bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic, Clinical Underpinnings of Brain Change Along Two Neuroanatomical Dimensions of Clinically-defined Alzheimer’s Disease
Authors: Wen Junhao , Yang Zhijian , Nasrallah Ilya M. , Cui Yuhan , Erus Guray , Srinivasan Dhivya , Abdulkadir Ahmed , Mamourian Elizabeth , Skampardoni Ioanna , Hwang Gyujoon , Singh Ashish , Bergman Mark , Bao Jingxuan , Varol Erdem , Zhou Zhen , Boquet-Pujadas Aleix , Chen Jiong , Toga Arthur W. , Saykin Andrew J. , Hohman Timothy J. , Thompson Paul M. , Villeneuve Sylvia , Gollub Randy , Sotiras Aristeidis , Wittfeld Katharina , Grabe Hans J. , Tosun Duygu , Bilgel Murat , An Yang , Marcus Daniel S. , LaMontagne Pamela , Benzinger Tammie L. , Heckbert Susan R. , Austin Thomas R. , Launer Lenore J. , Espeland Mark , Masters Colin L , Maruff Paul , Fripp Jurgen , Johnson Sterling C. , Morris John C. , Albert Marilyn S. , Bryan R. Nick , Resnick Susan M. , Ferrucci Luigi , Fan Yong , Habes Mohamad , Wolk David , Shen Li , Shou Haochang , Davatzikos Christos ,   iSTAGING, the AI4AD, and the ADSP phenotypic harmonization consortia, the BLSA, the PREVENT-AD, and the ADNI studies
Published: September 2022

AbstractAlzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised clustering technique known as Surreal-GAN, through which we identified two dominant dimensions of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g.,APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated toAPOEdifferentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed thatAPOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction – driven by genes different fromAPOE– which may collectively contribute to the early pathogenesis of AD.
Inhibitory andin silicomolecular docking ofXeroderris stuhlmannii(Taub.) Mendonca & E.P. Sousa phytochemical compounds on human α-glucosidases
Authors: Nyathi Brilliant , Bvunzawabaya Jonathan Tatenda , Mudawarima Chido Venissa P , Manzombe Emily , Tsotsoro Kudakwashe , Selemani Major Allen , Munyuki Gadzikano , Rwere Freeborn 
Published: September 2022

ABSTRACTEthnopharmacological relevanceHerbal traditional medicine is used by millions of people in Africa for treatment of ailments such as diabetes mellitus, stomach disorders and respiratory diseases.Xeroderris stuhlmannii (Taub.) Mendonca & E.P. Sousa (X. stuhlmannii(Taub.)) is a medicinal plant used traditionally in Zimbabwe to treat type 2 diabetes mellitus (T2DM) and its complications. However, there is no scientific evidence to support its inhibitory effect against digestive enzymes (α-glucosidases) that are linked to high blood sugar in humans.Aim of the study: This work aims to investigate whether bioactive phytochemicals of crudeX. stuhlmannii(Taub.) can scavenge free radicals and inhibit α-glucosidases in order to reduce blood sugar in humans.Materials and methodsHere we examined the free radical scavenging potential of crude aqueous, ethyl acetate and methanolic extracts ofX. stuhlmannii(Taub.) using the diphenyl-2-picrylhydrazyl assayin vitro. Furthermore, we carried outin vitroinhibition of α-glucosidases (α-amylase and α-glucosidase) by the crude extracts using chromogenic 3,5-dinitrosalicylic acid and p-nitrophenyl-α-D-glucopyranoside substrates. We also used molecular docking approaches (Autodock Vina) to screen for bioactive phytochemical compounds targeting the digestive enzymes.ResultsOur results showed that phytochemicals inX. stuhlmannii(Taub.) aqueous, ethyl acetate and methanolic extracts scavenged free radicals with IC50values ranging from 0.002-0.013 μg/mL. Furthermore, crude aqueous, ethyl acetate and methanolic extracts significantly inhibited α-amylase and α-glucosidase with IC50values of 10.5-29.5 μg/mL (versus 54.1±0.7 μg/mL for acarbose) and 8.8-49.5 μg/mL (versus 161.4±1.8 μg/mL for acarbose), respectively.In silicomolecular docking findings and pharmacokinetic predictions showed that myricetin is likely a novel plant-derived α-glucosidase inhibitor.ConclusionCollectively, our findings suggest pharmacological targeting of digestive enzymes byX. stuhlmannii(Taub.) crude extracts may reduce blood sugar in humans with T2DM via inhibition of α-glucosidases.
The energetic effect of hip flexion and retraction in walking at different speeds: a modeling study
Authors: Jin Jian , Kistemaker Dinant , van Dieën Jaap H. , Daffertshofer Andreas , Bruijn Sjoerd M. 
Published: September 2022

AbstractIn human walking, power for propulsion is generated primarily via ankle and hip muscles. The addition of a ‘passive’ hip spring to simple bipedal models appears more efficient than using only push-off impulse, at least, when hip spring associated energetic costs are not considered. Hip flexion and retraction torques, however, are not ‘free’, as they are produced by muscles demanding metabolic energy. Studies evaluating the inclusion of hip actuation costs, especially during the swing phase, and the hip actuation’s energetic benefits are few and far between. It is also unknown whether these possible benefits/effects may depend on speed. We simulated a planar flat-feet model walking stably over a range of speeds. We asked whether the addition of independent hip flexion and retraction remains energetically beneficial when considering work-based metabolic cost of transport (MCOT) with different efficiencies of doing positive and negative work. We found asymmetric hip actuation can reduce the estimated MCOT relative to ankle actuation by up to 6%, but only at medium speeds. The corresponding optimal strategy is zero hip flexion and some hip retraction actuation. The reason for this reduced MCOT is a reduction in collision loss being larger than the associated increase in hip negative work. Both terms require positive mechanical work to compensate, yielding a larger reduction in metabolic work per step than the reduction in step length. Our study shows how ankle actuation, hip flexion, and retraction actuation can be coordinated to reduce MCOT.
Graph construction method impacts variation representation and analyses in a bovine super-pangenome
Authors: Leonard Alexander S. , Crysnanto Danang , Mapel Xena M. , Bhati Meenu , Pausch Hubert 
Published: September 2022

AbstractSeveral models and algorithms have been proposed to build pangenomes from multiple input assemblies, but their impact on variant representation, and consequently downstream analyses, is largely unknown. We create multi-species “super-pangenomes” using pggb, cactus, and minigraph with theBos taurus taurusreference sequence and eleven haplotype-resolved assemblies from taurine and indicine cattle, bison, yak, and gaur. We recover 221k nonredundant structural variations (SVs) from the pangenomes, of which 135k (61%) are common to all three. SVs derived from assembly-based calling show high agreement with the consensus calls from the pangenomes (96%), but validate only a small proportion of variations private to each graph. Pggb and cactus, which also incorporate base-level variation, have approximately 95% exact matches with assembly-derived small variant calls, which significantly improves the edit rate when realigning assemblies compared to minigraph. We use the three pangenomes to investigate 9,566 variable number tandem repeats (VNTRs), finding 63% have identical predicted repeat counts in the three graphs, while minigraph can over or underestimate the count given its approximate coordinate system. We examine a highly variable VNTR locus and show that repeat unit copy number impacts expression of proximal genes and non-coding RNA. Our findings indicate good consensus between the three pangenome methods but also show their individual strengths and weaknesses that need to be considered when analysing different types of variants from multiple input assemblies.
Temporal asymmetries and interactions between dorsal and ventral visual pathways during object recognition
Authors: Ayzenberg Vladislav , Simmons Claire , Behrmann Marlene 
Published: September 2022

AbstractDespite their anatomical and functional distinctions, there is growing evidence that the dorsal and ventral visual pathways interact to support object recognition. However, the exact nature of these interactions remains poorly understood. Is the presence of identity-relevant object information in the dorsal pathway simply a byproduct of ventral input? Or, might the dorsal pathway be a source of input to the ventral pathway for object recognition? In the current study, we used high-density EEG – a technique with high temporal precision and spatial resolution sufficient to distinguish parietal and temporal lobes – to characterize the dynamics of dorsal and ventral pathways during object viewing. Using multivariate analyses, we found that category decoding in the dorsal pathway preceded that in the ventral pathway. Importantly, the dorsal pathway predicted the multivariate responses of the ventral pathway in a time-dependent manner, rather than the other way around. Together, these findings suggest that the dorsal pathway is a critical source of input to the ventral pathway for object recognition.
Improved models for the relationship between age and the probability of trypanosome infection in female tsetse, Glossina pallidipes Austen
Authors: Hargrove J. W. , Van Sickle J. 
Published: September 2022

AbstractBetween 1990 and 1999, at Rekomitjie Research Station, Zambezi Valley, Zimbabwe, 29,360 female G. pallidipes were dissected to determine their ovarian category and trypanosome infection status. Overall prevalences were 3.45% and 2.66% for T. vivax and T. congolense, respectively, declining during each year as temperatures increased from July - December. Fits to age-prevalence data using Susceptible-Exposed-Infective (SEI) and SI compartmental models were statistically better than those obtained using a published catalytic model, which made the unrealistic assumption that no female tsetse survived more than seven ovulations. The improved models require knowledge of fly mortality, estimated separately from ovarian age distributions. Infection rates were not significantly higher for T. vivax than for T. congolense. For T. congolense in field-sampled female G. pallidipes, we found no statistical support for a model where the force of infection was higher at the first feed than subsequently. The long survival of adult female tsetse, combined with feeding at intervals ≤ 3 days, ensures that post-teneral feeds, rather than the first feed, play the dominant role in the epidemiology of T. congolense infections in G. pallidipes. This is supported by estimates that only about 3% of wild hosts at Rekomitjie were harbouring sufficient T. congolense to ensure that tsetse feeding off them take an infected meal, so that the probability of ingesting an infected meal is low at every meal.
Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers
Authors: Nussbaum Daniel P. , Martz Colin A. , Waters Andrew M. , Barrera Alejandro , Rutter Justine C. , Cerda-Smith Christian G. , Stewart Amy E. , Wu Chao , Cakir Merve , Levandowski Cecilia B. , Kantrowitz David E. , McCall Shannon J , Pierobon Mariaelena , Petricoin Emanuel F. , Smith J. Joshua , Reddy Timothy E. , Der Channing J. , Taatjes Dylan J. , Wood Kris C. 
Published: September 2022

AbstractAcquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this novel class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved population-level process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, tumor-specific resistance programs.
GABAergic LRP1 is a key link between obesity and memory function
Authors: Uner Aaron Aykut , Hou Zhi-Shuai , Aydogan Ahmet , Rodrigues Kellen C.C. , Young Jennie , Choi Anthony , Yang Won-Mo , Kim Woojin S. , Prevot Vincent , Caldarone Barbara J. , Hyman Bradley T. , Lee Hyon , Kim Young-Bum 
Published: September 2022

ABSTRACTObjectiveLow-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Loss of LRP1 from inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. Its dysfunction has been associated with cognitive decline, dementia, and Alzheimer’s disease. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood.MethodsMice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) are subjected to conduct behavioral tests of locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. We evaluated the relationships between behavior and metabolic risk factors.ResultsDeletion of LRP1 in GABAergic neurons caused a significant impairment in memory function. In the spatial Y-maze test,Vgat-Cre; LRP1loxP/loxPmice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxPmice). In addition, GABAergic neuron-specific LRP1-deficient mice had a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice when the contextual and cued fear conditioning tests were conducted. These effects were accompanied by increased neuronal necrosis and neuroinflammation in the hippocampus. Importantly, the distance and duration in the novel arm and the performance of the reversal water T-maze test negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J.ConclusionsOur findings demonstrate that LRP1 from GABAergic neurons is important in normal memory function. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance and impacts memory function, reinforcing the potential importance of LRP1 in neural system integrity.
Rapid protection of nonhuman primates against Marburg virus disease using a single low-dose VSV-based vaccine
Authors: O’Donnell Kyle L. , Feldmann Friederike , Kaza Benjamin , Clancy Chad S. , Hanley Patrick W. , Fletcher Paige , Marzi Andrea 
Published: September 2022

AbstractMarburg virus (MARV) is the causative agent of Marburg virus disease (MVD) which has a case fatality rate up to ~90% in humans. Recently, there were cases reported in Guinea and Ghana highlighting this virus as a high-consequence pathogen potentially threatening global public health. There are no licensed treatments or vaccines available today.We used a vesicular stomatitis virus (VSV)-based vaccine expressing the MARV-Angola glycoprotein (VSV-MARV) as the viral antigen. Previously, a single dose of 1×107 plaque-forming units (PFU) administered 7 days before challenge resulted in uniform protection from disease in cynomolgus macaques. Here, we sought to lower the vaccination dose to allow for more doses per vial in an emergency outbreak situation. We administered 1×105 or 1×103 PFU 14 days before challenge and achieved uniform protection in both groups. When we administered 1×103 PFU 7 days before challenge, vaccination resulted in uniform protection with no detectable viremia. Antigen-specific IgG responses were induced by both vaccine concentrations and were sustained until the study endpoint. Neutralizing antibody responses and antibody-dependent cellular phagocytosis were observed with both vaccination doses and timelines. The cellular response after vaccination was characterized by early induction of NK cell activation. Additionally, antigen-specific memory T cell subsets were detected in all vaccination cohorts indicating that while the primary protective mechanism of VSV-MARV is the humoral response, a functional cellular response is also induced.Overall, this data highlights VSV-MARV as a viable and fast-acting MARV vaccine candidate suitable for deployment in emergency outbreak situations and supports its clinical development.One Sentence SummaryA single low dose of VSV-MARV administered 14 or 7 days before challenge protects NHPs uniformly from lethal disease.
Digitally managed larviciding as a cost-effective intervention for urban malaria: Operational lessons from a pilot in São Tomé and Príncipe guided by the Zzapp system
Authors: Vigodny Arbel , Ben Aharon Michael , Wharton-Smith Alexandra , Fialkoff Yonatan , Houri Yafin Arnon , Bragança Fernando , Da Graça Flavio Soares , Gluck Dani , D’Abreu João Alcântara Viegas , Rompão Herodes 
Published: September 2022

AbstractBackgroundOnce a mainstay of malaria elimination operations, larval source management—the treatment of mosquito breeding habitats–has been marginalized in Africa, due to insufficient effectiveness. However, the development of new technologies, and mosquitoes’ growing resistance to insecticides used in bed nets and house spraying raise renewed interest in this method.MethodsA digitally managed larviciding operation in three of the seven districts of São Tomé and Príncipe (STP) was launched by the Ministry of Health and ZzappMalaria LTD, guided by the Zzapp map-and-GPS mobile application and dashboard. During the operation, quality assurance procedures and field management methods were developed and implemented.Findings12,788 water bodies were located and treated a total of 128,864 times. The reduction impact on mosquito population and on malaria cases was 74·90% and 52·65%, respectively. The overall cost per person protected (PPP) was US$0·78 and US$0·41 PPP in the urban areas. Various cost and effectiveness drivers were identified.InterpretationDigitally managed larviciding can yield highly cost-effective results, especially in urban areas. Digital tools facilitate standardization of operations, implementation of quality assurance procedures, and monitoring of fieldworkers’ performance. Digitally generated spatial data also have the potential to assist integrated vector management operations. A randomized controlled trial with a larger sample is needed to further substantiate findings.FundingThe operation was funded by ZzappMalaria LTD and the STP Ministry of Health (MOH).
Post-mating parental behavior trajectories differ across four species of deer mice
Authors: Khadraoui Mehdi , Merritt Jennifer R. , Hoekstra Hopi E. , Bendesky Andres 
Published: September 2022

AbstractAmong species, parental behaviors vary in their magnitude, onset relative to reproduction, and sexual dimorphism. In deer mice (genus Peromyscus), while most species are promiscuous with low paternal care, monogamy and biparental care have evolved at least twice under different ecological conditions. Here, in a common laboratory setting, we monitored parental behaviors of males and females of two promiscuous (eastern deer mouse P. maniculatus and white-footed mouse P. leucopus) and two monogamous (oldfield mouse P. polionotus and California mouse P. californicus) species from before mating to after giving birth. In the promiscuous species, females showed parental behaviors largely after parturition, while males showed little parental care. In contrast, both sexes of monogamous species performed parental behaviors. However, while oldfield mice began to display parental behaviors before mating, California mice showed robust parental care behaviors only postpartum. These different parental-care trajectories in the two monogamous species align with their socioecology. Oldfield mice have overlapping home ranges with relatives, so infants they encounter, even if not their own, are likely to be closely related. By contrast, California mice disperse longer distances into exclusive territories with possibly unrelated neighbors, decreasing the inclusive fitness benefits of caring for unfamiliar pups before parenthood. Together, we find that patterns of parental behaviors in Peromyscus are consistent with predictions from inclusive fitness theory.
Comparison of calling pipelines for whole genome sequencing: an empirical study demonstrating the importance of mapping and alignment
Authors: Betschart Raphael O. , Thiéry Alexandre , Aguilera-Garcia Domingo , Zoche Martin , Moch Holger , Twerenbold Raphael , Zeller Tanja , Blankenberg Stefan , Ziegler Andreas 
Published: September 2022

AbstractRapid advances in high-throughput DNA sequencing technologies have enabled the conduct of whole genome sequencing (WGS) studies, and several bioinformatics pipelines have become available. The aim of this study was the comparison of 6 WGS data pre-processing pipelines, involving two mapping and alignment approaches (GATK utilizing BWA-MEM2 2.2.1, and DRAGEN 3.8.4) and three variant calling pipelines (GATK 4.2.4.1, DRAGEN 3.8.4 and DeepVariant 1.1.0). We sequenced one genome in a bottle (GIAB) sample 70 times in different runs, and one GIAB trio in triplicate. The truth set of the GIABs was used for comparison, and performance was assessed by computation time, F1score, precision, and recall. In the mapping and alignment step, the DRAGEN pipeline was faster than the GATK with BWA-MEM2 pipeline. DRAGEN showed systematically higher F1score, precision, and recall values than GATK for single nucleotide variations (SNVs) and Indels in simple-to-map, complex-to-map, coding and non-coding regions. In the variant calling step, DRAGEN was fastest. In terms of accuracy, DRAGEN and DeepVariant performed similarly and both superior to GATK, with slight advantages for DRAGEN for Indels and for DeepVariant for SNVs. The DRAGEN pipeline showed the lowest Mendelian inheritance error fraction for the GIAB trios. Mapping and alignment played a key role in variant calling of WGS, with the DRAGEN outperforming GATK.