bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pseudomonas aeruginosa synthesizes the autoinducers of its oxylipin-dependent quorum sensing system extracellularly
Authors: Martínez Eriel , Orihuela Carlos J. , Campos-Gomez Javier 
Published: September 2021

ABSTRACTThe oxylipin-dependent quorum sensing system (ODS) of Pseudomonas aeruginosa relies on the production and sensing of two oxylipin autoinducers, 10S-hydroxy-(8E)-octadecenoic acid (10-HOME) and 7S,10S dihydroxy-(8E)-octadecenoic acid (7,10-DiHOME). Here, and contrary to the prevailing notion that bacterial autoinducers are synthesized intracellularly, we show that 10-HOME and 7,10-DiHOME biosynthesis occurs extracellularly, and this requires the secretion of the oxylipin synthases. We implemented a genetic screen of P. aeruginosa strain PAO1, which identified fourteen genes required for the synthesis of oxylipins. Among the identified genes, four encoded components of the ODS system and the other ten were part of the Xcp type II secretion system (T2SS). We created a deletion mutant of xcpQ, which encodes the outer membrane component of Xcp, and found it recapitulated the impaired functionality of the transposon mutants. Upon further examination, the lack of ODS function was demonstrated to be caused by the blocking of the DS enzymes secretion. Notably, the xcpQ mutant activated the ODS system when exposed to 10-HOME and 7,10-DiHOME, indicating that the sensing component of this quorum sensing system remains fully functional. In contrast with the detrimental effect previously described for T2SS in biofilm formation, here we observed that T2SS was required for robust in vitro and in vivo biofilm formation in an ODS dependent manner. To the best of our knowledge, this study is the first to find QS autoinducers that are synthetized in the extracellular space and provides new evidence for the role of the T2SS for biofilm formation in P. aeruginosa.IMPORTANCEWe previously showed that the ODS quorum sensing system of P. aeruginosa produces and responds to oxylipins derived from host oleic acid by enhancing biofilm formation and virulence. Herein, we developed a genetic screen strategy to explore the molecular basis for oxylipins synthesis and detection. Unexpectedly, we found that the ODS autoinducer synthases cross the outer membrane using the Xcp Type 2 secretion system of P. aeruginosa and thus, the biosynthesis of oxylipins occur extracellularly. Biofilm formation, which was thought to be impaired as result of Xcp activity, was found to be enhanced as result of ODS activation. This is a unique QS system strategy and reveals a new way by which P. aeruginosa interacts with the host environment.
Genome-scale metabolic modeling reveals increased reliance on valine catabolism in clinical isolates of Klebsiella pneumoniae
Authors: Jenior Matthew L , Dickenson Mary E , Papin Jason A 
Published: September 2021

AbstractInfections due to carbapenem-resistant Enterobacteriaceae have recently emerged as one of the most urgent threats to hospitalized patients within the United States and Europe. By far the most common etiological agent of these infections is Klebsiella pneumoniae, frequently manifesting in hospital-acquired pneumonia with a mortality rate of ∼50% even with antimicrobial intervention. We performed transcriptomic analysis of data collected from in vitro characterization of both laboratory and clinical isolates revealed shifts in expression of multiple master metabolic regulators across isolate types. Metabolism has been previously shown to be an effective target for antibacterial therapy, and GENREs have provided a powerful means to accelerate identification of potential targets in silico. Combining these techniques with the transcriptome meta-analysis, we generated context-specific models of metabolism utilizing a well-curated GENRE of K. pneumoniae (iYL1228) to identify novel therapeutic targets. Functional metabolic analyses revealed that both composition and metabolic activity of clinical isolate-associated context-specific models significantly differs from laboratory isolate-associated models of the bacterium. Additionally, we identified increased consumption of L-valine in clinical isolate-specific growth simulations. Importantly, valine has been shown to augment macrophage phagocytosis, and this result could be indicative of an immunosuppressive strategy Klebsiella pneumoniae evolved for survival during infection. These findings warrant future studies for potential efficacy of valine transaminase inhibition as a target against K. pneumoniae infection.ImportanceIncidences of infection by Klebsiella pneumoniae have grown in frequency to become the leading agents of CRE infection among hospitalized patients in the United States and Europe. Transcriptomic meta-analysis of data collected from both laboratory and clinical isolates indicated significant shifts in expression of key transcription factors related to metabolism. Metabolic network reconstructions have previously proven effective for quickly identifying potential targets in silico, therefore we combined these approaches by integrating the transcriptomic data from each isolate type into a well-curated GENRE of K. pneumoniae to predict emergent metabolic patterns. Leveraging this systems-biology approach we found discordant patterns of active metabolism between clinical and laboratory isolates, with a striking difference in L-valine catabolism. Exogenous valine is known to increase macrophage phagocytosis, and our results may support immunomodulatory activity in K. pneumoniae evolved to avoid host clearance.
Low levels of Fe and Se with high IL-6/IL-10 likely influence nutritional immunity in tuberculosis patients
Authors: Kaushik Sandeep R. , Sahu Sukanya , Guha Hritusree , Saha Sourav , Das Ranjit , Kupa Rukuwe-u , Kapfo Wetetsho , Deka Trinayan , Basumatary Rumi , Thong Asunu , Dasgupta Arunabha , Goswami Bidhan , Pandey Amit Kumar , Saikia Lahari , Khamo Vinotsole , Das Anjan , Nanda Ranjan Kumar 
Published: September 2021

AbstractTuberculosis (TB) patients present dysregulated immunity, iron metabolism and anaemia of inflammation. In this study, circulatory cytokines, trace metals, and iron-related proteins (hepcidin, ferroportin, transferrin, DMT1, Nramp1, ferritin, ceruloplasmin, hemojuvelin, aconitase, transferring receptor) were monitored in case (active tuberculosis patients: ATB) and control (non-tuberculosis: NTB and healthy) study populations (n=72, male, 42.94 mean age (16-83)). Using serum elemental and cytokine levels, a partial least square discriminate analysis model (PLS-DA) was built and variables with a VIP score of >0.6 were selected as important markers. A biosignature of IL-13, IL-12(p70), IFN-γ, IL-10, IL-5, IL-18, IL-4, Selenium, and Aluminium clustered ATB away from controls. Interestingly, low iron and selenium levels, while high copper and aluminum levels were observed in ATB subjects. All the important serum cytokines were positively correlated in ATB subjects. A low abundance of transferrin, ferroportin, and hemojuvelin, while higher ferritin and ceruloplasmin levels explained an altered iron metabolism in ATB subjects which partially resolved upon completion of treatment. Further, the identified biosignature in TB patients, that explained anemia of inflammation, along with perturbed iron homeostasis could be useful targets for the development of host-directed adjunct therapeutics.
Professional practice for COVID-19 risk reduction among health care workers: a Cross-Sectional Study with Matched Case-Control Comparison
Authors: Sarah Wilson , Audrey Mouet , Camille Jeanne-Leroyer , France Borgey , Emmanuelle Odinet-Raulin , Xavier Humbert , Simon Le Hello , Pascal Thibon 
Published: September 2021

AbstractBackgroundHealth care workers (HCWs) are particularly exposed to COVID-19 and therefore it is paramount to study preventive measures in this population.AimTo investigate socio-demographic factors and professional practice associated with the risk of COVID-19 among HCWs in health establishments in Normandy, FranceMethodsA cross-sectional and 3 case-control studies were conducted in order to explore the possible risk factors that lead to SARS-CoV2 transmission within HCWs, based on an online questionnaire. The case-control studies focused on risk factors associated with care of COVID-19 patients, care of non COVID-19 patients and contacts between colleagues.FindingsAmong 2,058 respondents, respectively 1,363 (66.2%) and 695 (33.8%) in medical and medico-social establishments, 301 (14.6%) reported having been infected by SARS-CoV2. When caring for COVID-19 patients, HCWs who declared wearing respirators, either for all patient care (ORa 0.39; 95% CI: 0.29-0.51) or only when exposed to aerosol-generating procedures (ORa 0.56; 95% CI: 0.43-0.70), had a lower risk of infection compared with HCWs who declared wearing mainly surgical masks. During care of non COVID-19 patients, wearing mainly a respirator was associated with a higher risk of infection (ORa 1.84; 95% CI: 1.06-3.37). An increased risk was also found for HCWs who changed uniform in workplace changing rooms (ORa 1.93; 95% CI: 1.63-2.29).ConclusionCorrect use of PPE adapted to the situation and risk level is essential in protecting HCWs against infection.
Pre-conceptional maternal vitamin B12 supplementation improves offspring neurodevelopment at 2 years of age: PRIYA trial
Authors: D’souza Naomi , Behere Rishikesh V , Patni Bindu , Deshpande Madhavi , Bhat Dattatray , Bhalerao Aboli , Sonawane Swapnali , Shah Rohan , Ladkat Rasika , Yajnik Pallavi , Kumaran Kalyanaraman , Fall Caroline , Yajnik Chittaranjan S 
Published: September 2021

AbstractBackgroundNutritional interventions during the first 1000 days of life improves lifelong health. Better pre-conceptional maternal nutrition improves the nutrition of the early embryo. Vitamins B12 and folate are important for fetal neural development. Vitamin B12 deficiency is common in India.MethodsIn the Pune Rural Intervention in Young Adolescents (PRIYA) adolescents (N=557, 226 females) were provided with vitamin B12 (2µg/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayley’s Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. We examined cord blood concentrations of brain-derived neurotropic factor (BDNF).ResultsParticipants in the three groups had similar baseline B12 levels. These improved in the B12 supplemented groups at pre-conceptional and pregnancy (28 weeks gestation) measurements, reflected in higher cord holo-TC levels compared to the placebo. Neurodevelopmental outcomes are available for 74 children. Offspring in the B12 alone group (n=21) performed better than the placebo (n=27) on cognition (p=0.044) and language (p=0.020) domains (adjusted for maternal baseline B12 levels). There were no differences between the B12+MMN (n=26) and placebo group. Cord blood BDNF levels were highest in the B12 alone group (not statistically significant).ConclusionPre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening in the pre-conceptional period.
Second wave of the Covid-19 pandemic in Delhi, India: high seroprevalence not a deterrent?
Authors: Sharma Nandini , Sharma Pragya , Basu Saurav , Bakshi Ritika , Gupta Ekta , Agarwal Reshu , Dushyant Kumar , Mundeja Nutan , Marak Zeasley , Singh Sanjay , Singh Gautam Kumar , Rustagi Ruchir , Sarin S K 
Published: September 2021

ABSTRACTBackgroundWe report the findings of a large follow-up community-based serosurvey and correlating it with the COVID-19 test-positivity rate and the case load observed during the peak of the second wave of the Covid-19 pandemic in Delhi, India.MethodsIndividuals of age ≥5 years were recruited from 274 wards of the state (population ∼ 19.6 million) during January 11 to January 22’ 2021. A total of 100 participants each were included from all the wards for a net sample size of ∼28,000. A multi-stage sampling technique was applied for selection of participants for the household serosurvey. Anti SARS CoV-2 IgG antibodies were detected by using the VITROS assay (90% Sn, 100% Sp).ResultsAntibody positivity was observed in 14,298 (50.76%) of the 28,169 samples. The age, sex and district population weighted seroprevalence of the IgG SARS-CoV-2 was 50.52% (95% C.I. 49.94-51.10) and after adjustment for assay characteristics was 56.13% (95% C.I. 55.49-56.77). On adjusted analysis, participants aged ≥50 years, of female gender, housewives, having ever lived in containment zones, urban slum dwellers, and diabetes or hypertensive patients had significantly higher odds of SARS-CoV-2 antibody positivity.The peak infection rate and the test positivity rate since October 2020 were initially observed in mid-November 2020 with a subsequent steep declining trend, followed by a period of persistently low case burden lasting until the first week of March 2021. This was followed by a steady increase followed by an exponential surge in infections from April 2021 onwards culminating in the second wave of the pandemic.ConclusionsThe presence of infection induced immunity from SARS-CoV-2 even in more than one in two people can be ineffective in protecting the population.
Transcriptomic-based quantification of the epithelial-hybrid-mesenchymal spectrum across biological contexts
Authors: Mandal Susmita , Tejaswi Tanishq , Janivara Rohini , Srikrishnan Syamanthak , Thakur Pradipti , Sahoo Sarthak , Chakraborty Priyanka , Sohal Sukhwinder Singh , Levine Herbert , George Jason T , Jolly Mohit Kumar 
Published: September 2021

AbstractEpithelial-mesenchymal plasticity (EMP) underlies embryonic development, wound healing, and cancer metastasis and fibrosis. Cancer cells exhibiting EMP often have more aggressive behavior, characterized by drug resistance, and tumor-initiating and immuno-evasive traits. Thus, the EMP status of cancer cells can be a critical indicator of patient prognosis. Here, we compare three distinct transcriptomic-based metrics – each derived using a different gene list and algorithm – that quantify the EMP spectrum. Our results for 96 cancer-related RNA-seq datasets reveal a high degree of concordance among these metrics in quantifying the extent of EMP. Moreover, each metric, despite being trained on cancer expression profiles, recapitulates the expected changes in EMP scores for non-cancer contexts such as lung fibrosis and cellular reprogramming into induced pluripotent stem cells. Thus, we offer a scoring platform to quantify the extent of EMP in vitro and in vivo for diverse biological applications including cancer.
Lipid chaperone LBP-8 coordinates with nuclear factors to promote longevity in Caenorhabditis elegans
Authors: Duffy Jonathon , Zhang Qinghao , Jung Sung Y. , Wang Meng C. 
Published: September 2021

AbstractEukaryotic cells are composed of a variety of organelles. Their coordination plays crucial roles in cellular homeostasis and organism longevity and is mediated by proteins with the ability to transport between different organelles. In Caenorhabditis elegans, LBP-8 is a pro-longevity lipid chaperone that can localize to both lysosomes and the nucleus. Here we profiled LBP-8’s binding partners using immunoprecipitation and mass spectrometry. From the 45 identified candidates, we discovered four nuclear factors that are required for the LBP-8-induced longevity. Among them, RPC-2, an RNA Polymerase III core subunit, is also necessary for the nuclear localization of LBP-8. Moreover, we have screened nuclear transport machinery components, and revealed the requirement of the nuclear import, not export, for the LBP-8 longevity effects. Together, these results suggest that the lipid chaperone LBP-8 relies on specific nuclear factors to retain in the nucleus and regulate longevity.
Effective population size for culturally evolving traits
Authors: Deffner Dominik , Kandler Anne , Fogarty Laurel 
Published: September 2021

ABSTRACTPopulation size has long been considered an important driver of cultural diversity and complexity. Results from population genetics, however, demonstrate that in populations with complex demographic structure or mode of inheritance, it is not the census population size, N, but the effective size of a population, Ne, that determines important evolutionary parameters. Here, we examine the concept of effective population size for traits that evolve culturally, through processes of innovation and social learning. We use mathematical and computational modeling approaches to investigate how cultural Ne and levels of diversity depend on (1) the way traits are learned, (2) population connectedness, and (3) social network structure. We show that one-to-many and frequency-dependent transmission can temporally or permanently lower effective population size compared to census numbers. We caution that migration and cultural exchange can have counter-intuitive effects on Ne. Network density in random networks leaves Ne unchanged, scale-free networks tend to decrease and small-world networks tend to increase Ne compared to census numbers. For one-to-many transmission and different network structures, effective size and cultural diversity are closely associated. For connectedness, however, even small amounts of migration and cultural exchange result in high diversity independently of Ne. Our results highlight the importance of carefully defining effective population size for cultural systems and show that inferring Ne requires detailed knowledge about underlying cultural and demographic processes.AUTHOR SUMMARYHuman populations show immense cultural diversity and researchers have regarded population size as an important driver of cultural variation and complexity. Our approach is based on cultural evolutionary theory which applies ideas about evolution to understand how cultural traits change over time. We employ insights from population genetics about the “effective” size of a population (i.e. the size that matters for important evolutionary outcomes) to understand how and when larger populations can be expected to be more culturally diverse. Specifically, we provide a formal derivation for cultural effective population size and use mathematical and computational models to study how effective size and cultural diversity depend on (1) the way culture is transmitted, (2) levels of migration and cultural exchange, as well as (3) social network structure. Our results highlight the importance of effective sizes for cultural evolution and provide heuristics for empirical researchers to decide when census numbers could be used as proxies for the theoretically relevant effective numbers and when they should not.
RBBP4 modulates gene activity through acetylation and methylation of histone H3 lysine 27
Authors: Mu Weipeng , Murcia Noel S , Smith Keriayn N. , Menon Debashish U , Yee Della , Magnuson Terry 
Published: September 2021

AbstractRBBP4 is a core subunit of polycomb repressive complex 2 (PRC2) and HDAC1/2-containing complexes, which are responsible for histone H3 lysine 27 (H3K27) methylation and deacetylation respectively. However, the mechanisms by which RBBP4 modulates the functions of these complexes remain largely unknown. We generated viable mouse embryonic stem cell lines with RBBP4 mutations that disturbed methylation and acetylation of H3K27 on target chromatin and found that RBBP4 is required for PRC2 assembly and H3K27me3 establishment on target chromatin. Moreover, in the absence of EED and SUZ12, RBBP4 maintained chromatin binding on PRC2 loci, suggesting that the pre-existence of RBBP4 on nucleosomes serves to recruit PRC2 to restore H3K27me3 on newly synthesized histones. As such, disruption of RBBP4 function led to dramatic changes in transcriptional profiles. In spite of the PRC2 association, we found that transcriptional changes were more closely tied to the deregulation of H3K27ac rather than H3K27me3 where increased levels of H3K27ac were found on numerous cis-regulatory elements, especially putative enhancers. These data suggest that RBBP4 controls acetylation levels by adjusting the activity of HDAC complexes. As histone methylation and acetylation have been implicated in cancer and neural disease, RBBP4 could serve as a potential target for disease treatment.
A neural hub that coordinates learned and innate courtship behaviors
Authors: Ben-Tov Mor , Duarte Fabiola , Mooney Richard 
Published: September 2021

AbstractHolistic behaviors often require the coordination of innate and learned movements. The neural circuits that enable such coordination remain unknown. Here we identify a midbrain cell group (A11) that enables male zebra finches to coordinate their learned songs with various innate behaviors, including female-directed calling, orientation and pursuit. Anatomical mapping reveals that A11 is at the center of a complex network including the song premotor nucleus HVC as well as brainstem regions crucial to innate calling and locomotion. Notably, lesioning A11 terminals in HVC blocked female-directed singing, but did not interfere with female-directed calling, orientation or pursuit. In contrast, lesioning A11 cell bodies abolished all female-directed courtship behaviors. However, males with either type of lesion still produced songs when in social isolation. Lastly, monitoring A11 terminals in HVC showed that during courtship A11 inputs to the song premotor cortex signal the transition from innate to learned vocalizations. These results show how a brain region important to reproduction in both birds and mammals coordinates learned vocalizations with innate, ancestral courtship behaviors.
ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia
Authors: Lai Jenny , Demirbas Didem , Kim Junho , Jeffries Ailsa M. , Tolles Allie , Park Junseok , Chittenden Thomas W. , Buckley Patrick G. , Yu Timothy W. , Lodato Michael A. , Lee Eunjung Alice 
Published: September 2021

AbstractWhileATMloss-of-function has long been identified as the genetic cause of Ataxia Telangiectasia (A-T), how this genetic mutation leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear.ATMexpression is enriched in microglia, the resident immune cell of the central nervous system, throughout cerebellar development and adulthood. Microglial activation has been strongly implicated in neurodegenerative disease and observed in rodent and cellular models ofATMdeficiency. Here, we find evidence of prominent inflammation of microglia in cerebellum from A-T patients using single-nucleus RNA-sequencing. A-T microglia have transcriptomic signatures of aging and neurodegenerative disease associated microglia. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis related genes in granule and Purkinje neurons, and microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we studied microglia and neurons that we generated from A-T patient vs. control induced pluripotent stem cells (iPSCs). Transcriptomic profiling of A-T iPSC-derived microglia revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, adding A-T microglia to co-cultures with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may play a critical role in the development and progression of neurodegeneration in Ataxia Telangiectasia.