bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of the drug/metabolite transporter 1 as a marker of quinine resistance in a NF54×Cam3.IIP. falciparumgenetic cross
Authors: Kanai Mariko , Mok Sachel , Yeo Tomas , Shears Melanie J. , Ross Leila S. , Jeon Jin H. , Narwal Sunil , Haile Meseret T. , Tripathi Abhai K. , Mlambo Godfree , Kim Jonathan , Gil-Iturbe Eva , Okombo John , Fairhurst Kate J. , Bloxham Talia , Bridgford Jessica L. , Sheth Tanaya , Ward Kurt E. , Park Heekuk , Rozenberg Felix D. , Quick Matthias , Mancia Filippo , Lee Marcus C.S. , Small-Saunders Jennifer L. , Uhlemann Anne-Catrin , Sinnis Photini , Fidock David A. 
Published: September 2024

AbstractThe genetic basis ofPlasmodium falciparumresistance to quinine (QN), a drug used to treat severe malaria, has long been enigmatic. To gain further insight, we used FRG-NOD human liver-chimeric mice to conduct aP. falciparumgenetic cross between QN-sensitive and QN-resistant parasites, which also differ in their susceptibility to chloroquine (CQ). By applying different selective conditions to progeny pools prior to cloning, we recovered 120 unique recombinant progeny. These progeny were subjected to drug profiling and QTL analyses with QN, CQ, and monodesethyl-CQ (md-CQ, the active metabolite of CQ), which revealed predominant peaks on chromosomes 7 and 12, consistent with a multifactorial mechanism of resistance. A shared chromosome 12 region mapped to resistance to all three antimalarials and was preferentially co-inherited withpfcrt. We identified an ATP-dependent zinc metalloprotease (FtsH1) as one of the top candidates and observed using CRISPR/Cas9 SNP-edited lines thatftsh1is a potential mediator of QN resistance and a modulator of md-CQ resistance. As expected, CQ and md-CQ resistance mapped to a chromosome 7 region harboringpfcrt. However, for QN, high-grade resistance mapped to a chromosome 7 peak centered 295kb downstream ofpfcrt. We identified the drug/metabolite transporter 1 (DMT1) as the top candidate due to its structural similarity to PfCRT and proximity to the peak. Deleting DMT1 in QN-resistant Cam3.II parasites significantly sensitized the parasite to QN but not to the other drugs tested, suggesting that DMT1 mediates QN response specifically. We localized DMT1 to structures associated with vesicular trafficking, as well as the parasitophorous vacuolar membrane, lipid bodies, and the digestive vacuole. We also observed that mutant DMT1 transports more QN than the wild-type isoformin vitro. Our study demonstrates that DMT1 is a novel marker of QN resistance and a new chromosome 12 locus associates with CQ and QN response, withftsh1is a potential candidate, suggesting these genes should be genotyped in surveillance and clinical settings.
Zebrafish Polymerase Theta and human Polymerase Theta: orthologues with homologous function
Authors: Thomas Corey , Green Sydney , Kimball Lily , Schmidtke Isaiah R , Griffin Makayla , Rothwell Lauren , Par Ivy , Schobel Sophia , Palacio Yayleene , Towle-Weicksel Jamie B , Weicksel Steven E 
Published: September 2024

ABSTRACTDNA Polymerase Theta (Pol θ) is a conserved an A-family polymerase that plays an essential role in repairing double strand breaks, through micro-homology end joining, and bypassing DNA lesions, through translesion synthesis, to protect genome integrity. Despite its essential role in DNA repair, Pol θ is inherently error-prone. Recently, key loop regions were identified to play an important role in key functions of Pol θ.Here we present a comparative structure-function study of the polymerase domain of zebrafish and human Pol θ. We show that these two proteins share a large amount of sequence and structural homology. However, we identify differences in the amino acid composition within the key loop areas shown to drive characteristic Pol θ functions. Despite these differences zebrafish Pol θ still displays characteristics identify in human Pol θ, including DNA template extension in the presence of different divalent metals, microhomology-mediated end joining, and translesion synthesis. These results will support future studies looking to gain insight into Pol θ function on the basis of evolutionarily conserved features.
Homeodomain protein codes specify neuronal diversity in the first ganglion of theDrosophilavisual system
Authors: Xu Chundi , Newstein Peter , Sastry Rishi G. , Doe Chris Q. 
Published: September 2024

AbstractRecent advances in single-cell transcriptional profiling have enabled us to map diverse neuron types acrossDrosophila, mice, and even human brains, yet we still lack a mechanistic understanding of how these neuron types arise in the brain and expand during evolution. We identified homeodomain transcription factor (HDTF) codes in newborn neurons that specify the five neuron types (L1-L5) in theDrosophilalamina, the first ganglion of the visual system. Specifically, we discovered that the pan-lamina HDTF Scro is required for lamina progenitors to exit proliferation and differentiate into lamina neurons. Furthermore, we showed that specific HDTFs are expressed in distinct newborn neurons and specify different lamina neuron types: Zfh1 for L1 and L3, Dve for L2, and Bsh for L4 and L5. Intriguingly, we found that the loss of both Dve and Bsh causes L2, L4, and L5 neurons to revert to L1 and L3 neuron types, potentially representing ancestral lamina neuron types. HDTFs are evolutionarily conserved and broadly expressed in brains across species. Based on these findings, we propose a model in which distinct HDTFs in newborn neurons specify different neuron types in the brain and have been utilized to expand neuron diversity during evolution.
Remote cognitive tests predict neurodegenerative biomarkers in the Insight 46 cohort
Authors: Del Giovane Martina , Giunchiglia Valentina , Cai Ziyuan , Leoni Marguerite , Street Rebecca , Lu Kirsty , Wong Andrew , Popham Maria , Nicholas Jennifer M. , Trender William , Helleyer Peter J. , Parker Thomas D. , Murray-Smith Heidi , Malhotra Paresh A. , Crutch Sebastian J. , Richards Marcus , Hampshire Adam , Schott Jonathan M. 
Published: September 2024

AbstractBACKGROUNDAlzheimer’s disease-related biomarkers detect pathology years before symptoms emerge, when disease-modifying therapies might be most beneficial. Remote cognitive testing provides a means of assessing early changes. We explored the relationship between neurodegenerative biomarkers and cognition in cognitively normal individuals.METHODSWe remotely deployed 13 computerised Cognitron tasks in 255 Insight 46 participants. We generated whole brain, hippocampal, and white matter hyperintensity volumes at ages 69-71, rates of change over two-years, amyloid load and positivity. We examined the relationship between Cognitron, biomarkers, and standard neuropsychological tests.RESULTSSlower response time on a delayed recognition task predicted amyloid positivity (OR=1.79,CI:1.15, 2.95). Brain and hippocampal atrophy rates correlated with poorer visuospatial performance (b=-0.42, CI:-0.80, -0.05) and accuracy on immediate recognition (b=-0.01, CI:-0.01, -0.001), respectively. Standard tests correlated with Cognitron composites (rho=0.43, p<0.001).DISCUSSIONRemote computerised testing correlates with standard supervised assessments and holds potential for studying early cognitive changes associated with neurodegeneration.
Socioeconomic inequalities and diabetes complications: An analysis of administrative data from Hungary
Authors: Elek Péter , Mayer Balázs , Varga Orsolya 
Published: September 2024

AbstractBackgroundDiabetes complications are associated with increased healthcare costs and worsened patient outcomes. In this paper we analyze how individual-level demographic and territorial-level socioeconomic and healthcare variables influence the presence and severity of diabetes complications and their relationship with mortality.MethodsOur study utilizes anonymized administrative data from Hungary, containing outpatient and inpatient records of all diabetes patients between 2010 to 2017. We construct settlement-year level and individual-year level panel datasets to analyze diabetes prevalence, incidence and complications, employing Poisson and logit models to explore associations between complications and the explanatory variables. The adapted Diabetes Complications Severity Index (aDCSI) is employed to quantitatively evaluate the severity of complications by aggregating individual complication scores from ICD-10 diagnosis codes.ResultsDiabetes prevalence and incidence are higher in settlements with above-median unemployment rates, where patients exhibit more severe complications, as shown by higher average aDCSI scores. Among socioeconomic factors, unemployment rate is particularly associated with increased aDCSI scores, while better healthcare access is associated with lower aDCSI scores in unadjusted but with higher scores in adjusted models. The presence and severity of complications, especially renal, cardio-vascular and peripheral vascular ones, substantially increase five-year inpatient mortality. Most of the mortality difference by settlement-level unemployment rate disappears when complications are accounted for.ConclusionsTerritorial-level socioeconomic disparities, especially elevated unemployment rates, significantly exacerbate the severity of diabetes complications, which subsequently heightens the mortality risk among diabetic patients. Enhancing health-care access in lower socioeconomic regions may alleviate these disparities and lessen the impact of complications.
Assessment of Health-Related Quality of Life (HRQoL) of Type 2 Diabetic Patients in Ghana
Authors: Ahiale Christine , Kumah Augustine 
Published: September 2024

AbstractBackgroundOver the last decades, non-communicable diseases such as diabetes have remarkably increased due to rapid urbanization, unhealthy lifestyles, and ageing. The World Health Organization (WHO) indicates that the “diabetes epidemic” will continue in the coming decades, yielding enormous human and economic costs around the world. This study aims at accessing the health-related Quality of Life (QoL) of Type 2 Diabetic Patients in Ghana.MethodThis was a hospital-based cross-sectional descriptive study conducted in the 3 regions in Ghana among 1194 patients with type 2 diabetes who were seeking healthcare at the regional hospitals of the selected regions for at least 12 months. A multi-stage sampling technique was used in recruiting the participants. The WHOQOL-BREF tool was adopted to assess the health-related QoL of diabetic patients. Data was analyzed using STATA version 16.1, and the findings were presented in the tables. Statistical significance was set at (P < 0.05).ResultsOut of the 1194 participants, 90% (1079) reported a satisfactory quality of life. The majority (60.3%) of participants were above 50 years of age. The overall mean score of the QoL was 6.25 (±1.28) for all four domains: psychological, physical, social, relationship, and environmental health. Marital status, occupational status, and self-reported health status predicted overall QOL. Males have a better quality of life than females, and those below 50 also have a better quality of life than those above 50. Similarly, those employed had a better quality of life than the unemployed; however, those who were married, unmarried, educated, and non-educated had no significant differences in their quality of life. Sex was associated with all the domains. Marital status was associated with the environmental, social, and psychological domains. Age was associated with psychological and physical domains. On predictors of quality of life, all demographic variables (age, sex, educational status, marital status, and employment status) predicted quality of life across all domains.ConclusionThis study provided valuable insights on predictors of health-related QoL among type 2 diabetic patients in Ghana, which would guide policymakers, healthcare providers, and stakeholders in improving diabetes management and ultimately enhancing the quality of life for individuals living with diabetes in Ghana. Evidence-based interventions should be implemented to address the factors influencing the QoL of diabetic patients in Ghana.
Mapping and engineering RNA-controlled architecture of the multiphase nucleolus
Authors: Quinodoz SA , Jiang L , Abu-Alfa AA , Comi TJ , Zhao H , Yu Q , Wiesner LW , Botello JF , Donlic A , Soehalim E , Zorbas C , Wacheul L , Košmrlj A , Lafontaine DLJ , Klinge S , Brangwynne CP 
Published: September 2024

AbstractBiomolecular condensates are key features of intracellular compartmentalization. As the most prominent nuclear condensate in eukaryotes, the nucleolus is a layered multiphase liquid-like structure and the site of ribosome biogenesis. In the nucleolus, ribosomal RNAs (rRNAs) are transcribed and processed, undergoing multiple maturation steps that ultimately result in formation of the ribosomal small subunit (SSU) and large subunit (LSU). However, how rRNA processing is coupled to the layered nucleolar organization is poorly understood due to a lack of tools to precisely monitor and perturb nucleolar rRNA processing dynamics. Here, we developed two complementary approaches to spatiotemporally map rRNA processing and engineerde novonucleoli. Using sequencing in parallel with imaging, we found that rRNA processing steps are spatially segregated, with sequential maturation of rRNA required for its outward movement through nucleolar phases. Furthermore, by generating syntheticde novonucleoli through an engineered rDNA plasmid system in cells, we show that defects in SSU processing can alter the ordering of nucleolar phases, resulting in inside-out nucleoli and preventing rRNA outflux, while LSU precursors are necessary to build the outermost layer of the nucleolus. These findings demonstrate how rRNA is both a scaffold and substrate for the nucleolus, with rRNA acting as a programmable blueprint for the multiphase architecture that facilitates assembly of an essential molecular machine.
Motility-dependent processes inToxoplasma gondiitachyzoites and bradyzoites: same same but different
Authors: Kent Robyn S. , Ward Gary E. 
Published: September 2024

AbstractThe tachyzoite stage of the apicomplexan parasiteToxoplasma gondiiutilizes motility for multiple purposes during its lytic cycle, including host cell invasion, egress from infected cells, and migration to new uninfected host cells to repeat the process. Bradyzoite stage parasites, which establish a new infection in a naïve host, must also use motility to escape from the cysts that are ingested by the new host and then migrate to the gut wall, where they either invade cells of the intestinal epithelium or squeeze between these cells to infect the underlying connective tissue. We know very little about the motility of bradyzoites, which we analyze in detail here and compare to the well-characterized motility and motility-dependent processes of tachyzoites. Unexpectedly, bradyzoites were found to be as motile as tachyzoites in a 3D model extracellular matrix, and they showed increased invasion into and transmigration across certain cell types, consistent with their need to establish the infection in the gut. The motility of the two stages was inhibited to the same extent by cytochalasin D and KNX-002, compounds known to target the parasite’s actomyosin-based motor. In contrast, other compounds that impact tachyzoite motility (tachyplegin and enhancer 5) have less of an effect on bradyzoites, and rapid bradyzoite egress from infected cells is not triggered by treatment with calcium ionophores, as it is with tachyzoites. The similarities and differences between these two life cycle stages highlight the need to characterize both tachyzoites and bradyzoites for a more complete understanding of the role of motility in the parasite life cycle and the effect that potential therapeutics targeting parasite motility will have on disease establishment and progression.
Enzyme Activity Regulates Substrate Diffusion by Modulating Viscosity in Crowded Milieu
Authors: Bevilacqua Alessandro , Maciel Mauricio Rios , Pascarelli Stefano , Dindo Mirco , Shen Amy Q. , Laurino Paola 
Published: September 2024

AbstractEnzymatic activity and its tight regulation are fundamental for cellular metabolism and life. While classical models of enzyme kinetics explain the behaviour of enzymes in buffer solutions, there are elusive properties that emerge from enzymes in their native, crowded environment. In this study, we harness liquid-liquid phase separation (LLPS) to createin vitrodroplets that mimic cytosolic protein crowding, offering a unique window to understand enzyme kinetics within well controlled microenvironments. We discover that the enzyme self-regulates its activity by modifying the shear viscosity of both the protein-rich droplets and the surrounding bulk solution. Through microscopy and rheology techniques, we discovered a significant correlation between enzyme activity and the shear viscosity of the droplets and bulk solution, influencing substrate diffusion. Our findings suggest that enzymes control their activity, influencing the organization and dynamics of macromolecular crowding within droplets. These results provide new insights into how enzymes regulate both their physical environment and metabolic processes in cell.
Tris inhibits a GH1 β-glucosidase by a linear mixed inhibition mechanism
Authors: Chagas Rafael S. , Marana Sandro R. 
Published: September 2024

AbstractHere we demonstrate that Tris (2-amino-2-(hydroxymethyl)-1,3-propanediol), largely used as buffering agent, is a linear mixed inhibitor (Ki= 12 ± 2 mM and α = 3 ± 1) of the GH1 β-glucosidase from the insectSpodoptera frugiperda(Sfβgly). Such inhibition mechanism implies in the formation of a non-productive ESI complex involving Sfβgly, substrate and Tris. In addition, Tris binding reduces by 3 fold the enzyme affinity for the substrate. Hence, at concentrations higher than theKi, Tris can completely abolish Sfβgly activity, whereas even at lower concentrations the presence of Tris causes underestimation of β-glucosidase kinetic parameters (Kmandkcat). In agreement to the inhibition mechanism, computational docking showed that Tris could bind to a pocket placed at the lateral of the active site opening in the Sfβgly-substrate complex, hence leading to the formation of a ESI complex. Computational docking also showed that Tris may find binding spots in the interior of the active site of the Sfβgly and several GH1 β-glucosidases. Moreover, the variety of their active site shapes results in a multiplicity of binding profiles, foreseeing different inhibition mechanism. Thus, Tris inhibition is probably common among GH1 β-glucosidases. This remark should be taken into account in their study, highlighting the importance of the appropriate buffer for accurate enzyme characterization.
Impact of social isolation stress on safety learning and the structure of defensive behavior during a spatial-based learning task involving thermal threat
Authors: Villalon Stephanie A. , Felix-Ortiz Ada C. , Lozano-Ortiz Kelly , McCarrey John R. , Burgos-Robles Anthony 
Published: September 2024

AbstractSafety learning during threat and adversity is critical for behavioral adaptation, resiliency, and survival. Using a novel mouse paradigm involving thermal threat, we recently demonstrated that safety learning is highly susceptible to stress. Yet, our previous study primarily considered male mice and did not thoroughly scrutinize the relative impacts of stress on potentially distinct defensive mechanisms implemented by males and females during the thermal task. The present study assessed these issues while analyzing a variety of defensive behaviors related to safety-seeking, escape, coping, protection, ambivalence, and risk-taking. After a two-week social isolation stress period, mice were required to explore a box arena that had thermal threat and safety zones (5°C vs 30°C, respectively). Since visuospatial cues clearly differentiated the threat and safety zones, the majority of the no-stress controls (69-75%) in both sexes exhibited optimal memory formation for the safety zone. In contrast, the majority of the stress-exposed mice in both sexes (69-75%) exhibited robust impairment in memory formation for the safety zone. Furthermore, while the control groups exhibited many robust correlations among various defensive behaviors, the stress-exposed mice in both sexes exhibited disorganized behaviors. Thus, stress severely impaired the proper establishment of safety memory and the structure of defensive behavior, effects that primarily occurred in a sex-independent manner.
Variants inLrrk2andSncadeficiency do not alter the course of primary encephalitis due to neurotropic reovirus T3D in newborn mice
Authors: Lunn Michaela O. , Rousso Christopher , Tomlinson Julianna J. , Brown Earl G. , Schlossmacher Michael G. 
Published: September 2024

AbstractVariants of the leucine-rich repeat kinase-2 (LRRK2) and α-synuclein (SNCA) genes are associated with Parkinson’s disease risk. We previously demonstrated that twoLrrk2knock-in variants as well asSncaexpression alter survival rates from combined pneumonitis and encephalitis following intranasal inoculation of newborn mice with a double-stranded RNA virus: respiratory-enteric-orphan virus, serotype-3 strain Dearing (reovirus T3D). Here, we examined whether outcomes of direct inoculation of the brain by reovirus T3D, which invariably causes lethal encephalitis within 15 days, would also be modified by variants inLrrk2andSnca. When we inoculated newborn mice intracerebrally with 5×102plaque-forming units of reovirus T3D, we found that, when compared to wild-type littermates, Lrrk2 p.G2019S mutant mice and kinase-dead p.D1994S mutant animals showed the same time-to-death intervals post-infection, revealed no sex difference, and had similar viral titres in the brain. Furthermore, the reduction or absence of endogenous α-synuclein also did not alter the course of encephalitis in parallel studies. These outcomes are in contrast to those following the intranasal inoculation paradigm of newborn mice, in which Lrrk2 and wild-type α-synuclein were both protective in infection outcomes. Together, these findings suggest that the Parkinson’s disease-linkedLrrk2andSncagenes contribute predominantly to systemic, innate responses by the host following reovirus T3D exposure.
Tailocin-mediated interactions among Soft RotPectobacteriaceae
Authors: Borowicz Marcin , Krzyżanowska Dorota M. , Sobolewska Marta , Narajczyk Magdalena , Mruk Inez , Czaplewska Paulina , Pédron Jacques , Barny Marie-Anne , Yves Canto Pierre , Dziadkowiec Joanna , Czajkowski Robert 
Published: September 2024

AbstractBacteria carry phage-derived elements within their genomes, some of which can produce phage-like particles (tailocins) used as weapons to kill kin strains in response to environmental conditions. This study investigates the production and activity of tailocins by plant pathogenic bacteria:Pectobacterium,Dickeya,andMusicolagenera, which compete for niche, providing an attractive model to study the ecological role of tailocins. Microscopy revealed that most analyzed strains (88%) produced tailocins. Tailocin-mediated killing interactions were assessed across 351 strain pairs, showing thatDickeyaspp. had a higher likelihood of killing neighbors (57.1%) thanPectobacteriumspp. (21.6%). Additionally,Dickeyaspp. strains exhibited broader phylogenetic killing, targeting bothPectobacteriumspp. andMusicolasp., whilePectobacteriumspp. tailocins were genus-specific. Mutual killing was observed in 33.9% of interactions, predominantly withinDickeyaspp. Although tailocins were morphologically indistinguishable between producers, genomic analyses identified conserved clusters having distinct differences betweenPectobacteriumspp. andDickeyaspp tailocins. This suggests different origins of these particles. Induction experiments demonstrated that tailocin production was boosted by hydrogen peroxide, supporting the role of these particles in bacteria-bacteria competition during infection. Tailocins were detectable in infected potato tissue but not in river water, highlighting the particular ecological relevance of tailocins in plant environments.