bluuebunny/crossref_metadata_2025_split huggingface dataset:
The chloroplast located HKT transporter plays an important role in sporophyte development inPhyscomitrium patens
Authors: Yanez-Dominguez Carolina , Macedo-Osorio Karla , Lagunas-Gomez Daniel , Torres-CIfuentes Diana , Castillo-Gonzalez Juan , Zavala Guadalupe , Pantoja Omar 
Published: August 2024

ABSTRACTCell survival depends on the maintenance of cell homeostasis that involves all the biochemical, genomic and transport processes that take place in all the organelles within an eukaryote cell. In particular, ion homeostasis is required to regulate the membrane potential and solute transport across all membranes, any alteration in these parameters will reflect in the malfunctioning of any organelle. In plant cells, sodium transporters play a central role in keeping the concentrations of this cation across all membranes under physiological conditions to prevent its toxic effects. HKT transporters are a family of membrane proteins exclusively present in plants, with some homologs being present in prokaryotes. HKT transporters have been associated to salt tolerance in plants, retrieving any leak of the cation into the xylem, or removing it from aerial parts to be transported to the roots along the phloem. This function has been assigned as most of the HKT transporters are located at the plasma membrane. Here, we report the localization of the moss HKT fromPhyscomitrium patensto the thylakoid membrane, and its mutation that leads to several alterations in the phenotype of the organism, together with the changes in expression of close to 1000 genes. Down regulation of photosynthesis related genes and the upregulation of glycolysis/respiration and ion transport genes help to explain the observed phenotype.
Gasdermin D deficiency attenuates development of ascending aortic dissections in a novel mouse model
Authors: Javed Muhammad J. , Howard Rachael M. , Li Hua , Carrasco Laura , Dirain Marvin L.S , Su Gang , Cai Guoshuai , Upchurch Gilbert R. , Jiang Zhihua 
Published: August 2024

AbstractBackgroundThoracic aortic dissection (TAD) is a silent killer. Approximately two-thirds of the cases occur in the ascending aorta (i.e. type A dissection) and majority of them are unrelated to genetic mutations. However, animal models of spontaneous type A dissection are not widely available. In the present study, a novel mouse TAD model was created. Further, the role of gasdermin D (GSDMD) in TAD development was evaluated.MethodsTADs were created by treating ascending aorta of adult mice (C57BL/6J) with active elastase (40.0 U/ml) and β-aminopropionitrile (Act E+BAPN). The temporal progress of the TAD pathology was rigorously characterized by histological evaluation and scanning electron microscopy, while potential mechanisms explored with bulk RNA sequencing of specimens collected at multiple timepoints. With this novel TAD model, further experiments were performed with Gsdmd−/−mice to evaluate its impact on TAD formation.ResultsThe ascending aorta challenged with Act E+BAPN developed pathology characterized by an early onset of intimomedial tears (complete penetration) and intramural hematoma, followed by progressive medial loss and aortic dilation. Ingenuity Pathway Analysis and functional annotation of differentially expressed genes suggested that a unique inflammatory micro-environment, rather than general inflammation, promoted the onset of TADs by specifically recruiting neutrophils to the aortic wall, while the pathology at the advanced stage was driven by T-cell mediated immune injury. Gsdmd−/−attenuated medial loss, adventitial fibrosis, and dilation of TADs. This protective effect was associated with a reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) positive cells and T-cells in TADs.ConclusionsA novel mouse TAD model was created in the ascending aorta. It produces a unique microenvironment to activate different immune cell subsets, promoting onset and subsequent remodeling of TADs. Consistently, Gsdmd−/−attenuates TAD development, with modulation of cell death and T-cell response likely acting as the underlying mechanism.Graphical Abstract
Multi-omic and functional screening reveal targetable vulnerabilities inTP53mutated multiple myeloma
Authors: Tsallos Dimitrios , Ikonen Nemo , Miettinen Juho J. , Majumder Muntasir Mamun , Eldfors Samuli , Västrik Imre , Parsons Alun , Suvela Minna , Dunphy Katie , Dowling Paul , Bazou Despina , O’Gorman Peter , Lievonen Juha , Silvennoinen Raija , Anttila Pekka , Heckman Caroline A. 
Published: August 2024

ABSTRACTDespite development of several effective therapies for multiple myeloma (MM), the prognosis of patients with partial deletion of chromosome 17 (del(17p)) andTP53aberrations remains poor. By applying comprehensive multi-omics profiling analyses (whole exome and transcriptome sequencing plus proteomics) and functionalex vivodrug screening to samples from 167 patients with MM, we uncovered novel therapeutic vulnerabilities specific toTP53mutated MM. Our findings revealed a distinct sensitivity profile to a range of inhibitors (mitotic, topoisomerase, HDAC, HSP90, IGF1R and PI3K/AKT/mTOR inhibitors) irrespective of 17p deletion status. Conversely, no increase in sensitivity was observed for monoallelicTP53(del(17p) with WTTP53) when compared to WTTP53samples, highlighting the remaining unmet clinical need. Notably, plicamycin, an RNA synthesis inhibitor linked to modulation of chromatin structure and increased transcription, emerged as particularly efficacious forTP53mutated MM. The increased sensitivity correlated with higher protein expression of the drug targets: HDAC2, HSP90AA1 and multiple ribosomal subunits. Additionally, we observed increased RNA expression of G2M checkpoint, E2F targets and mTORC1 signaling in our cohort and the MMRF-CoMMpass (NCT01454297) study inTP53mutated MM. Harmonization of multi-omics data withex vivodrug screening results revealed thatTP53mutated MM is functionally distinct from MM with monoallelicTP53, and demonstrates that MM with mutatedTP53, with and without del(17p), may be targetable by approved drugs. These results further indicate the need for regular monitoring by sequencing to identify these patients.KEY POINTSTP53mutation in myeloma confers sensitivity to multiple compounds, including approved drugs, irrespective of del(17p) status.TP53mutated myeloma links to higher expression of drug targets involved in cell proliferation, mRNA processing, and chromatin modulation.
Comparative Effectiveness Of Bedaquiline On One-Year Mortality In Rifampicin-Resistant Tuberculosis: A Target Trial Emulation
Authors: Ngarega Miriam , Ndebele Felex , Segwaba Pulane , Bohlela Sthabiso , Sibeko Zandile , Setlhare Leole , Scott Lesly E , Stevens Wendy , Fanampe Boitumelo , Charalambous Salome , Churchyard Gavin , Van Rie Annelies 
Published: August 2024

AbstractBackgroundThree phase II clinical trials generated the evidence for recommending bedaquiline for the treatment of rifampicin-resistant tuberculosis (RR-TB). These trials were not powered to assess the effect of bedaquiline on mortality. Observational studies reported lower mortality in patients treated with bedaquiline-containing regimens but did not fully account for differences between patients who did and did not receive bedaquiline in the real world.MethodsUsing data from two studies on 622 patients, of whom 195 initiated a bedaquiline-containing regimen, we applied rigorous causal inference by emulating a trial that would randomize patients diagnosed with RR-TB by the Xpert MTB/RIF assay to a bedaquiline-containing regimen or a non-bedaquiline-containing regimen. We used multiple imputation to address missing data, inverse probability of treatment weighting (IPTW) to emulate randomized assignment and estimated the odds of one-year mortality using a marginal structural logistic model.ResultsBy using IPTW, we achieved conditional exchangeability for observed differences in age, gender, HIV status,Mycobacterium tuberculosisresistance pattern, and history of tuberculosis treatment between patients who did or did not initiate a bedaquiline-containing regimen. By emulating the design of a randomized trial, we found that had all patients been treated with a bedaquiline-containing regimen, there would have been a 67% reduction in the odds of one-year mortality compared to when none of the patients initiated a bedaquiline-containing regimen (OR: 0·33, 95%CI: 0·19-0·59)ConclusionBy emulating a randomized trial using real-world data, our results demonstrate that the initiation of a bedaquiline-containing regimen causes a 67% reduction in the odds of one-year mortality.Key messageWe assessed the causal effect of initiating a bedaquiline-containing regimen compared to a non-bedaquiline-containing regimen on one-year mortality. We found that a bedaquiline-containing regimen causes a 67% reduction in the odds of one-year mortality, underscoring the need for expanded access to such effective regimens.
Implementation of digital chest radiography for childhood tuberculosis diagnosis at district hospital level in six high tuberculosis burden and resources limited countries
Authors: Melingui Bernard Fortune , Joshi Basant , Taguebue Jean-Voisin , Massom Douglas Mbang , Terquem Etienne Leroy , Norval Pierre-Yves , Salomao Angelica , Bunnet Dim , Eap Tek Chhen , Borand Laurence , Khosa Celso , Moh Raoul , Mwanga-Amumpere Juliet , Eang Mao Tan , Manhiça Ivan , Mustapha Ayeshatu , Balestre Eric , Beneteau Samuel , Wobudeya Eric , Marcy Olivier , Orne-Gliemann Joanna , Bonnet Maryline 
Published: August 2024

AbstractObjectivesChest X-ray (CXR) plays an important role in childhood tuberculosis (TB) diagnosis but access to quality CXR remains a major challenge in resource-limited settings. Digital CXR (d-CXR) can solve some image quality issues and facilitate their transfer for quality control. We describe the implementation of introducing d-CXR in twelve district hospitals (DH) in 2021-22 across Cambodia, Cameroon, Ivory Coast, Mozambique, Sierra Leone and Uganda as part of the TB-Speed decentralization study on childhood tuberculosis diagnosis.MethodsFor digitization of CXR Digital Radiography (DR) plates was set-up on existing analogue radiography machines. D-CXR were transferred to an international server at Bordeaux University and downloaded by sites’ clinicians for interpretation. We assessed the pre-intervention (baseline situation and d-CXR set-up) and per-intervention (uptake, challenges and health care workers’ (HCW) perceptions) of d-CXR implementation. We used a convergent mixed method approach utilizing process data, individual interviews with 113 HCWs involved in performing or interpreting d-CXRs and site support supervision reports.ResultsOf 3104 children with presumptive TB, 1642 (52.9%) had at least one d-CXR including 1505, 136 and 1 children with one, two and three d-CXR respectively, resulting in a total of 1780 d-CXR. Of them, 1773 (99.6%) were of good quality and 1772/1773 (99.9%) were interpreted by sites’ clinicians. 164 children had no d-CXR performed despite attending the radiography department: 126, 37 and 1 with one, two and three attempts, respectively. D-CXRs were not performed in 21.6% (44/203) due to connectivity problem between the DR plate captor and the computer. HCWs reported good perceptions of d-CXR and of the DR plates provided. The main challenge was the upload to and download from the server of d-CXRs, due to limited internet access.ConclusionD-CXR using DR plates was feasible at district hospital level and provided good quality images but required overcoming operational challenges.
The impact of financial support and budgeting on medication availability and purchasing behavior in the Nigerian primary healthcare system
Authors: Hagedorn Brittany , Han Rui 
Published: August 2024

AbstractPrevious work has shown that primary healthcare facilities can benefit from both in-kind support (e.g., medication shipments) as well as increased cash-on-hand to spend to address service readiness gaps. However, there is limited evidence on how facility managers choose to spend available cash or how their decisions to manage their facility budgets are affected by in-kind support.Economic theory suggests that the optimal allocation of cash resources would depend on the context and constraints to how it can be spent, and expenditures would in turn affect the availability of supplies and medications. We test this theory using regression analysis on data from the Nigeria Service Delivery Indicators for Health (SDI), a health facility survey from twelve states in 2013 that included both hospitals and primary healthcare centers (PHCs).We find that facilities with financial resources available to them have higher availability of essential medicines, especially if the facility had earmarked some cash for medication expenditures. However, earmarking for other expenditure categories did not have the same effect on medication availability, which indicates that budgeting processes are an important factor in ensuring medication availability. We find that cash support had large effect (p < 0.001) on availability and that in-kind donations had a negative effect on the probability of expenditure of medications. Additionally, we find the difference between hospitals and PHCs is due to their financial situation (variables become insignificant once support variables were in regressions).Regression analyses also showed that facilities that received in-kind medications had higher availability, but this only had a significant effect in facilities that did not have cash available to spend on medications, implying that facilities are able to address their own supply needs when they have resources available to them. Thus, in-kind supplies should be targeted to facilities that cannot otherwise procure them. Overall, facilities appear to be making effective trade-offs in the context of limited resources and they should receive both cash and support for appropriate budgeting and procurement practices.
International healthcare workers’ experiences and perceptions of the 2022 multi-country mpox outbreak
Authors: Apea Vanessa , Titanji Boghuma K. , Dakin Francesca H. , Hayes Rosalie , Smuk Melanie , Kawu Habiba , Waters Laura , Levy Itsik , Kuritzkes Daniel R. , Gandhi Monica , Rockstroh Jürgen , Schechter Mauro , Holt Martin , Palich Romain , Cortes Claudia P. , Nozza Silvia , Mussini Cristina , Calmy Aleaxandra , Crabtree Ramirez Brenda E. , Blanco José L. , Bhagani Sanjay , Dewsnap Claire , Orkin Chloe ,   the Mpox SHARE-NET writing group
Published: August 2024

AbstractIn May 2022, the most widespread outbreak of sustained transmission of mpox outside of countries historically affected countries in Western and Central Africa occurred. We aimed to examine the personal and clinical experiences of international healthcare workers (HCWs) during this public health emergency. We conducted an international cross-sectional survey study between August and October 2022, examining the experiences and perceptions of HCWs clinically involved with the 2022 mpox response. Respondents were recruited via an international network of sexual health and HIV clinicians responding to mpox and promoted through clinical associations and social media. Survey domains included: clinical workload; preparedness; training and support at work; psychological well-being and vaccination. 725 multi-national healthcare workers across 41 countries were included in the analysis. 91% were physicians specialised in Sexual Health or Infectious Diseases; with 34% (n=247) of all respondents involved in mpox policy. A substantial proportion of respondents (n=296, 41%) reported working longer hours during the mpox outbreak, with no concomitant removal of other clinical responsibilities. 30% (n=218) of respondents reported that they had never heard of mpox before the outbreak and over 25% of the respondents reported that they had misdiagnosed someone initially. This culminated in a high prevalence of moral distress at 30%. Less than 9% of HCWs in the region of the Caribbean, Central America and South America had been offered a vaccine as compared to almost 1/3 in the other regions. Where offered, there were high levels of uptake across all regions. Our findings highlight a critical need for addressing the profound gaps in HCW knowledge about re-emerging diseases with pandemic potential. Strengthening the resilience of global health systems and prioritising internationally coordinated approaches to global vaccine deployment is imperative.
The oncometabolite D-2-hydroxyglutarate promotes DNA hypermethylation at lineage-specific enhancers controlling microglial activation in IDHmutgliomas
Authors: Laurenge Alice , Pugliese Pietro , Richard Quentin , Mathon Bertrand , Jouannet Stéphanie , Hayat Yvette , Scuderi Sarah , Capelle Laurent , Marijon Pauline , Labreche Karim , Alentorn Agustí , Verreault Maïté , Idbaih Ahmed , Birzu Cristina , Huillard Emmanuelle , Pottier Nina , Desmons Aurore , Fayache Inès , Kaas Garrett A. , Kingsley Philip J. , Marnett Lawrence J. , Duplus Eric , El-Habr Elias , Salas Lucas A. , Mokhtari Karima , Tran Suzanne , Touat Mehdi , Bielle Franck , Suvà Mario L. , Iavarone Antonio , Ceccarelli Michele , Mallat Michel , Sanson Marc , Castro-Vega Luis Jaime 
Published: August 2024

AbstractTumor-associated macrophages and microglia (TAMs) are highly abundant myeloid cells in gliomas, with their phenotypes and immune responses shaped by ontogeny and microenvironment. TAMs display distinctive transcriptional programs based on the IDH status of tumors, yet the underlying signaling mechanisms remain largely unknown. Herein, we uncover that CD11B+ myeloid cells in human IDH-mutant gliomas exhibit DNA hypermethylation, predominantly at distal enhancers. This hypermethylation impairs the binding of core transcription factors that govern microglial responses, resulting in reduced expression of inflammatory and glycolytic metabolism programs. Prolonged exposure of human primary microglia to D-2-hydroxyglutarate (D-2HG) inhibits TET-mediated demethylation at lineage-specific enhancers, evidenced by elevated 5mC/5hmC ratios near binding motifs. D-2HG-treated microglia showed reduced proinflammatory capacity and enhanced oxidative phosphorylation, consistent with the remodeled enhancer landscape. Conversely, depletion of D-2HG following treatment of a glioma patient with an IDH-mutant inhibitor unleashed microglial reactivity, as assessed by snRNA-seq. Our findings provide a mechanistic rationale for the hyporesponsive state of microglia in IDH-mutant gliomas and support the concept that oncometabolites may disrupt the function of immune cells residing in the tumor microenvironment.
The selective culture and enrichment of major rumen bacteria on three distinct anaerobic culture media
Authors: Buckner Alice M. , Glendinning Laura , Palma Hidalgo Juan M. , van Munster Jolanda M. , Stevens Mark , Watson Mick , Newbold C. Jamie 
Published: August 2024

AbstractRuminants play an important part in global food security, but also emit methane which contributes to global warming. Microbes in the rumen strongly influence the energy retention efficiency from the host’s plant-based diet and produce methane as a by-product. While thousands of novel microbial genomes have been assembled from metagenome sequence data, their culturability is ill-defined. Here different media were used to isolate microbes from rumen fluid. 34 genera were grown, and the majority belonged to the phylumBacillota(75.28% ± 6.34),Bacteroidota(19.99% ± 4.85),Pseudomonadota(2.46% ± 2.01), andActinomycetota(2.09% ± 1.07). The most abundant genera wereSelenomonas(28.08% ± 11.71),Streptococcus(22.67% ± 6.06),Prevotella(18.71% ± 4.02), and unclassifiedLachnospiraceae(11.50% ± 2.54). When comparing the mean relative abundance of these genera between media, 31 were significantly enriched on at least one medium. The composition of the source rumen fluid was vastly different to those cultured.Bacteroidota(52.53% ± 5.10) predominated, with byBacillota(41.00% ± 3.96), the archaealEuryarchaeota(5.12% ± 1.94),Pseudomonadota(1.22% ± 0.78), andActinomycetota(0.12% ± 0.08) comprising the rest. The most abundant genera werePrevotella(29.13% ± 4.16),Butyrivibrio(18.21% ± 2.08),Succiniclasticum(15.57% ± 5.03), unclassifiedBacteroidetes(13.91% ± 1.67), and unclassifiedPrevotellaceae(9.50% ± 2.01). These data further emphasise the importance of using defined media to selectively enrich for different microbial taxa. This is essential to understand the complex workings of the rumen microbes to enhance digestion efficiency and reduce the loss of energy as methane.
Spatio-temporal variability of airborne viruses over sub-Antarctic South Georgia: Effects of sampling device and proximity of the ocean
Authors: Das Ritam , Malard Lucie , Pearce David A. , Rahlff Janina 
Published: August 2024

AbstractStudying airborne viral diversity in pristine, remote environments like the sub-Antarctic island South Georgia provides crucial insights into viral ecology and their role in sustaining unique ecosystems. Viruses influence microbial dynamics and nutrient cycles, which are vital for ecological balance and long-term ecosystem sustainability. We explored the community composition of airborne viral operational taxonomic units (vOTUs) of two sites in South Georgia, using various sampling devices and viral metagenomics. The Coriolis µ device (wet collection) was the most effective, yielding 30 viral scaffolds. Two-thirds of the scaffolds were from sea-level samples, indicating that location impacts viral diversity. Protein-based clustering of 39 vOTUs revealed similarities of 15 with known marine viruses, suggesting oceanic influence on the island’s airborne viral community. Genes related to UV damage protection and photosynthesis from two airborne vOTUs were widely distributed in the major oceans, emphasizing the potential resilience in changing climates. Host predictions indicated associations with bacterial genera likeRickettsia,Myroides, and Bacteroidota. Some vOTUs matched viruses from extremophiles, indicating adaptations to harsh environments. This study provides a baseline for understanding the complexity and sustainability of airborne viral communities in remote ecosystems, underscoring the need for continued monitoring in the face of environmental change.Sustainability StatementAntarctic microbes have potentially unique adaptations to extreme cold and harsh conditions. Viruses that infect these microbes may play a pivotal role in shaping these adaptations and thus understanding virus-host interactions is vital for preserving the unique microbial biodiversity of Antarctica. Moreover, investigating the dynamics of viral aerosolization in and around Antarctica is important for understanding the global dispersal of viruses and their potential impacts on distant ecosystems. Monitoring microbial viruses in Antarctica is essential for tracking community changes over time. Since Antarctica is often considered one of the last pristine environments on Earth, understanding the role of microbial viruses is relevant for developing conservation strategies to protect this ecosystem from potential anthropogenic impacts, including unintentional introduction of foreign microorganisms and viruses. Our research aligns with Sustainable Development Goals Life below water (SDG14) and Life on land (SDG15).