bluuebunny/crossref_metadata_2025_split huggingface dataset:
A FLASH model of radiolytic oxygen depletion and reactive oxygen species for differential tumor and normal-tissue response
Authors: Ma Jiangjun , Gao Hao , Shen Xing , Bai Xuemin , Tang Min 
Published: October 2023

AbstractObjectiveFLASH-RT can potentially improve the sparing of normal tissues while preserving the tumoricidal efficiency, owing to the radiation with ultra-high dose rate. However, the FLASH mechanism remains to be solved. A popular FLASH model is based on radiolytic oxygen depletion (ROD), which explains for radiation protection of normal tissues under FLASH-RT. However, ROD does not explain the preservation of tumoricidal efficiency for tumors. This work will develop a ROS+ROD FLASH model that can explain the differential tumor and normal-tissue response.ApproachThe new FLASH model utilizes reactive oxygen species (ROS) in addition to ROD, and takes into account that ROS level decreases during FLASH-RT. Specifically, the differential-equation model takes into account that the basic ROS level is lower during FLASH-RT and the degeneration rates of ROS are different in tumor cells and healthy cells. Based on this ROS+ROD FLASH model, the surviving fractions of tumor and normal cells are respectively compared between conventional radiotherapy (CONV-RT) and FLASH-RT.Main resultsWhile ROD alone does not distinguish the response of tumors and normal tissues to FLASH-RT, the proposed new FLASH model based on ROD and ROS successfully explained the differential response of tumors and normal tissues to FLASH-RT, i.e., the preserved tumoricidal capability, which cannot be explained by ROD alone, and the extra normal-tissue protection owing to the ultra-high dose rate.SignificanceSince the ROS level decreases slower in tumors than in normal tissues, during FLASH-RT, ROS decreases more in normal tissue, thus can get more protection. By incorporating ROS in addition to ROD, the new FLASH model can not only recover all results by previous FLASH model with ROD alone, but also explain the differential response: preserved lethality of FLASH-RT to tumors and improved protection to normal tissues.
Global risk of selection and spread ofPlasmodium falciparumhistidine-rich protein 2 and 3 gene deletions
Authors: Watson Oliver J. , Tran Thu Nguyen-Anh , Zupko Robert J , Symons Tasmin , Thomson Rebecca , Visser Theodoor , Rumisha Susan , Dzianach Paulina A , Hathaway Nicholas , Kim Isaac , Juliano Jonathan J. , Bailey Jeffrey A. , Slater Hannah , Okell Lucy , Gething Peter , Ghani Azra , Boni Maciej F , Parr Jonathan B. , Cunningham Jane 
Published: October 2023

AbstractIn the thirteen years since the first report ofpfhrp2-deleted parasites in 2010, the World Health Organization (WHO) has found that 40 of 47 countries surveyed worldwide have reportedpfhrp2/3gene deletions. Due to a high prevalence ofpfhrp2/3deletions causing false-negative HRP2 RDTs, in the last five years, Eritrea, Djibouti and Ethiopia have switched or started switching to using alternative RDTs, that target pan-specific-pLDH orP. falciparumspecific-pLDH alone of in combination with HRP2. However, manufacturing of alternative RDTs has not been brought to scale and there are no WHO prequalified combination tests that use Pf-pLDH instead of HRP2 forP. falciparumdetection. For these reasons, the continued spread ofpfhrp2/3deletions represents a growing public health crisis that threatens efforts to control and eliminateP. falciparummalaria. National malaria control programmes, their implementing partners and test developers desperately seekpfhrp2/3deletion data that can inform their immediate and future resource allocation. In response, we use a mathematical modelling approach to evaluate the global risk posed bypfhrp2/3deletions and explore scenarios for how deletions will continue to spread in Africa. We incorporate current best estimates of the prevalence ofpfhrp2/3deletions and conduct a literature review to estimate model parameters known to impact the selection ofpfhrp2/3deletions for each malaria endemic country. We identify 20 countries worldwide to prioritise for surveillance and future deployment of alternative RDT, based on quickly selecting forpfhrp2/3deletions once established. In scenarios designed to explore the continued spread of deletions in Africa, we identify 10 high threat countries that are most at risk of deletions both spreading to and subsequently being rapidly selected for. If HRP2-based RDTs continue to be relied on for malaria case management, we predict that the major route forpfhrp2deletions to spread is south out from the current hotspot in the Horn of Africa, moving through East Africa over the next 20 years. We explore the variation in modelled timelines through an extensive parameter sensitivity analysis and despite wide uncertainties, we identify three countries that have not yet switched RDTs (Senegal, Zambia and Kenya) that are robustly identified as high risk forpfhrp2/3deletions. These results provide a refined and updated prediction model for the emergence ofpfhrp2/3deletions in an effort to help guidepfhrp2/3policy and prioritise future surveillance efforts and innovation.
Genotype prediction of 336,463 samples from public expression data
Authors: Razi Afrooz , Lo Christopher C. , Wang Siruo , Leek Jeffrey T. , Hansen Kasper D. 
Published: October 2023

AbstractTens of thousands of RNA-sequencing experiments comprising hundreds of thousands of individual samples have now been performed. These data represent a broad range of experimental conditions, sequencing technologies, and hypotheses under study. The Recount project has aggregated and uniformly processed hundreds of thousands of publicly available RNA-seq samples. Most of these samples only include RNA expression measurements; genotype data for these same samples would enable a wide range of analyses including variant prioritization, eQTL analysis, and studies of allele specific expression. Here, we developed a statistical model based on the existing reference and alternative read counts from the RNA-seq experiments available through Recount3 to predict genotypes at autosomal biallelic loci in coding regions. We demonstrate the accuracy of our model using large-scale studies that measured both gene expression and genotype genome-wide. We show that our predictive model is highly accurate with 99.5% overall accuracy, 99.6% major allele accuracy, and 90.4% minor allele accuracy. Our model is robust to tissue and study effects, provided the coverage is high enough. We applied this model to genotype all the samples in Recount3 and provide the largest ready-to-use expression repository containing genotype information. We illustrate that the predicted genotype from RNA-seq data is sufficient to unravel the underlying population structure of samples in Recount3 using Principal Component Analysis.
KCC2 Enhancers Normalize Reflex Responses and Improve Locomotor Function after Chronic Spinal Cord Injury
Authors: Bilchak Jadwiga N. , Caron Guillaume , Danner Simon M. , Côté Marie-Pascale 
Published: October 2023

AbstractWithin a year after a spinal cord injury (SCI), 75% of individuals develop spasticity. While normal movement relies on the ability to adjust reflexes appropriately, and on reciprocal inhibition of antagonistic muscles, spastic individuals display hyperactive spinal reflexes and involuntary muscle co-contractions. Current anti-spastic medications can suppress uncontrolled movements, but by acting on GABAergic signalling, these medications lead to severe side-effects and weakened muscle force, making them incompatible with activity-based therapies. We have previously shown that pharmacologically enhancing activity of KCC2, a chloride cotransporter, reduces signs of spasticity in anesthetized chronic SCI rats. Here, we examine the effect of enhancing KCC2 in awake animals, using a battery of tests to assess multiple reflex pathways required for normal movement as well as locomotor function. Sprague-Dawley rats were implanted with chronic EMG electrodes bilaterally in ankle flexor and ankle extensor muscles and received a complete spinal transection at T12. Four weeks following SCI, the stretch reflex, the non-nociceptive cutaneous reflex pathway, the flexor withdrawal reflex, and the crossed-extensor reflex pathway as well as locomotor function were evaluated before and after receiving the KCC2 enhancer, CLP290. Our results show that enhancing KCC2 activity normalizes reflex responses in multiple pathways and reduces muscle co-contraction without weakening motor output, thereby improving stepping ability. This work reveals the substantial potential for KCC2 enhancers as a novel antispastic treatment.
Physiological and transcriptomic characterization of cold acclimation in endodormant grapevine under different temperature regimes
Authors: Wang Hongrui , Kovaleski Al P. , Londo Jason P. 
Published: October 2023

AbstractIt is essential for the survival of grapevines in cool climate viticultural regions that vines properly acclimate in the late fall and early winter and develop freezing tolerance. Climate change-associated abnormities in temperature during the dormant season, including oscillations between extreme cold and prolonged warmth, impacts cold acclimation and threatens the sustainability of the grape and wine industry. We conducted two experiments in controlled environment to investigate the impacts of different temperature regimes on cold acclimation ability in endodormant grapevine buds through a combination of freezing tolerance based physiological and RNA-seq based transcriptomic monitoring. Results show that the freezing tolerance of buds was not altered from field levels when exposed to stable temperatures ranging from 2 °C to 22 °C but was enhanced when exposed to temperature cycling (7±5 °C). We also characterized the transcriptomic response of endodormant buds to high and low temperatures and the potential genetic control for the maintenance of endodormancy. Several pathways that were previously reported to be responsive or functional during cold acclimation, such as theICE-CBF-CORcascade, were not observed to play a role in the enhancement of freezing tolerance or the sensing of different temperatures, indicating our current understanding of the genetic control of cold acclimation remains a challenge when generalizing across plant species and phenological stages.
Simultaneous whole-head electrophysiological recordings using EEG and OPM-MEG
Authors: Seedat Zelekha A. , Pier Kelly St , Holmes Niall , Rea Molly , Al-Hilaly Layla , Tierney Tim M. , Pardington Rosemarie , Mullinger Karen J. , Cross J. Helen , Boto Elena , Brookes Matthew J. 
Published: October 2023

ABSTRACTElectroencephalography (EEG) and magnetoencephalography (MEG) non-invasively measure human brain electrophysiology. They differ in nature; MEG offers better performance (higher spatial precision) whilst EEG (a wearable platform) is more practical. They are also complementary, with studies showing that concurrent MEG/EEG provides advantages over either modality alone, and consequently clinical guidelines for MEG in epilepsy recommend simultaneous acquisition of EEG. In recent years, new instrumentation – optically pumped magnetometers (OPMs) – has had a significant impact on MEG, offering improved performance, lifespan compliance, and wearable sensors. Nevertheless, the ability to carry out simultaneous EEG/OPM-MEG remains critical. Here, we investigated whether simultaneous, wearable, whole-head EEG and OPM-MEG measurably degrades signal quality in either modality. We employed two tasks: a motor task known to modulate beta oscillations, and an eyes-open/eyes-closed task known to modulate alpha oscillations. In both, we characterised the performance of EEG alone, MEG alone, and concurrent EEG/OPM-MEG. Our results show that the SNR of the beta response was very similar, regardless of whether modalities were used individually or concurrently. Likewise, our alpha band recordings demonstrated that signal contrast was stable, regardless of the concurrent recording. These results combined suggest that there are no fundamental barriers to simultaneous wearable EEG/OPM-MEG, and consequently this technique is ripe for neuroscientific and clinical adoption. This will be particularly important in the clinical sphere where a direct comparison between simultaneous EEG and OPM-MEG recordings will facilitate interpretation of OPM-MEG data in patients.
Proportion of cancer cases and deaths attributable to potentially modifiable risk factors in Peru prior to the COVID-19 pandemic
Authors: De La Cruz-Vargas Jhony A. , Ramos Willy , Chanduví Willer , Correa-López Lucy E. , Guerrero Nadia , Loayza-Castro Joan , Tami-Maury Irene M. , Venegas Diego 
Published: October 2023

ABSTRACTOBJECTIVETo estimate the fraction of cancer cases and deaths attributable to potentially modifiable risk factors in Peru in 2018, prior to the COVID-19 pandemic.MATERIAL AND METHODSAn ecological study was carried out using the prevalence of exposure of the Peruvian population to modifiable risk factors for cancer, relative risk of each risk factor, and number of cancer cases and deaths in 2018 as inputs. We used the Parkin formula with a Montecarlo statistical simulation model to calculate the population attributable fraction (PAF) and confidence intervals. The number of new cancer cases and deaths attributable to each risk factor was calculated by multiplying the number of cases and deaths in each sex by the PAF of each risk factor.RESULTS38.4% of new cases (34.4% in men and 41.8% in women) and 43.2% of deaths by cancer in Peru (43.1% in men and 43.2% in women) were attributable to modifiable risk factors. The number of cancers attributable was 25,591 (10,616 in men and 14,975 in women) and the number of deaths attributable to cancer was 14,922 (6,996 in men and 7,926 in women). The modifiable risk factors that caused a greater number of cases and deaths were HPV infection (4563 cases, 2410 deaths), current tobacco use (3387 cases, 2198 deaths), and Helicobacter pylori infection (2686 cases, 1874 deaths). The oncogenic infections made up the group of risk factors that presented a greater PAF (16.6% for cases, 19.1% for deaths) followed by other unhealthy lifestyle factors (14.1% for cases, 16.5% for deaths), tobacco (7.2% for cases, 7.3% for deaths) and ultraviolet radiation (0.5% for cases, 0.3% for deaths).CONCLUSIONPrior to the COVID-19 pandemic, a proportion of 38.4% of cancer cases and 43.2% of cancer deaths in Peru during 2018 were attributable to modifiable risk factors. Most preventable cancer cases and deaths are linked to oncogenic infections, primarily caused by HPV and Helicobacter pylori.
Environmentally persistent free radicals in household dust: the seasonal and longitudinal trends
Authors: Vilcins Dwan , Dangal Prakash , Lomnicki Slawomir , Cormier Stephania , Lee Wen Ray , Sly Peter D 
Published: October 2023

AbstractObjectiveEpidemiological links between air pollution and adverse health outcomes are strong, but the mechanism(s) remain obscure. A newly recognised combustion by-product, environmentally persistent free radicals (EPFRs), may be the missing link. EPFRs persist for extended periods of time in the environment, however very little is known about the presence of EPFRs inside homes where prolonged exposure is likely to occur. The objective of this study is to explore the presence of EPFRs in household dust and ascertain if EPFR concentration is stable across time and season.Material and methodsThe ORChID/ELLF cohort is a longitudinal birth cohort (n=82) with dust samples collected from the family vacuum cleaner at multiple time points. EPFR characteristics were assessed with electron paramagnetic resonance. Our team developed an algorithm to estimate oxygen-weighted concentration and impact score for risk of adverse health outcomes. Kruskal-Wallis rank sum test and Fisher’s exact tests were used to assess seasonal differences. A simple mixed-effects linear regression, with random intercepts on participant ID, was employed for longitudinal analysis of EPFR concentration in households that did not move.Results83 participants returned 238 dust samples. EPFRs were measured in virtually all samples. EPFR concentration was stable across visits, when controlling for season and ambient air pollution (p=0.05), Oxygen-weighted EPFRs were also stable. There was a seasonal trend, with concentration (p=<0.01), oxygen weighted concentration (p=<0.01) and g factor (p=0.05) all significantly lower in summer months.ConclusionOur results indicate that the concentration of EPFRs in household dust are stable across time in households that did not move, but the oxygen-centred radicals are more sensitive to changes. These findings suggest that exposure to EPFRs occurs in the home and may be a significant place for exposure to highly biologically reactive EPFRs.
Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen inRUNX1Haplodeficiency
Authors: Carpio-Cano Fabiola Del , Mao Guangfen , Goldfinger Lawrence E. , Wurtzel Jeremy , Guan Liying , Alam Afaque Mohammad , Lee Kiwon , Poncz Mortimer E. , Rao A. Koneti 
Published: October 2023

AbstractPlatelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. GermlineRUNX1haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMM), is associated with thrombocytopenia, platelet dysfunction and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen and IgG levels were decreased in a FPDMM patient. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, siRNARUNX1knockdown (KD) increased uptake of these proteins over 24 hours compared to control cells, with increases in caveolin-1 and flotillin-1 (two independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes) and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1.RUNX1knockdown increased colocalization of albumin with flotillin and of fibrinogen with RAB11 suggesting altered trafficking of both. The increased albumin and fibrinogen uptake and levels of caveolin-1, flotillin-1, LAMP2 and IFITM3 were recapitulated by shRNARUNX1knockdown in CD34+-derived MK. These studies provide the first evidence that inRUNX1-haplodeficiency platelet endocytosis of albumin and fibrinogen is impaired and that megakaryocytes have enhanced endocytosis with defective trafficking leading to loss of these proteins by distinct mechanisms. They provide new insights into mechanisms governing endocytosis and α-granule deficiencies inRUNX1-haplodeficiency.Key pointsPlatelet content and endocytosis of α-granule proteins, albumin, fibrinogen and IgG, are decreased in germline RUNX1 haplodeficiency.InRUNX1-deficient HEL cells and primary MK endocytosis is enhanced with defective trafficking leading to decreased protein levels.
Comparative Immune profiling in Pancreatic Ductal Adenocarcinoma Progression Among South African patients
Authors: Elebo Nnenna , Abdel-Shafy Ebtesam A. , Omoshoro-Jones Jones A.O. , Nsingwane Zanele , Hussein Ahmed A.A. , Smith Martin , Candy Geoffrey , Cacciatore Stefano , Fru Pascaline , Nweke Ekene Emmanuel 
Published: October 2023

ABSTRACTIntroductionPancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of only 11%. PDAC is characterized by an immunosuppressive microenvironment; thus, there have been multiple attempts to target it, although with little success. A better understanding of the immune landscape in PDAC is required to help elucidate the roles of these cells for effective targeting. This study investigated the expression of circulating key immune cell markers in South African PDAC patients.MethodBlood samples were obtained from a total of 34 PDAC patients consisting of 22 resectable (RPC), 8 locally advanced (LAPC) and 4 metastatic (MPC), 6 Chronic Pancreatitis (CP), and 6 healthy volunteers (HC). Immunophenotyping, real-time polymerase chain reactions (PCR), enzyme-linked immunosorbent assay (Elisa), and reactive oxygen species (ROS) assays were conducted. Statistical analysis was conducted in R (version 3.6.1) and Wilcoxon and Kruskal-Wallis rank-sum tests were used to compare between groups. Kaplan-Meier analysis and Spearman’s rank test were used for survival and correlation analyses, respectively.ResultsGranulocyte and neutrophil levels were significantly elevated while lymphocytes decreased with PDAC severity. The total percentages of CD4+, CD8+, and CD3+CD4-CD8-T-cells increased across the group. Of note are the reduction of CD16+NKTs across the RPC (p= 0.002), LAPC (p= 0.01), and MPC (p= 0.017) groups when compared to HC. Both NK (p= 0.0047) and NKTs (p= 0.0027) increased in RPC but decreased in both LAPC and MPC when compared to HC. Although there was no statistical correlation or differences observed when comparing the PDAC groups with the control groups, RPC had the highest foldchange for bothCD4(11.75 ± 44.31) andCD3(30.47 ± 75.01) while the LAPC group had the highest fold change forCD8(3.86 ± 7.35) andCD16(51.69 ± 108.9) genes compared to MPC. The inflammatory status of PDAC was assessed by DEPPD levels of serum which were elevated in RPC (p= 0.003) and LAPC (p= 0.008) but decreased in MPC (p= 0.025), compared to the HC group. ROS was shown to be positively correlated with GlycA (R=0.45,p= 0.00096).ConclusionThe expression of these immune cell markers observed in this pilot study provides insight into their potential roles in tumour progression in the patient group and suggests their potential utility in the development of immunotherapeutic strategies.
Identifying and ranking novel independent features for cardiovascular disease prediction in people with type 2 diabetes
Authors: Dziopa K , Chaturvedi N , Asselbergs F W , Schmidt A F 
Published: October 2023

AbstractBackgroundCVD prediction models do not perform well in people with diabetes. We therefore aimed to identify novel predictors for six facets of CVD, (including coronary heart disease (CHD), Ischemic stroke, heart failure (HF), and atrial fibrillation (AF)) in people with T2DM.MethodsAnalyses were conducted using the UK biobank and were stratified on history of CVD and of T2DM: 459,142 participants without diabetes or a history of CVD, 14,610 with diabetes but without CVD, and 4,432 with diabetes and a history of CVD. Replication was performed using a 20% hold-out set, ranking features on their permuted c-statistic.ResultsOut of the 600+ candidate features, we identified a subset of replicated features, ranging between 32 for CHD in people with diabetes to 184 for CVD+HF+AF in people without diabetes. Classical CVD risk factors (e.g. parental or maternal history of heart disease, or blood pressure) were relatively highly ranked for people without diabetes. The top predictors in the people with diabetes without a CVD history included: cystatin C, self-reported health satisfaction, biochemical measures of ill health (e.g. plasma albumin). For people with diabetes and a history of CVD top features were: self-reported ill health, and blood cell counts measurements (e.g. red cell distribution width). We additionally identified risk factors unique to people with diabetes, consisting of information on dietary patterns, mental health and biochemistry measures. Consideration of these novel features improved risk classification, for example per 1000 people with diabetes 133 CVD and 165 HF cases appropriately received a higher risk.ConclusionThrough data-driven feature selection we identified a substantial number of features relevant for prediction of cardiovascular risk in people with diabetes, the majority of which related to non-classical risk factors such as mental health, general illness markers, and kidney disease.