bluuebunny/crossref_metadata_2025_split huggingface dataset:
The slowdown of growth rate controls the single-cell distribution of biofilm matrix production via a SinI-SinR-SlrR network
Authors: Chen Zhuo , Zarazúa-Osorio Brenda , Srivastava Priyanka , Fujita Masaya , Igoshin Oleg A. 
Published: July 2022

AbstractIn Bacillus subtilis, a master regulator Spo0A controls several cell-differentiation pathways. Under moderate starvation, phosphorylated Spo0A (Spo0A~P) induces biofilm formation by indirectly activating genes controlling matrix production in a subpopulation of cells via a SinI-SinR-SlrR network. Under severe starvation, Spo0A~P induces sporulation by directly and indirectly regulating sporulation gene expression. However, what determines the heterogeneity of individual cell fates is not fully understood. In particular, it is still unclear why, despite being controlled by a single master regulator, biofilm matrix production and sporulation are mutually exclusive on a single-cell level. In this work, with mathematical modeling, we showed that the fluctuations in the growth rate and the intrinsic noise amplified by the bistability in the SinI-SinR-SlrR network could explain the single-cell distribution of matrix production. Moreover, we predicted an incoherent feed-forward loop: the decrease in the cellular growth rate activates matrix production by increasing in Spo0A phosphorylation level but represses it via changing the relative concentrations of SinR and SlrR. Experimental data provide evidence to support model predictions. In particular, we demonstrate how the degree to which matrix production and sporulation appear mutually exclusive is affected by genetic perturbations.ImportanceThe mechanisms of cell-fate decisions are fundamental to our understanding of multicellular organisms and bacterial communities. However, even for the best-studied model systems we still lack a complete picture of how phenotypic heterogeneity of genetically identical cells is controlled. Here, using B. subtilis as a model system, we employ a combination of mathematical modeling and experiments to explain the population-level dynamics and single-cell level heterogeneity of biofilm gene expression. The results demonstrate how the two cell fates, biofilm matrix production and sporulation, can appear mutually exclusive without explicitly inhibiting one another. Such a mechanism could be used in a wide range of other biological systems.
Deciphering the conformations and dynamics of FG-nucleoporins in situ
Authors: Yu M. , Heidari M. , Mikhaleva S. , Tan P.S. , Mingu S. , Ruan H. , Reinkermeier C.D. , Obarska-Kosinska A. , Siggel M. , Beck M. , Hummer G. , Lemke E.A. 
Published: July 2022

AbstractThe ∼120 MDa nuclear pore complex (NPC) acts as a gatekeeper for the molecular traffic between the nucleus and the cytosol. Small cargo readily passes through the transport channel, yet large cargo requires specialized nuclear transport receptors. While the scaffold structure that anchors the NPC in the double-layered nuclear envelope has been resolved to remarkable details, the spatial organization of intrinsically disordered nucleoporins (NUPs) within the central channel remains enigmatic. These so-called FG-NUPs account for about one-third of the total mass of the NPC and form the actual transport barrier. Here we combined site-specific fluorescent labeling in non-fixed cells and fluorescent lifetime imaging microscopy (FLIM) to directly decipher the conformations of an essential constituent of the permeability barrier, NUP98, inside the functioning NPCs using Fluorescence resonance energy transfer (FRET). With detailed measurements of the distance distribution of eighteen NUP98 segments combined with coarse-grained modeling, we mapped the uncharted biochemical environment inside the nanosized transport channel. We found that ‘good-solvent’ conditions for a polymer dominate the inside of the nanosized NPC, expand the FG-domain in situ and facilitate nuclear transport, in sharp contrast to the collapsed NUP98 FG-chain in aqueous solution. The combination of fluorescence microscopy, high-resolution electron tomography, and molecular simulation opens a window into the so-far unresolved organization of the FG-NUPs at the center of NPC function, allowing us to reconcile scientific models of nuclear transport.
A fungal secondary metabolism gene cluster enables mutualist-pathogen transition in root endophyteColletotrichum tofieldiae
Authors: Hiruma Kei , Aoki Seishiro , Utami Yuniar Devi , Okamoto Masanori , Kawamura Nanami , Nakamura Masami , Ohmori Yoshihiro , Sugita Ryohei , Tanoi Keitaro , Sato Toyozo , Iwasaki Wataru , Saijo Yusuke 
Published: July 2022

SUMMARYPlant-associated fungi show diverse lifestyles from pathogenic to mutualistic to the host; however, the principles and mechanisms through which they shift the lifestyles require elucidation. The root fungusColletotrichum tofieldiae(Ct) promotesArabidopsis thalianagrowth under phosphate limiting conditions. We reveal aCtstrain, designatedCt3, that severely inhibits plant growth.Ct3pathogenesis occurs through activation of host abscisic acid (ABA) pathways via a fungal secondary metabolism gene cluster related to sesquiterpene ABA and botrydial (BOT) biosynthesis. ABA-BOT cluster activation during root infection suppresses host nutrient uptake-related genes and changes the mineral contents, suggesting its role in manipulating host nutrition states. Conversely, disruption or environmental suppression of the cluster rendersCt3beneficial for plant growth, in a manner dependent on host phosphate starvation response regulators. Our findings indicate that a fungal metabolism cluster provides a means by which infectious fungi modulate lifestyles along the parasitic–mutualistic continuum in fluctuating environments.
Mycobacterium tuberculosis requires the outer membrane lipid phthiocerol dimycocerosate for starvation-induced antibiotic tolerance
Authors: Block Alisha M. , Namugenyi Sarah B. , Palani Nagendra P. , Brokaw Alyssa M. , Zhang Leanne , Beckman Kenneth B. , Tischler Anna D. 
Published: July 2022

ABSTRACTTolerance of Mycobacterium tuberculosis to antibiotics contributes to the long duration of tuberculosis (TB) treatment and the emergence of drug-resistant strains. M. tuberculosis drug tolerance is induced by nutrient restriction, but the genetic determinants that promote antibiotic tolerance triggered by nutrient limitation have not been comprehensively identified. Here, we show that M. tuberculosis requires production of the outer membrane lipid phthiocerol dimycocerosate (PDIM) to tolerate antibiotics under nutrient-limited conditions. We developed an arrayed transposon (Tn) mutant library in M. tuberculosis Erdman and used orthogonal pooling and transposon sequencing (Tn-seq) to map the locations of individual mutants in the library. We screened a subset of the library (~1,000 mutants) by Tn-seq and identified 32 and 102 Tn mutants with altered tolerance to antibiotics in stationary phase and phosphate-starved conditions, respectively. Two mutants recovered from the arrayed library, ppgK::Tn and clpS::Tn, showed increased susceptibility to two different drug combinations in both nutrient-limited conditions, but their phenotypes were not complemented by the Tn-disrupted gene. Whole genome sequencing revealed single nucleotide polymorphisms in both the ppgK::Tn and clpS::Tn mutants that prevented PDIM production. Complementation of the clpS::Tn ppsD Q291* mutant with ppsD restored PDIM production and antibiotic tolerance, demonstrating that loss of PDIM sensitized M. tuberculosis to antibiotics. Our data suggest that drugs targeting production of PDIM, a critical M. tuberculosis virulence determinant, have the potential to enhance the efficacy of existing antibiotics, thereby shortening TB treatment and limiting development of drug resistance.IMPORTANCEMycobacterium tuberculosis causes 10 million cases of active TB disease and over 1 million deaths worldwide each year. TB treatment is complex, requiring at least 6 months of therapy with a combination of antibiotics. One factor that contributes to the length of TB treatment is M. tuberculosis phenotypic antibiotic tolerance, which allows the bacteria to survive prolonged drug exposure even in the absence of genetic mutations causing drug resistance. Here we report a genetic screen to identify M. tuberculosis genes that promote drug tolerance during nutrient starvation. Our study revealed the outer membrane lipid phthiocerol dimycocerosate (PDIM) as a key determinant of M. tuberculosis antibiotic tolerance triggered by nutrient starvation. Our study implicates PDIM synthesis as a potential target for development of new TB drugs that would sensitize M. tuberculosis to existing antibiotics to shorten TB treatment.
β-catenin activity induces an RNA biosynthesis program promoting therapy resistance in T Acute Lymphoblastic Leukemia
Authors: García-Hernández Violeta , Arambilet David , Guillén Yolanda , Lobo-Jarne Teresa , Gekas Christos , Vega-García Nerea , Sentis Inés , Trincado Juan Luis , Márquez-López Ian , Heyn Holger , Camos Mireia , Espinosa Lluis , Bigas Anna 
Published: July 2022

ABSTRACTUnderstanding the molecular mechanisms that contribute to the appearance of chemotherapy resistant cell populations is necessary to improve cancer treatment. We have now investigated the role of β-catenin/CTNNB1 in the evolution of T-Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by β-catenin, TCF/LEF factors and ZBTB33/Kaiso in T-ALL cell lines, which is highly and significantly represented in 5 out of 6 refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of β-catenin target genes involved with RNA-processing function are sufficient to segregate T-ALL refractory patients in three independent cohorts. We demonstrate the implication of β-catenin in RNA and protein synthesis in T-ALL and provide experimental evidence that β-catenin is crucial for the cellular response to chemotherapy, mainly in the cellular recovery phase after treatment.We propose that combination treatments involving chemotherapy plus β-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients.
Interleukin-1α and Leukemia Inhibitory Factor Promote Extramedullary Hematopoiesis
Authors: Barisas Derek A.G. , Kim Minseo , Subramanian Madhav , Kabir Ashraf Ul , Krchma Karen , Wu Jun , Zinselmeyer Bernd H. , Stewart Colin L , Choi Kyunghee 
Published: July 2022

AbstractExtramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, the spleen frequently serves as an EMH organ and provides myeloid cells that may worsen pathology. Here, we examined the relationship between HSPCs and their splenic niche in EMH secondary to solid tumor. We identify an inflammatory gene signature characterized by TNFα expression in HSPCs. We show a role for IL-1α in producing this gene signature and TNFα expression in HSPCs in activating splenic niche activity. We also demonstrate that tumor-derived Leukemia Inhibitory Factor (LIF) induces proliferation of splenic niche cells. IL-1α and LIF display cooperative effects in activating EMH and are both upregulated in some human cancers. Together, these data expand avenues for developing niche-directed therapies and further exploring EMH accompanying inflammatory pathologies like cancer.
Using polygenic risk score about complex traits to predict production performance in crossbreeding of yeast
Authors: Dai Yi , Shi Guohui , Chen Mengmeng , Chen Guotao , Wu Qi 
Published: July 2022

AbstractThe cultivation of hybrids with favorable complex traits is one of the important goals for animal, plant, and microbial breeding practices. A method that can well predict the production performance of hybrids will be of great significance to the whole research and practice. In our study, polygenic risk scores (PRS) were introduced to estimate the production performance of Saccharomyces Cerevisiae. The genetic variation of 971 published isolates and their growth ratios under 35 medium conditions were analyzed by genome-wide association analysis, and the precise p-value threshold for each phenotype was calculated. Risk markers for the above 35 phenotypes were obtained. By estimating genotype of F1 hybrids according to that of the parents, the PRS of 613 F1 hybrids was predicted. There was a significant linear correlation between YPD40 and PRS in F1 and their parents (R2=0.2582, R2=0.2414, respectively), which indicates that PRS can be used to estimate the production performance of individuals and their hybrids. Our method can provide a reference for strains selection and F1 prediction in yeasts cross-breeding, reduce the workload and improve the work efficiency.
Faecal carriage of ESBL-producingEscherichia coliin a remote region of Niger
Authors: Jacquier Hervé , Assao Bachir , Chau Françoise , Guindo Ousmane , Condamine Bénédicte , Magnan Mélanie , Bridier-Nahmias Antoine , Sayingoza-Makombe Nathan , Moumouni Aissatou , Page Anne-Laure , Langendorf Céline , Coldiron Matthew E , Denamur Erick , de Lastours Victoire 
Published: July 2022

SummaryObjectiveWhole genome sequencing (WGS) of extended-spectrum β-lactamase-producingEscherichia coli(ESBL-E. coli) in developing countries is lacking. Here we describe the population structure and molecular characteristics of ESBL-E. colifaecal isolates in rural Southern Niger.MethodsStools of 383 healthy participants were collected among which 92.4% were ESBL-E. colicarriers; 90 of these ESBL-E. colicontaining stools (109 ESBL-E. coliisolates) were further analysed by WGS, using short- and long-reads.ResultsMost isolates belonged to the commensalism-adapted phylogroup A (83.5%), with high clonal diversity. TheblaCTX-M-15gene was the major ESBL determinant (98.1%), chromosome-integrated in approximately 50% of cases, in multiple integration sites. When plasmid-borne,blaCTX-M-15was found in IncF (57.4%) and IncY plasmids (26.2%). Closely related plasmids were found in different genetic backgrounds. Genomic environment analysis ofblaCTX-M-15in closely related strains argued for mobilisation between plasmids or from plasmid to chromosome.ConclusionsMassive prevalence of community faecal carriage of CTX-M-15-producingE. coliwas observed in a rural region of Niger due to the spread of highly diverse A phylogroup commensalism-adapted clones, with frequent chromosomal integration ofblaCTX-M-15. Plasmid spread was also observed. These data suggest a risk of sustainable implementation of ESBL in community faecal carriage.
Mechanisms for the prevention of adolescent intimate partner violence: a realist review of interventions in low- and middle-income countries
Authors: Lowe Hattie , Dobbin Jo , Kiss Ligia , Mak Joelle , Mannell Jenevieve , Watson Daniella , Devakumar Delanjathan 
Published: July 2022

AbstractAdolescent girls are among those at the greatest risk of experiencing intimate partner violence (IPV). Despite adolescence being widely regarded as a window of opportunity to influence attitudes and behaviours related to gender equality, evidence on what works to prevent IPV at this critical stage is limited outside of high-income school-based settings. Even less is understood about the mechanisms of change in these interventions. We conducted a realist review of primary prevention interventions for adolescent IPV in low- and middle-income countries (LMICs) to synthesise evidence on how they work, for whom, and under which circumstances. The review took place in four iterative stages: 1) exploratory scoping, 2) developing initial programme theory, 3) systematic database search, screening and extraction, and 4) purposive searching and refinement of programme theory. We identified eleven adolescent IPV prevention interventions in LMICs, most of which demonstrated a positive impact on IPV experience and/or perpetration (n=10). Most interventions (n=9) implemented school-based or community-based interactive peer-group education to transform attitudes and norms around gender and relationships for behaviour change. The central mechanism of change related to gender transformative content prompting adolescents to critically reflect on their attitudes and relationships, leading to a reconceptualisation of their values and beliefs. This central mechanism was supported by two secondary implementation mechanisms: 1) the design and delivery of interventions: interactive, age-appropriate education delivered in peer-groups provided adolescents a safe space to engage with content and build communication skills, and 2) the target group: social norms interventions targeting the wider community created enabling environments supportive of individual change. This review highlights the immense potential of gender transformative interventions during the critical period of adolescence for IPV prevention. Future interventions should consider the broader drivers of adolescent IPV and ensure intersectionality informed approaches to maximise their potential to capitalise on this window of opportunity.
Medical complaints after 3 vs 2 doses SARS-CoV-2 mRNA vaccination
Authors: Methi Fredrik , Gran Jon Michael , Valberg Morten , Kinge Jonas Minet , Telle Kjetil , Magnusson Karin 
Published: July 2022

AimsTo examine whether individuals vaccinated with three doses of mRNA SARS-CoV-2 vaccines have an altered incidence of medical complaints compared to individuals not vaccinated with three doses.MethodsUsing longitudinal exact 1:1 matching on days since 2nd dose, calendar month and a set of covariates, we obtained a matched sample with 138 581 individuals aged 18-70 years that had the 3rd dose at 20-30 weeks after the 2nd dose and an equally large control group that did not. Main outcomes were medical records of common complaints seen in primary care for up to 90 days after the treatment.ResultsDepending on type of complaint, the estimated 90-day cumulative incidence varied between 70 and 5000 per 100 000 individuals. Among individuals aged 18-44 years, the number of medical complaints was lower for individuals with three doses: Fatigue: 662, 95% confidence interval=473-850, shortness of breath: 160 (90-230) and brain fog: 65 (22-108) fewer per 100 000 vaccinated. No decrease in incidence was observed for musculoskeletal pain, cough or heart palpitations. When individuals where censored from the analysis from the date of positive SARS-CoV-2 test, these absolute differences were smaller. Similar analyses gave higher estimates among individuals aged 45-70 years, yet more ambiguous results when censored at positive test.ConclusionIndividuals vaccinated with dose 3 had reduced incidence of complaints compared to matched controls with only 2 doses. Analyses with vs without censoring at positive test implied that this reduction might be explained by a reduced COVID-19 incidence among the 3-dose-vaccinated.
Influence of family history on penetrance of hereditary cancers in a population setting
Authors: Jackson L , Weedon MN , Harrison JW , Wood AR , Ruth KS , Tyrrell J , Wright CF 
Published: July 2022

AbstractBackgroundWe sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort.MethodsWe analysed 454,712 UK Biobank participants with exome sequence and clinical data. We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for age, sex, death, recruitment centre, screening and prophylactic surgery).ResultsWomen with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was significantly higher in those with a first-degree family history (relative hazard 10.29 and 7.82, respectively) than those without (7.82 and 4.66). Penetrance to age 60 was also higher in those with a family history (44.7% and 24.1%) versus those without (22.8% and 17.9%). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of bowel cancer that was significantly higher in those with a family history (relative hazard 63.7, 68.4 and 12.1) than those without (20.9, 18.6 and 5.9). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (27.1% and 25.2%) versus those without (15.2% and 3.2%).ConclusionsIndividuals with pathogenic cancer syndrome variants are at significantly less elevated risk of cancer in the absence of family history (risk ratio 0.57), so invasive follow-up may be unwarranted.
Establishing causal relationships between sleep and adiposity traits using Mendelian randomisation
Authors: Hayes Bryony L , Vabistsevits Marina , Martin Richard M , Lawlor Deborah A , Richmond Rebecca C , Robinson Timothy 
Published: July 2022

ABSTRACTObjectiveTo systematically evaluate the direction of any potential causal effect between sleep and adiposity traits.MethodsTwo-sample Mendelian randomization (MR) was used to assess the association of genetically predicted sleep traits on adiposity and vice versa. Using data from UK Biobank and 23andme, the sleep traits explored were morning-preference (chronotype) (N=697,828), insomnia (N=1,331,010), sleep duration (N=446, 118), napping (N=452,633) and daytime-sleepiness (N=452,071). Using data from the GIANT and EGG consortia, the adiposity traits explored were adult BMI, hip circumference (HC), waist circumference (WC), waist-to-hip ratio (WHR) (N=322,154) and child-BMI (N=35,668).ResultsWe found evidence that insomnia symptoms increased mean WC, BMI and WHR (difference in means WC=0.39 SD (95% CI=0.13, 0.64), BMI=0.47 SD (0.22, 0.73) and WHR=0.34 SD (0.16, 0.52)). Napping increased mean WHR (0.23 SD (0.08, 0.39). Higher HC, WC, and adult-BMI increased odds of daytime-sleepiness (HC=0.02 SD (0.01, 0.04), WC=0.04 SD (0.01, 0.06) and BMI 0.02 SD (0.00, 0.04), respectively). We also found that higher mean child-BMI resulted in lower odds of napping (−0.01 SD (0.02, 0.00).ConclusionsThe effects of insomnia on adiposity, and adiposity on daytime-sleepiness, suggest that poor sleep and weight gain may contribute to a feedback loop that could be detrimental to overall health.