bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethambutol and Meropenem/Clavulanate Synergy Promotes Enhanced Extracellular and Intracellular Killing ofMycobacterium tuberculosis
Authors: Olivença Francisco , Pires David , Silveiro Cátia , Gama Bianca , Holtreman Frederico , Anes Elsa , Catalão Maria João 
Published: October 2023

AbstractIncreasing evidence supports the repositioning of beta-lactams for tuberculosis (TB) therapy. However, additional research on the interaction of these drugs with conventional anti-TB agents is still warranted. Since the complex cell envelope ofMycobacterium tuberculosis(Mtb) may pose an additional obstacle to the diffusion of beta-lactams, an improved activity upon combination with drugs that inhibit the synthesis of outer cell wall elements is particularly relevant. In this context, we aimed to determine potential synergies between beta-lactams and the antimycobacterial drugs ethambutol and isoniazid. This was followed by experiments that aimed to confirm if the increased antimicrobial effects remained within the intracellular milieu and if they promoted heightened immune responses. Results of checkerboard assays with H37Rv and eight clinical isolates, including four drug-resistantMtbstrains, exposed that only the treatments containing ethambutol and beta-lactams achieved synergistic effects, while the standard ethambutol and isoniazid association failed to produce synergy in any of the tested isolates. InMtb-infected THP-1 macrophages, combinations of ethambutol with increasing meropenem concentrations consistently displayed superior killing activities over the individual antibiotics. Flow cytometry with BODIPY FL vancomycin, which binds directly to the peptidoglycan, confirmed an increased exposure of this layer after co-treatment. This was reinforced by the high IL-1β secretion levels found in infected macrophages after incubation with concentrations of meropenem above 5 mg/L, which indicated an exposure of the host innate response sensors to pathogen-associated molecular patterns in the PG. Our findings show that the proposed impaired access of beta-lactams to periplasmic transpeptidases is counteracted by concomitant administration with ethambutol. The efficiency of this combination may be attributed to the synchronized inhibition of arabinogalactan and peptidoglycan synthesis, two key cell wall components. Given that beta-lactams exhibit a time-dependent bactericidal activity, a more effective pathogen recognition and killing prompted by this association may be highly beneficial to optimize TB regimens containing carbapenems.
Energy metabolism modulates the regulatory impact of activators on gene expression
Authors: Qiao Sha , Bernasek Sebastian , Gallagher Kevin D. , Yamada Shigehiro , Bagheri Neda , Amaral Luis A.N. , Carthew Richard W. 
Published: October 2023

ABSTRACTGene expression is a regulated process fueled by ATP consumption. Therefore, regulation must be coupled to constraints imposed by the level of energy metabolism. Here, we explore this relationship both theoretically and experimentally. A stylized mathematical model predicts that activators of gene expression have variable impact depending on metabolic rate. Activators become less essential when metabolic rate is reduced and more essential when metabolic rate is enhanced. We find that in theDrosophilaeye, expression dynamics of theyangene are less affected by loss of EGFR-mediated activation when metabolism is reduced, and the opposite effect is seen when metabolism is enhanced. The effects are also seen at the level of pattern regularity in the adult eye, where loss of EGFR-mediated activation is mitigated by lower metabolism. We propose that gene activation is tuned by energy metabolism to allow for faithful expression dynamics in the face of variable metabolic conditions.
tRNA modifications inform tissue specific mRNA translation and codon optimization
Authors: Ando Daisuke , Rashad Sherif , Begley Thomas J , Endo Hidenori , Aoki Masashi , Dedon Peter C , Niizuma Kuniyasu 
Published: October 2023

AbstractThe tRNA epitranscriptome has been recognized as an important player in mRNA translation regulation. Our knowledge of the role of tRNA epitranscriptome in fine-tuning translation codon decoding at tissue or cell levels remains incomplete. Here, we analyzed seven tissues from mice for the expression of tRNA modifications and mature tRNAs as well as mRNA translation and codon decoding. Our analysis revealed distinct enrichment patterns of tRNA modifications in tissues. Queuosine (Q) tRNA modification was most enriched in the brain compared to other tissues, while mitochondrial tRNA modifications and tRNA expression was highest in the heart. Using three different metrics for codon analysis; isoacceptors frequencies, total codon frequencies, and A-site pausing, we revealed a strong bias towards A/T ending codons in most tissues except for the brain. Using this observation, we synthesized, and deliveredin vivo, codon mutated EGFP for Q-codons, where the C-ending Q-codons were replaced with U-ending codons. The protein levels of mutant EGFP were downregulated in liver, which is poor in Q, when NAC codons were exchanged for NAU codons, while in brain EGFP levels did not change. This data shows that understanding tRNA modifications enrichments across tissues is not only essential for understanding codon decoding and bias, but it can also be utilized for optimizing gene and mRNA therapeutics to be more tissue, cell, or condition specific.
“He stepped on my belly” An exploration of Intimate Partner Violence Experience and Coping Strategies among Pregnant Women in Southwestern-Uganda
Authors: Katushabe Eve , Ndinawe JohnBosco , Editor Abeneitwe , Agnes Katusiime , Nakidde Gladys , Asiimwe John Baptist , Batwala Vincent 
Published: October 2023

AbstractIntimate Partner Violence (IPV) associated with pregnancy remains a challenge globally and in the Ugandan context. However, literature on IPV experiences, support seeking and coping strategies during pregnancy remains limited in Uganda. This study explored the pregnant women’s IPV experiences, support seeking and coping strategies in Southwestern Uganda. Pregnant women with IPV experience during the index pregnancy were purposively approached for in-depth interviews and saturation of data was reached at 25 respondents. Data was analyzed inductively using thematic analysis.Women voiced experiences of IPV that included partners: spending nights away from home without any communication, refusal of accompaniment for antenatal care contacts, uncomfortable sexual intercourse positions, forced sexual intercourse, being slapped, punched, and kicked, failure to pay bills like rent, children’s school fees, transport money to seek medical care and food. Women preferred sharing IPV experiences with their biological mothers to midwives or any other person and some kept it to themselves. The main support given by their support systems was encouraging the victims to try and maintain their marriage and keeping quiet when the partner starts quarreling. Women coped by confiding in their relatives, keeping silent, self-consolation, tolerance of the perpetrator since they financially depended on them, distracting bad thoughts through thinking about good things like friends, self-blame and praying to God. Pregnant women did not understand the role of midwives in IPV nor did the midwives’ inquire about the IPV experience during Antenatal care contacts.The findings of this study point to the need for the Health system to incorporate a user friendly IPV screening tool onto the ANC card to enhance routine IPV screening by midwives and recruit counselors and peer supporters to assist midwives in providing individualized psychological support.
Competing risks multi-state model for time-to-event data analysis of HIV/AIDS: A retrospective cohort national datasets, Ethiopia
Authors: Kumsa Tsegaye Hailu , Mulu Andargachew , Mihret Adane , Asfaw Zeytu G. 
Published: October 2023

AbstractIntroductionWhen HIV/AIDS patients die from opportunistic infections that cause death to happen more quickly, competing dangers are present. The objective of the current study was to estimate the probability of HIV/AIDS patients dying from competing illnesses such as tuberculosis, diarrhea, other opportunistic infections, and unidentified infections.MethodsAll regional states, including the administrative cities of Addis Abeba and Dire Dawa, a retrospective cohort research was carried out between November 2019 to March 2020. There were 39590 HIV-positive individuals considered. We used competing risk models with a time-to-death horizon of 1212 for the total number of HIV-positive people. A competing event was thought to be death from various causes.ResultsOut of the total 1212 deaths, 542(44.7%) died competing with other opportunistic infection (TE-Esophageal Candidiasis, TO-oral, CT-CNS Toxoplasmosis, CM-Crypotococcal Meningitis…), 421 (34.7%) died due to tuberculosis and the remaining death were unknown/Not specified infection 222(18.3%) and diarrhea 27(2.2%). Rates of mortality caused by tuberculosis, competing with other opportunistic infection, diarrhea and unknown/Not specified were 3.5, 4.5, 0.2 and 1.8 per 1000 person-months, respectively. Responding to combined Antiretroviral Treatment (cART) 6 months after initiation, receiving Pneumocystis Pneumonia (PCP) prophylaxis, and higher CD4 count at diagnosis reduced the hazard of tuberculosis, other opportunistic infection and unknown and diarrhea causes of death. However, older age, late HIV.AIDS diagnosis, and the last HIV/AIDS WHO clinical stages increased the hazard of tuberculosis and other opportunistic disease mortality. Additionally, male gender, older age and last HIV clinical stages increased the mortality HIV/AIDS patients.ConclusionThe findings of this study demonstrated that TB, an opportunistic infection, was the primary cause of death in HIV/AIDS patients, despite the presence of several competing risks, such as diarrhea, other infections, and an undetermined or unclear cause. It’s important to use effective techniques to quickly detect those who have HIV or AIDS and provide them with care and treatment to increase their chances of surviving.
The experiences and impact of the COVID-19 pandemic on Young Carers: practice implications and planning for future health emergencies
Authors: Hayes D , Fancourt D , Burton A 
Published: October 2023

AbstractBackgroundYoung Carers faced significant challenges brought on by the COVID-19 pandemic. We explored the impact of the pandemic and associated restrictions on mental health, wellbeing and access to support in Young Carers in the United Kingdom (UK) to understand how to improve services, as well as support this population in future health emergencies.MethodWe conducted 22 qualitative semi-structured interviews from May to November 2021, with 14 Young Carers and 8 staff working in organisations that supported them. Interviews took place remotely over video or telephone call, discussing topics such as experiences of the pandemic on their health, wellbeing and caring responsibilities. We used reflexive thematic analysis to analyse interview transcripts.ResultsWe identified 4 overarching themes pertaining to the impact of the pandemic and associated restrictions on mental health, wellbeing, and access to support in Young Carers in the UK: 1) challenges to following the guidelines, 2) changes to and loss of routine, 3) changes in provision of informal and formal support and 4) better understanding of inner resilience and goals. Many participants struggled with their mental health and wellbeing as a result of pandemic related restrictions, impacting on support structures for themselves, as well as the individual cared for. However, positive impacts pertained to additional support from local authority and third sector organisations.ConclusionsOur findings highlight some of the changes that affected Young Carers during the COVID-19 pandemic. The impact of changes to routine and a reduction in pre-pandemic support were the greatest concerns reported by participants in this study. The additional support provided by local authority and third sector organisations during social restrictions suggests such organisations could play a greater role in supporting this population going forward, and that schools and Governments may wish to put in additional strategies and provisions to protect this population in the future.
Large-Scale Analysis Reveals Racial Disparities in the Prevalence of ADHD and Conduct Disorders
Authors: Shalaby Noha , Sengupta Sourav , Williams Jamal B. 
Published: October 2023

AbstractObjectiveThe primary purpose of this study is to highlight trends in the prevalence of Attention Deficit/Hyperactivity Disorders (ADHD) and Conduct Disorders (CD) between non-Hispanic White and non-Hispanic Black populations and identify potential diagnostic disparities between these groups.MethodsDe-identified electronic health record data on the TriNetX platform of patients diagnosed with ADHD, CD, or both between January 2013 and May 2023 from 50 healthcare organizations in the US were used to investigate racial and sex disparities in the prevalence of ADHD and CD diagnoses.ResultsWith a cohort of 849,281 ADHD patients and 157,597 CD patients, non-Hispanic Whites were ∼26% more likely to receive ADHD diagnosis and ∼61% less likely to be diagnosed with CD than non-Hispanic Blacks. The mean age of diagnosis of ADHD was over 8 years higher for White patients than for Black patients, with a disproportionately higher number of White patients diagnosed in adulthood, compared to a comparatively negligible number of Blacks diagnosed with ADHD in the same age group. Additionally, Black females were the cohort least likely to be diagnosed with ADHD, while White females were the cohort least likely to be diagnosed with CD.ConclusionsRace disparities exist between Black and White populations, and sex disparities exist within each population. More information is needed to determine contributors to these differences, although implicit biases and systemic racism may be key contributing factors. Presenting evidence and increasing awareness of culturally relevant diagnoses can reduce unconscious bias and move toward more informed and objective psychiatric evaluations.
Conversions between noise exposure metrics 24-hour Leq, Ldn, and Lden: the impact of diurnal local bus traffic patterns on population annoyance in the United States
Authors: Seto Edmund , Huang Ching-Hsuan 
Published: October 2023

AbstractNoise during evening and nighttime hours tends to be associated with high annoyance, which is reflected in the use of community noise exposure metrics, such as the Ldnand Lden, that include penalties during these hours. Transportation noise sources may exhibit distinct diurnal patterns, but the impact of these patterns on different noise metrics has not been thoroughly evaluated, especially within the United States. In this study, we utilized General Transit Feed Specification (GTFS) data from 24 major cities in the U.S. to quantify diurnal traffic patterns for local buses, and the impact of these patterns on differences in noise metrics, such as LDay, LEvening, LNight, Ldn, and Lden, compared to the 24-hour LAeq24, Using mathematical conversions between the noise metrics, we found on average across the cities that the Ldnwas between 2.8 to 3.6 dB higher than the LAeq24, and the Ldenwas also 3.6 to 3.8 dB higher than the LAeq24for noise from local buses. This increase was mainly due to noise during daytime (LDay) that was higher than the 24-hour average noise, and dB penalties added to the Ldnand Ldenmetrics, which compensate for less bus traffic during evening and nighttime hours. We discuss the relevance of these conversions and the observed differences between the 24-hour LAeq24and the Ldnand Lden, which are used for health impact assessments of high annoyance, on public transportation planning.
Immunological variables and tumor types influence one-year survival probability in cancer patients: A comprehensive analysis using logistic regression and decision tree models
Authors: Malizia Alvaro López 
Published: October 2023

AbstractThe present study aimed to explore immunological variables associated with survival, TP53 gene expression, and primary diagnosis in patients with cancer. Based on these variables, logistic regression and decision tree models (lightGBM) were used to model the probability of one-year survival of patients following their initial diagnosis. Logistic regression revealed the significance of primary diagnosis categories such as Malignant Melanoma, Ovarian Cancer, and Glioblastoma as predictor variables. For the classification model, in addition to these tumor types, variables related to the immune system were also found to be important, including tumor cell percentage, stromal cell percentage, lymphocytes, and necrotic cells. In addition, unsupervised classification techniques were employed to explore the numerical dataset. For this methodology, the best clustering cohesion was observed with two groups determined using different algorithms. The clusters generated by k-means and DBSCAN exhibited differences in the proportion of infiltrating lymphocytes, neutrophils, and monocytes.
Engineered yeast cells simulating CD19+ cancers to control CAR T cell activation
Authors: Deichmann Marcus , Schiesaro Giovanni , Ramanathan Keerthana , Zeeberg Katrine , Koefoed Nanna M. T. , Ormhøj Maria , Friis Rasmus U. W. , Gill Ryan T. , Hadrup Sine R. , Jensen Emil D. , Jensen Michael K. 
Published: October 2023

AbstractChimeric antigen receptor (CAR) T cells have become an established immunotherapy and show promising results for the treatment of hematological cancers. However, modulation of surface levels of the targeted antigen in cancer cells affects the quality and safety of CAR T cell therapy. Here we present theSyntheticCellularAdvancedSignalAdapter (SCASA) system, based on successful engineering of yeast to simulate cancer cells with tunable surface-antigen densities, as a tool for controlled activation of CAR T cell responses and assessment of antigen density effects. Specifically, we demonstrate I) controllable antigen-densities of CD19 on yeast using G protein-coupled receptors (GPCRs), II) a customizable system allowing choice of signal input and modular pathway engineering for precise fine-tuning of the output, III) synthetic cell-cell communication with CAR T cells and the application of CD19-displaying yeast in the characterization of CAR designs, and IV) more efficient and robust activational control of clinically-derived CAR T cells in comparison to the NALM6 cancer cell line. Based on this yeast-based antigen-presenting cell system, we envision efficient assessment of how varying antigen densities in cancer cells affect CAR T cell responses and ultimately support development of safer and better quality of personalized cancer therapies.
PredictingPseudomonas aeruginosadrug resistance using artificial intelligence and clinical MALDI-TOF mass spectra
Authors: Nguyen Hoai-An , Peleg Anton Y. , Song Jiangning , Antony Bhavna , Webb Geoffrey I. , Wisniewski Jessica A. , Blakeway Luke V. , Badoordeen Gnei Z. , Theegala Ravali , Zisis Helen , Dowe David L. , Macesic Nenad 
Published: October 2023

AbstractMatrix-assisted laser desorption/ionization–time of flight mass spectrometry (MALDI-TOF MS) is widely used in clinical microbiology laboratories for bacterial identification but its use for prediction of antimicrobial resistance (AMR) remains limited. Here, we used MALDI-TOF MS with artificial intelligence (AI) approaches to successfully predict AMR inPseudomonas aeruginosa, a priority pathogen with complex AMR mechanisms. The highest performance was achieved for modern β-lactam/β-lactamase inhibitor drugs, namely ceftazidime/avibactam and ceftolozane/tazobactam, with area under the receiver operating characteristic curve (AUROC) of 0.86 and 0.87, respectively. As part of this work, we developed dynamic binning, a feature engineering technique that effectively reduces the high-dimensional feature set and has wide-ranging applicability to MALDI-TOF MS data. Compared to conventional methods, our approach yielded superior performance in 10 of 11 antimicrobials. Moreover, we showcase the efficacy of transfer learning in enhancing the performance for 7 of 11 antimicrobials. By assessing the contribution of features to the model’s prediction, we identified proteins that may contribute to AMR mechanisms. Our findings demonstrate the potential of combining AI with MALDI-TOF MS as a rapid AMR diagnostic tool forPseudomonas aeruginosa.
Molecular regulation of PPARγ/RXRα signaling by the novel cofactor ZFP407
Authors: Charrier Alyssa , Ockunzzi Jeremiah , Ghanta Siddharth V. , Buchner David A. 
Published: October 2023

AbstractCofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling. ZFP407 was previously demonstrated to regulate PPARγ target genes such asGLUT4, and its overexpression improved glucose homeostasis in mice. Here, using a series of molecular assays, including protein-interaction studies, mutagenesis, and ChIP-seq, ZFP407 was found to interact with the PPARγ/RXRα protein complex in the nucleus of adipocytes. Consistent with this observation, ZFP407 DNA binding sites significantly overlapped with PPARγ sites, with more than half of ZFP407 binding sites overlapping with PPARγ DNA binding sites. Transcription factor binding motifs enriched in these overlapping sites included GFY-Staf, ELF1, ETS, ELK1, and ELK4, which regulate key functions within adipocytes. Site-directed mutagenesis of frequent PPARγ phosphorylation or SUMOylation sites did not prevent its regulation by ZFP407, while mutagenesis of ZFP407 regions necessary for RXR and PPARγ binding abrogated any impact of ZFP407 on PPARγ activity. These data suggest that ZFP407 controls the activity of PPARγ, but does so independently of post-translational modifications, likely by direct binding, establishing ZFP407 as a newly identified PPARγ cofactor. In addition, ZFP407 was also found to bind to DNA in regions that did not overlap with PPARγ. These DNA binding sites were more significantly enriched for the transcription factor binding motifs of GFY and ZNF143, which may contribute to the non-PPARγ dependent functions of ZFP407 in adipocytes and other cell types.