively in distant, but not local recurrences. In concordance with transcriptomic profiling ofESR1mutant tumors, genome-edited Y537S and D538G cell models have a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and theTIMP3/MMPaxis, which functionally confers enhanced cell-cell contacts while decreased cell-ECM adhesion. Context-dependent migratory phenotypes revealed co-targeting of Wnt and ER as vulnerability. Mutant ESR1 exhibits non-canonical regulation of several metastatic pathways including secondary transactivation andde novoFOXA1-driven chromatin remodeling. Collectively, our data supports evidence forESR1mutation-driven metastases and provides insight for future preclinical therapeutic strategies.SignificanceContext and allele-dependent transcriptome and cistrome reprogramming in genome-editedESR1mutation cell models elicit diverse metastatic phenotypes, including but not limited to alterations in cell adhesion and migration. The gain-of-function mutations can be pharmacologically targeted, and thus may be key components of novel therapeutic treatment strategies for ER-mutant metastatic breast cancer.
An invariantTrypanosoma vivaxvaccine antigen inducing protective immunity
Authors: Autheman Delphine , Crosnier Cécile , Clare Simon , Goulding David A. , Brandt Cordelia , Harcourt Katherine , Tolley Charlotte , Galaway Francis , Khushu Malhar , Ong Han , Ramirez Alessandra Romero , Duffy Craig W. , Jackson Andrew P. , Wright Gavin J. 
Published: February 2021

AbstractTrypanosomes are protozoan parasites that cause infectious diseases including human African trypanosomiasis (sleeping sickness), and nagana in economically-important livestock animals1,2. An effective vaccine against trypanosomes would be an important control tool, but the parasite has evolved sophisticated immunoprotective mechanisms including antigenic variation3that present an apparently insurmountable barrier to vaccination. Here we show using a systematic genome-led vaccinology approach4and a murine model ofTrypanosoma vivaxinfection5that protective invariant subunit vaccine antigens can be identified. Vaccination with a single recombinant protein comprising the extracellular region of a conserved cell surface protein localised to the flagellum membrane termed “invariant flagellum antigen fromT. vivax” (IFX) induced long-lasting protection. Immunity was passively transferred with immune serum, and recombinant monoclonal antibodies to IFX could induce sterile protection and revealed multiple mechanisms of antibody-mediated immunity, including a major role for complement. Our discovery identifies a vaccine candidate for an important parasitic disease that has constrained the socioeconomic development of sub-Saharan African countries6and challenges long-held views that vaccinating against trypanosome infections cannot be achieved.
Rabies anterograde monosynaptic tracing reveals organization of spinal sensory circuits
Authors: Pimpinella Sofia , Zampieri Niccolò 
Published: February 2021

AbstractSomatosensory neurons detect vital information about the environment and internal status of the body, such as temperature, touch, itch and proprioception. The circuit mechanisms controlling the coding of somatosensory information and the generation of appropriate behavioral responses are not clear yet. In order to address this issue, it is important to define the precise connectivity patterns between primary sensory afferents dedicated to the detection of different stimuli and recipient neurons in the central nervous system. In this study we used a rabies tracing approach for mapping spinal circuits receiving sensory input from distinct, genetically defined, modalities. We analyzed the anatomical organization of spinal circuits involved in coding of thermal and mechanical stimuli and showed that somatosensory information from distinct modalities is relayed to partially overlapping ensembles of interneurons displaying stereotyped laminar organization, thus highlighting the importance of positional features and population coding for the processing and integration of somatosensory information.
External technology acquisition, exploitation and process innovation performance in emerging market small and medium sized enterprises: the moderating role of organizational slack
Authors: Charmjuree Thammanoon , Badir Yuosre F. , Safdar Umar 
Published: February 2021

PurposeThis study is among the very few to examine the firm's simultaneous use of both dimensions of open innovation and its influences on the firm's process innovation performance (PIP). Specifically, the authors consider the relationship between firm's external technology acquisition (ETA) and external technology exploitation (ETE) and examine their direct, indirect and mediating effect on the firm's PIP. The authors also examine the moderating effect of the organizations' unabsorbed slack (UASL) on the relationship between ETA and ETE.Design/methodology/approachAnalyzing data collected from 311 small- and medium-sized software development firms in emerging market; Thailand, we show that both ETA and ETE have a positive effect on PIP and that ETE fully mediates the relationship between ETA and PIP.FindingsThe authors show that both ETA and ETE have a positive effect on PIP and that ETE fully mediates the relationship between ETA and PIP. Moreover, the relationship between ETA and ETE is positively moderated by the firms' unabsorbed slack (UASL) and that the influence of ETA on PIP through ETE is stronger under higher unabsorbed slack.Originality/valueThe authors extend the “traditional” performance outcome of outbound dimension of open innovation concept, which focuses exclusively on commercialization and market (Chesbrough, 2003b), by showing that ETE positively influences the firm's PIP. Moreover, the study explains the mechanism through which ETA influence the firm's PIP by proposing that ETE fully mediates the relationship between ETA and PIP.