bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics
Authors: Lo Chris Wai Hang , Gillett Alexandra C. , Iveson Matthew H. , Kamp Michelle , Fabbri Chiara , Wong Win Lee Edwin , Handley Dale , Pain Oliver , Vassos Evangelos , Wray Naomi R. , Whalley Heather C. , Li Danyang , Young Allan H. , Mcintosh Andrew M. ,   AMBER Research Team, Lewis Cathryn M. 
Published: November 2024

AbstractBackgroundSelective serotonin reuptake inhibitors (SSRIs) are a first-line pharmacological therapy in major depressive disorder (MDD), but treatment response rates are low. Clinical trials lack the power to study the genetic contribution to SSRI response. Real-world evidence from electronic health records provides larger sample sizes, but novel response definitions are needed to accurately define SSRI non-responders.MethodsIn UK Biobank (UKB) and Generation Scotland, SSRI switching was defined using a ≤ 90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Non-switchers were participants with ≥ 3 consecutive prescriptions for an SSRI. In UKB, clinical, demographic and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated.ResultsIn UKB, 5,133 (13.2 %) SSRI switchers and 33,680 non-switchers were defined. The mean time to switch was 28 days. Switching patterns were consistent across UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (OR [95% CI] for university degree compared to no qualifications: 0.727 [0.666-0.794]) were associated with lower levels of switching. PGS for non-remission, based on clinical studies, were associated with increased risk of switching (OR: 1.07 [1.02-1.12], p = 0.007). MDD PGS and family history of depression were not significantly associated with switching. The heritability (h2) of SSRI switching was approximately 4% on the observed scale.ConclusionThis study identified SSRI switching as a proxy of drug non-response, scalable across biobanks, capturing demographic and genetics of treatment non-response, and independent of the genetics of MDD.
Differential Impacts of the COVID-19 Pandemic on Sociodemographic Groups in England: A Mathematical Model Framework
Authors: Oyedele Gbeminiyi J. , Vlaev Ivo , Tildesley Michael J. 
Published: November 2024

AbstractThe Coronavirus disease-2019 (COVID-19) pandemic has had a significant impact on the world, redefining how we work, respond to public health emergencies and control efforts, and sparking increased research efforts. In this study, we have developed a deterministic, ordinary differential equation multi-risk structured model of the disease outcomes, with a focus on the total number of infections, reported cases, hospitalised individuals, and deaths in the population. The model takes into account sociodemographic risk-structure and age structured dynamics, as well as time-sensitive nonpharmaceutical interventions (lockdowns) to help observe the disease trajectory following the implementation of control measures. The primary focus of this study is to demonstrate the impact of different patterns of social mixing within and between deprivation deciles in England, to understand disparities in disease outcomes. Our analysis reveals that the diagonal kind of mixing, similar to “within-group homogenous” type of mixing assumption, results in a higher number of disease outcome compared to other types of mixing assumptions. We also explore the effectiveness of movement restriction (the first national lockdown) in controlling the spread of the virus in each social group, in order to understand how to target interventions in the future. Our analysis confirms significant disparities in infection outcomes between sociodemographic groups in England.Author summaryThe global impact of the coronavirus pandemic 2019 was evident, but different sociodemographic groups experienced disproportionate disease outcomes. In this paper, we present results from a mathematical model that simulates COVID-19 outcomes across diverse sociodemographic groups in England. Our work uses a mathematical framework that combines age and deprivation decile, to examine the disproportionate outcome in the number of infection, hospitalisation, and mortality based on social mixing patterns. Our work demonstrated the elevated risk for more deprived groups, where social and occupational factors increase contact rates, therefore intensifying disease spread. By distinguishing disease dynamics among deprivation deciles, this model offers insights for policymakers to design more equitable health strategies. This approach emphasis the need for policies that address the vulnerabilities of specific social groups to mitigate the effects of pandemics.
Health care worker's perspective on the MDR-TB treatment guidelines in South Africa
Authors: Ramasir Serisha , Oosthuizen Frasia , Bangalee Varsha 
Published: November 2024

Background Treatment guidelines are developed and updated according to evidence-based research. Healthcare workers in the public health sector are responsible for the implementation of said guidelines. The multi-drug resistant tuberculosis (MDR-TB) guideline has undergone major changes over the past 5 years. These changes included shorter treatment regimens and the introduction of novel drugs. These changes have consequently impacted the management of MDR-TB patients. Objectives To establish healthcare workers' perspectives on the MDR-TB guidelines and managing patients with MDR-TB. Methods Healthcare workers employed in MDR-TB departments at Murchison District Hospital in KwaZulu-Natal were invited to complete a written questionnaire. These healthcare workers comprised of doctors, nurses, pharmacists, and data capturers. The questionnaire consisted of both open- and closed-ended questions. Descriptive statistics were generated for closed-ended questions using SPSS (version 25). Open-ended questions were transcribed onto Microsoft Excel and analyzed for common and emerging themes. Results There were 44 staff employed in the inpatient and outpatient MDR-TB unit. Thirty-four of participants agreed to participate in the questionnaire. HIV co-infection was highlighted as a contributor to complicating the management of MDR-TB patients. The most common co-morbidities associated with MDR-TB patients were diabetes, anaemia and hypertension. The socioeconomic influence on outcomes were highlighted throughout patient responses. Conclusion The MDR-TB program has come been progressive in its approach to gaining control over MDR-TB. The SBR is an effective regimen with a few safety concerns. The nature of ADRs associated with the regimen are serious with myelosuppression highlighted as a common ADR. The impact of socio-economic factors on treatment outcomes is an important factor that should be considered in addition to MDR-TB regimens. The BPaL regimen may offer benefits of a shorter duration and reduced pill burden but there are concerns over the safety of the regimen. The success of the MDR-TB program requires a holistic approach combining patient factors with an effective, safe and convenient regimen.
Medical Students’ Knowledge, Attitudes, and Motivation towards Antimicrobial Resistance Efforts in Eastern Uganda
Authors: Babuya Jonathan , Waruingi Daniel , Mungujakisa Douglas , Ahimbisibwe Osmas , Kako Victoria Ruth , Aporu Faith , Mugume Emmanuel , Nyamupachitu Julian , Kiyimba Kenedy 
Published: November 2024

AbstractIntroductionTo promote holistic learning about Antimicrobial Resistance (AMR), catalyze multidisciplinary engagement, and innovative AMR interventions, it is important that learning goes beyond the classroom and students embrace different extracurricular interventions. This study aimed to determine knowledge, attitudes, and motivations influencing medical students’ engagement in AMR Club Initiatives at Busitema University in Uganda.MethodologyThis was descriptive cross-sectional study conducted at Busitema University among undergraduate student pursuing Bachelors of Medicine and Surgery, Bachelor of Nursing, and Bachelor of Science in Anesthesia and Critical care. A semi structured pre-tested questionnaire was shared among the study participants. Bloom cut-off method was used to analyse the knowledge of the participants, chi square test used for bivariate analysis and multivariable logistic regression used for determining factors independently associated to students’ engagement in AMR club activities.Results71.5% of the 193 students had sufficient knowledge (determined using Bloom’s cutoff categories from 60% and above as sufficient and below 60% as insufficient) on AMR with an average score of 68.18% (SD= ±16.12). 90% of participants recognized the significance of incorporating AMR within their curriculum, and 87.5% appreciated the need for training AMR using a One Health ApproachThe most common reasons why students engaged in extracurricular efforts to address AMR such as forming AMR clubs were found to be; influence from peers (n= 42), university support (n=35), and inspiration from peer mentors’ work (n=35).ConclusionThe students were found to have a high level of knowledge and positive attitudes towards AMR but reported the need for further in-depth training. Extra-curricular engagement such as participation in an AMR Club was found to positively influence students’ engagement in AMR interventions.
Evaluation of a prioritization system for mild traumatic brain injury case ascertainment from emergency department records
Authors: MacMillan Katherine , Klotz Tasha , Silverberg Noah D. 
Published: November 2024

AbstractObjectiveTo evaluate modifications to a tiered priority chart review system designed to efficiently identify patients with mild traumatic brain injury (mTBI), via medical chart review, that presented to an emergency department or urgent and primary care center (ED/UPCC) for research purposes.MethodsWe initially created a tiered priority chart review system and applied it to screening N=17,072 electronic ED/UPCC medical charts in study 1 (Clinicaltrials.govID#NCT04704037). Chief complaints with high positive predictive value (PPV) for correctly identifying possible/probable mTBI cases were moved to a higher tier and those with low positive predictive value were downgraded to create a tiered priority chart review system. This revised system was then used in a second research study (Clinicaltrials.govID#NCT05365776), and PPV values were calculated for the new sample (N=4,434). The original and revised tiered priority system were compared with respect to overall efficiency.ResultsPPV for specific chief complaint key terms varied markedly from 0% to 61% and resulted in an empirically-driven resorting of the priority tiers. After excluding clearly ineligible participants, 49% of charts reviewed in the first study and 60% of charts reviewed in the second study were identified as a possible or probable mTBI. This indicates an improvement in overall efficiency (12%; χ2(1)=114.7, p<.001) compared to the original system.ConclusionThe revised tiered priority chart review system was more efficient at identifying patients with mTBI for the purposes of mTBI study recruitment.
Bivalent interaction through an intrinsically disordered linker promotes transcription activation complex assembly in Notch signaling
Authors: Cook Cyril , Ramsey Kristen M. , Barrick Doug 
Published: November 2024

AbstractThe Notch signaling pathway regulates cellular differentiation by activating transcription through an unusual heterotrimeric complex comprising the Notch receptor’s intracellular domain (NICD), the DNA-binding protein CSL, and the coactivator MAML. NICD has two binding sites for CSL, a short motif in the RAM region and an ankyrin domain (ANK), connected by an intrinsically disordered linker and which form a bivalent ternary complex with CSL and MAML. Although bivalency is required for maximal transcription activation, the energetic contributions of bivalency and heterotrimer formation within this essential complex are unknown. To elucidate the energetics of bivalency we first determine the free energy of the CSL-ANK-MAML heterotrimer, using isothermal titration calorimetry and developing an obligate heterotrimer model to analyze the data. By comparing this heterotrimerization reaction with binding reactions involving different regions of RAMANK, we determine the energetic contribution of bivalency to heterotrimer assembly. We show that bivalency through the disordered linker increases the effective concentration of ANK, and that the bivalent interaction enhances occupancy of RAM and ANK at their binding sites on CSL by about three orders of magnitude. By redefining the standard state to a lower, more physiological protein concentration, we reveal the importance of the RAMANK intrinsically disordered linker for assembly of the Notch transcription activation complex. This work provides a framework whereby the energetic contributions of intrinsically disordered linkers to higher-order multivalent assembly may be analyzed.
Assessment of the Genetic Diversity of Atlantic Bottlenose Dolphin (Tursiops truncatus) Strandings in the Mississippi Sound (USA)
Authors: Arick Mark A. , Landrau-Giovannetti Nelmarie , Hsu Chuan-Yu , Grover Corrinne E. , Reichley Stephen , Magbanua Zenaida V. , Pechanova Olga , Moore Debra , Kayal Ehsan , Linhoss Anna , Madrigal Theresa , Peterman Mark , Ozdemir Ozan , Peterson Daniel G. , Solangi Moby , Lawrence Mark , Karsi Attila 
Published: November 2024

AbstractThe common bottlenose dolphin (Tursiops truncatus) is a key marine mammal species in the northern Gulf of Mexico, playing an essential role as a top predator. This study focuses on the genetic diversity and population structure of bottlenose dolphins stranded in the Mississippi Sound from 2010 to 2021. A total of 511 tissue samples (muscle, liver, lung, kidney, and brain) were collected from stranded dolphins, and mitochondrial DNA (mtDNA) was extracted for analysis. Using high-throughput sequencing methods, 417 samples were successfully amplified and sequenced, producing 386 complete mitogenomes. Genetic diversity metrics, such as nucleotide and haplotype diversity, were calculated, and population structure was inferred for both mitochondrial control region (mtCR) and whole mitogenome sequences. Using the whole mitogenome, the study identified four genetically distinct populations within the Mississippi Sound, demonstrating regional variation in dolphin populations. Notably, some individuals likely originated from populations outside the sampled area. The use of whole mitogenomes allowed for improved resolution of genetic diversity and population differentiation compared to previous studies using partial mtDNA sequences. These findings provide critical insights into the genetic structure of bottlenose dolphins in the region and highlight the value of using stranded animals for population genetic studies.
Pfs230 Domain 12 is a potent malaria transmission-blocking vaccine candidate
Authors: Inklaar Maartje R. , de Jong Roos M. , Da Dari F. , Hubregtse Lisanne L. , Meijer Maartje , Teelen Karina , van de Vegte-Bolmer Marga , van Gemert Geert-Jan , Stoter Rianne , Nagaoka Hikaru , Tsuboi Takafumi , Takashima Eizo , Spruijt Cornelia G. , Vermeulen Michiel , Dabire Roch K. , Arinaitwe Emmanuel , Cohuet Anna , Bousema Teun , Jore Matthijs M. 
Published: November 2024

AbstractMalaria transmission-blocking vaccines (TBV) target sexual stage parasites that are transmitted to mosquitoes and critical for spread of the pathogen. The clinically most advanced TBV candidate contains part of the Pro-domain (Pro) and Domain 1 (D1) ofPlasmodium falciparumsurface protein Pfs230. Subunit vaccines that contain other domains of Pfs230 have so far failed to induce functional antibodies. Here, we produced eight single domain fragments of Pfs230 inDrosophila melanogasterS2 cells and assessed their immunogenicity in mouse immunizations. In addition to D1-specific antibodies, antibodies raised against Domain 12 (D12) showed strong recognition of Pfs230 on the surface of female parasites. Importantly, D12-specific antibodies showed strong functional transmission-reducing activity in membrane feeding assays with cultured parasites, an activity that was complement-dependent. Murine D12-specific antibodies further reduced mosquito transmission of parasites acquired from naturally infected parasite carriers. The D12 antigen was recognized by sera from an all-age cohort of individuals who had been naturally exposed toPlasmodium falciparumwith antibody levels increasing with age. In conclusion, we identified Pfs230D12 as a promising new TBV candidate.Impact statementPfs230 Domain 12 induces antibodies in mice that strongly reduce transmission of lab-cultured and naturally circulating malaria parasites to mosquitoes.
Stability of the polarization agent AsymPolPOK in intact and lysed mammalian cells
Authors: Lagasca Dominique , Ghosh Rupam , Xiao Yiling , Frederick Kendra K. 
Published: November 2024

ABSTRACTDynamic nuclear polarization (DNP) solid-state NMR enables detection of proteins at endogenous concentrations in cells through sensitivity enhancement from nitroxide biradical polarization agents. AsymPolPOK, a novel water-soluble asymmetric nitroxide biradical, offers superior sensitivity and faster build-up times compared to existing agents like AMUPol. Here, we characterize AsymPolPOK in mammalian HEK293 cells, examining its cellular distribution, reduction kinetics, and DNP performance. We demonstrate that electroporation achieves uniform cellular delivery of AsymPolPOK, including nuclear permeation, with no cytotoxicity at millimolar concentrations. However, the cellular environment rapidly reduces AsymPolPOK to its monoradical form, with one nitroxide center showing greater reduction resistance than the other. While AsymPolPOK maintains high DNP enhancements and short build-up times in lysates, its performance in intact cells depends critically on delivery method and exposure time to cellular constituents. Electroporation yields higher, more uniform enhancements compared to incubation, but prolonged exposure to the cellular environment diminishes DNP performance in both cases. These findings establish the potential of AsymPolPOK as a polarization agent for in-cell DNP NMR while highlighting the need for developing more bio-resistant polarization agents to further advance cellular structural biology studies.
Movement ecology of captive-bred axolotls in restored and artificial wetlands: conservation insights for amphibian reintroductions and translocations
Authors: Ramos Alejandra G. , Mena Horacio , Schneider David , Zambrano Luis 
Published: November 2024

AbstractAmphibians are among the most endangered vertebrates globally due to habitat loss, environmental degradation, and urban expansion. The Mexican axolotl (Ambystoma mexicanum), a critically endangered aquatic species endemic to Xochimilco, exemplifies these challenges. This study evaluates the viability of restored and artificial wetlands for axolotl conservation by comparing movement patterns, home range sizes, and habitat use. Using VHF telemetry, we tracked captive-bred axolotls released into both environments. Axolotls survived and foraged successfully in both sites, with those in La Cantera Oriente (LCO) exhibiting larger home ranges and greater daily distances traveled than those in Xochimilco. A quadratic relationship between water temperature and movement indicated a narrow thermal preference. Additionally, age and sex influenced movement patterns, with younger axolotls and females traveling greater distances. Recaptured individuals gained weight, suggesting successful adaptation, although two axolotls were lost to avian predation in Xochimilco after the study concluded. These findings highlight the potential of artificial wetlands like LCO for axolotl conservation by providing stable conditions that may mitigate habitat degradation and climate change impacts. The study recommends integrating native and artificial habitats into conservation strategies, incorporating predator awareness training before release, and ongoing habitat monitoring to enhance survival outcomes for this iconic species.
The metabolic pathways underlying dynamic heterosis for plant height are robust biomarkers in rice
Authors: Dan Zhiwu , Chen Yunping , Huang Wenchao 
Published: November 2024

AbstractRobust biomarkers for complex phenotypes enable accurate predictions not only across different populations and environments but also developmental stages because quantitative changes in specific molecules over time are directly connected to phenotypic transformations that determine outcomes of both crop agronomic traits and human diseases. In this study, we conducted a network analysis of untargeted metabolite profiles to investigate dynamic heterosis for rice plant height, a trait that varies during development and contributes to yield heterosis. We found that the levels of pyruvaldehyde were predictive of height heterosis at the seedling stage, while 4-hydroxycinnamic acid showed significant positive correlations with height heterosis across all four developmental stages examined. Our analysis identified metabolic pathways associated with height heterosis, revealing that metabolomic variations at the elongation stage had a more substantial impact than those at other stages. We developed 11 significantly enriched pathways into metabolomic biomarkers with robust predictability for mature hybrids from another population grown under different conditions. This work elucidates the metabolomic landscape of dynamic height heterosis in rice and provides a practical strategy for identifying biomarkers capable of predicting complex phenotypes, irrespective of discrepancies in population, environment, and developmental stage.
Entangled adaptive landscapes facilitate the evolution of gene regulation by exaptation
Authors: Westmann Cauã Antunes , Goldbach Leander , Wagner Andreas 
Published: November 2024

AbstractExaptation, the co-option of existing traits for new functions, is a central process in Darwinian evolution. However, the molecular changes leading to exaptations remain unclear. Here, we investigated the potential of bacterial transcription factor binding sites (TFBSs) to evolve exaptively for the three globalE. colitranscription factors (TFs) CRP, Fis, and IHF. Using a massively parallel reporter assay, we mapped three combinatorially complete adaptive landscapes, encompassing all intermediate sequences between three pairs of strong TFBSs for each TF. Our results revealed that these landscapes are smooth and navigable, with a monotonic relationship between mutations and their impact on gene regulation. Starting from a strong TFBS for one of our TFs, Darwinian evolution can create a strong TFBS for another TF through a small number of individually adaptive mutations. Notably, most intermediate genotypes are prone to transcriptional crosstalk – gene regulation mediated by both TFs. Because our landscapes are smooth, Darwinian evolution can also easily create TFBSs that show such crosstalk whenever it is adaptive. Our study presents the first in vivo evidence that new TFBSs can evolve exaptively through multiple small and adaptive mutational steps. It also highlights the importance of regulatory crosstalk for the diversification of bacterial gene regulation.