bluuebunny/crossref_metadata_2025_split huggingface dataset:
TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer’s disease models
Authors: Wilson Edward N. , Wang Congcong , Swarovski Michelle S. , Zera Kristy A. , Ennerfelt Hannah E. , Wang Qian , Chaney Aisling , Gauba Esha , Ramos Benitez Javier A. , Le Guen Yann , Minhas Paras S. , Panchal Maharshi , Tan Yuting J. , Blacher Eran , Iweka Chinyere A. , Cropper Haley , Jain Poorva , Liu Qingkun , Mehta Swapnil S. , Zuckerman Abigail J. , Xin Matthew , Umans Jacob , Huang Jolie , Durairaj Aarooran S. , Serrano Geidy E. , Beach Thomas G. , Greicius Michael D. , James Michelle L. , Buckwalter Marion S. , McReynolds Melanie R. , Rabinowitz Joshua D. , Andreasson Katrin I. 
Published: March 2024

SUMMARYHuman genetics implicate defective myeloid responses in the development of late onset, age-associated Alzheimer’s disease (AD). Aging is characterized by a decline in myeloid metabolism that triggers maladaptive, neurotoxic immune responses. TREM1 is an amplifier of pro-inflammatory myeloid responses, and here we find thatTrem1deficiency prevents age-dependent changes in myeloid metabolism, inflammation, and hippocampal memory function.Trem1deficiency rescues age-associated declines in ribose-5P, a glycolytic intermediate and the precursor for purine, pyrimidine, and NAD+biosynthesis. In vitro,Trem1deficient microglia are resistant to bioenergetic changes induced by amyloid-ß42oligomers (Aß42), suggesting that Aß42stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD model of amyloid accumulation,Trem1haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy independent of amyloid accumulation or changes in the disease-associated microglial transcriptomic signature. In agingAPPSwemice,Trem1deficiency restores synaptic mitochondrial function and cerebral glucose uptake and prevents hippocampal memory decline. In post-mortem human brain, microglial TREM1 expression increases with clinical and neuropathological severity. Thus, TREM1-mediated disruption of myeloid metabolism, both in the periphery and brain, promotes cognitive decline in aging and amyloid accumulation, two major risk factors for AD development.
Single molecule fingerprinting reveals different growth mechanisms in seed amplification assays for different polymorphs of αSynuclein fibrils
Authors: Lau Derrick , Tang Yuan , Kenche Vijaya , Copie Thomas , Kempe Daryan , Jary Eve , Graves Noah J. , Biro Maté , Masters Colin L. , Dzamko Nicolas , Gambin Yann , Sierecki Emma 
Published: March 2024

ABSTRACTAlpha-synuclein (αSyn) aggregates, detected in the biofluids of patients with Parkinson’s disease, have the ability to catalyze their own aggregation, leading to an increase in the number and size of aggregates. This self-templated amplification is used by newly developed assays to diagnose Parkinson’s disease and turned the presence of αSyn aggregates into a biomarker of the disease. It has become evident that αSyn can form fibrils with slightly different structures, called “strains” or polymorphs, but little is known about their differential reactivity in diagnostic assays. Here we compared the properties of two well-described αSyn polymorphs. Using single molecule techniques, we observed that one of the polymorphs had an increased tendency to undergo secondary nucleation and we showed that this could explain the differences of reactivity observed inin vitroseed amplification assay and cellular assays. Simulations and high-resolution microscopy suggest that a 100-fold difference in apparent rate of growth can be generated by a surprisingly low number of secondary nucleation “points” (1 every 2,000 monomers added by elongation). When both strains are present in the same seeded reaction, secondary nucleation displaces proportions dramatically and causes a single strain to dominate the reaction as the major end-product.
Identifying effective evolutionary strategies for uncovering reaction kinetic parameters under the effect of measurement noises
Authors: Yeo Hock Chuan , Varsheni Vijay , Selvarajoo Kumar 
Published: March 2024

AbstractThe transition from explanative modelling of fitted data to the predictive modelling of unseen data for systems biology endeavors necessitates the effective recovery of reaction parameters. Yet, the relative efficacy of optimization algorithms in doing so remains under-studied, as to the specific reaction kinetics and the effect of measurement noises. To this end, we simulate the reactions of an artificial pathway using 4 kinetic formulations: generalized mass action (GMA), Michaelis-Menten, linear-logarithmic, and convenience kinetics. We then compare the effectiveness of 5 evolutionary algorithms (CMAES, DE, SRES, ISRES, G3PCX) for objective function optimization in kinetic parameter hyperspace to determine the corresponding estimated parameters. We quickly dropped the DE algorithm due to its poor performance. Baring measurement noise, we find CMAES algorithm to only require a fraction of the computational cost incurred by other EAs for both GMA and linear-logarithmic kinetics yet performing as well by other criteria. However, with increasing noise, SRES and ISRES perform more reliably for GMA kinetics, but at considerably higher computational cost. Conversely, G3PCX is among the most efficacious for estimating Michaelis-Menten parameters regardless of noise, while achieving numerous folds saving in computational cost. Cost aside, we find SRES to be versatilely applicable across GMA, Michaelis-Menten, and linear-logarithmic kinetics, with good resilience to noise. On the other hand, we could not identify the parameters of convenience kinetics using any algorithm. Together, we find algorithms that are effective under marked measurement noise for specific reaction kinetics, as a step towards predictive modelling for systems biology endeavors.
The Rhizobial effector NopT targets Nod factor receptors to regulate symbiosis inLotus japonicus
Authors: Bao Hanbin , Wang Yanan , Li Haoxing , Wang Qiang , Lei Yutao , Ye Ying , Wadood Syed F. , Zhu Hui , Stahelin Christian , Stacey Gary , Xu Shutong , Cao Yangrong 
Published: March 2024

AbstractIt is well-documented that type-III effectors are required by Gram-negative pathogens to directly target different host cellular pathways to promote bacterial infection. However, in the context of legume-rhizobium symbiosis, the role of rhizobial effectors in regulating plant symbiotic pathways remains largely unexplored. Here, we show that NopT, a YopT-type cysteine protease ofSinorhizobium frediiNGR234 directly targets the plant’s symbiotic signaling pathway by associating with two Nod factor receptors (NFR1 and NFR5 ofLotus japonicus). NopT inhibits cell death triggered by co-expression of NFR1/NFR5 inNicotiana benthamiana. Full-length NopT physically interacts with NFR1 and NFR5. NopT proteolytically cleaves NFR5 bothin vitroandin vivo, but can be inactivated by NFR1 as a result of phosphorylation. NopT plays an essential role in mediating rhizobial infection inL. japonicus. Autocleaved NopT retains the ability to cleave NFR5 but no longer interacts with NFR1. Interestingly, genomes of certainSinorhizobiumspecies only harbornopTgenes encoding truncated proteins without the autocleavage site. These results reveal an intricate interplay between rhizobia and legumes, in which a rhizobial effector protease targets NFR5 to dampen symbiotic signaling. NFR1 appears to counteract this process by phosphorylating the effector. This discovery highlights the role of a bacterial effector in regulating a signaling pathway in plants and opens up the perspective of developing kinase-interacting proteases to fine-tune cellular signaling processes in general.One-sentence summaryThe rhizobial effector NopT and two Nod factor receptors ofLotus japonicus, NFR1 and NFR5, mutually interact to precisely regulate rhizobial symbiosis.
Transcriptional repression ofGTL1under water-deficit stress promotes anthocyanin biosynthesis to enhance drought tolerance
Authors: Mano Noel Anthony , Shaikh Mearaj A. , Widhalm Joshua R. , Yoo Chan Yul , Mickelbart Michael V. 
Published: March 2024

AbstractThe transcription factor GT2-LIKE 1 (GTL1) has been implicated in orchestrating a transcriptional network of diverse physiological, biochemical, and developmental processes. In response to water-limiting conditions, GTL1 is a negative regulator of stomatal development, but its potential role in other water-deficit responses is unknown. We hypothesized that GTL1 regulates transcriptome changes associated with drought tolerance over leaf developmental stages. To test the hypothesis, gene expression was profiled by RNA-seq analysis in emerging and expanding leaves of wild-type and a drought-tolerantgtl1-4knockout mutant under well-watered and water-deficit conditions. Our comparative analysis of genotype-treatment combinations within leaf developmental age identified 459 and 1073 differentially expressed genes in emerging and expanding leaves, respectively, as water-deficit responsive GTL1-regulated genes. Transcriptional profiling identified a potential role of GTL1 in two important pathways previously linked to drought tolerance: flavonoid and polyamine biosynthesis. In expanding leaves, negative regulation ofGTL1under water-deficit conditions promotes biosynthesis of flavonoids and anthocyanins that may contribute to drought tolerance. Quantification of polyamines did not support a role for GTL1 in these drought-responsive pathways, but this is likely due to the complex nature of synthesis and turnover. Our global transcriptome analysis suggests that transcriptional repression of GTL1 by water deficit allows plants to activate diverse pathways that collectively contribute to drought tolerance.
Sex-specific sub-lethal effects of low virulence entomopathogenic fungi may boost the Sterile Insect Technique
Authors: Duneau David , Gallet Romain , Adhiambo Maureen , Delétré Emilie , Chailleux Anais , Khamis Fathiya , Subramanian Sevgan , Brévault Thierry , Fellous Simon 
Published: March 2024

AbstractBACKGROUNDThe Sterile Insect Technique (SIT) is a species-specific method for controlling insect pests. Recent studies have explored the combination of SIT with entomopathogenic microorganisms, known as boosted-SIT, to enhance its effectiveness. This study aimed to evaluate the potential of the entomopathogenic fungi,Metarhizium anisopliae, in boosting the SIT for managing the oriental fruit fly,Bactrocera dorsalis.METHODSAdult flies from a laboratory population ofB. dorsaliswere inoculated with one of eight strains ofM. anisopliaeto assess fungus virulence in each sex. Ideally, boosted-SIT should minimally impact sterile males and reduce female fecundity maximally. A brief exposure to fungal spores was efficient to infect males, and for them to transmit the fungus to females when hosted together for 24 hours.RESULTSOur results showed significant variations in the mortality induced by the strains in males, but not in females that exhibited low mortality. Strains varied in their sub-lethal effects on female fecundity, with almost a two-fold variation among strains. Furthermore, strains that had the lowest virulence on males tended to reduce female fecundity the most.CONCLUSIONOur study brings a proof of concept that it is possible to leverage boosted- SIT using carefully selected pathogen strains and their sub-lethal effects on both the male and female fruit fly.
Protective effects of nicotinamide in a mouse model of glaucoma DBA/2 studied by second-harmonic generation microscopy
Authors: Boodram Vinessia , Lim Hyungsik 
Published: March 2024

AbstractGlaucoma is a blinding disease where the retinal ganglion cells and their axons degenerate. Degradation of axonal microtubules is thought to play a critical role in the pathogenesis, but the mechanism is unknown. Here we investigate whether microtubule disruption in glaucoma can be alleviated by metabolic rescue. The morphology and integrity of microtubules of the retinal nerve fibers were evaluated by second-harmonic generation microscopy in a mouse model of glaucoma, DBA/2, which received a dietary supplement of nicotinamide to reduce metabolic stress. It was compared with control DBA/2, which did not receive nicotinamide, and non-glaucomatous DBA/2-Gpnmb+. We found that morphology but not microtubules are significantly protected by nicotinamide. Furthermore, from co-registered images of second-harmonic generation and immunofluorescence, it was determined that microtubule deficit was not due to a shortage of tubulins. Microtubule deficit colocalized with the sectors in which the retinal ganglion cells were disconnected from the brain, indicating that microtubule disruption is associated with axonal transport deficit in glaucoma. Together, our data suggests significant role axonal microtubules play in glaucomatous degeneration, offering a new opportunity for neuroprotection.
Laminar specificity and coverage of viral-mediated gene expression restricted to GABAergic interneurons and their parvalbumin subclass in marmoset primary visual cortex
Authors: Federer Frederick , Balsor Justin , Ingold Alexander , Babcock David P. , Dimidschstein Jordane , Angelucci Alessandra 
Published: March 2024

ABSTRACTIn the mammalian neocortex, inhibition is important for dynamically balancing excitation and shaping the response properties of cells and circuits. The various computational functions of inhibition are thought to be mediated by different inhibitory neuron types of which a large diversity exists in several species. Current understanding of the function and connectivity of distinct inhibitory neuron types has mainly derived from studies in transgenic mice. However, it is unknown whether knowledge gained from mouse studies applies to the non-human primate, the model system closest to humans. The lack of viral tools to selectively access inhibitory neuron types has been a major impediment to studying their function in the primate. Here, we have thoroughly validated and characterized several recently-developed viral vectors designed to restrict transgene expression to GABAergic cells or their parvalbumin (PV) subtype, and identified two types that show high specificity and efficiency in marmoset V1. We show that in marmoset V1 AAV-h56D induces transgene expression in GABAergic cells with up to 91-94% specificity and 79% efficiency, but this depends on viral serotype and cortical layer. AAV-PHP.eB-S5E2 induces transgene expression in PV cells across all cortical layers with up to 98% specificity and 86-90% efficiency, depending on layer. Thus, these viral vectors are promising tools for studying GABA and PV cell function and connectivity in the primate cortex.
How low can you go? Short-read polishing of Oxford Nanopore bacterial genome assemblies
Authors: Bouras George , Judd Louise M. , Edwards Robert A. , Vreugde Sarah , Stinear Timothy P. , Wick Ryan R. 
Published: March 2024

AbstractIt is now possible to assemble near-perfect bacterial genomes using Oxford Nanopore Technologies (ONT) long reads, but short-read polishing is still required for perfection. However, the effect of short-read depth on polishing performance is not well understood. Here, we introduce Pypolca (with default and careful parameters) and Polypolish v0.6.0 (with a new careful parameter). We then show that: (1) all polishers other than Pypolca-careful, Polypolish-default and Polypolish-careful commonly introduce false-positive errors at low depth; (2) most of the benefit of short-read polishing occurs by 25× depth; (3) Polypolish-careful never introduces false-positive errors at any depth; and (4) Pypolca-careful is the single most effective polisher. Overall, we recommend the following polishing strategies: Polypolish-careful alone when depth is very low (<5×), Polypolish-careful and Pypolca-careful when depth is low (5–25×), and Polypolish-default and Pypolca-careful when depth is sufficient (>25×).Data SummaryPypolca is open-source and freely available on Bioconda, PyPI, and GitHub (github.com/gbouras13/pypolca). Polypolish is open-source and freely available on Bioconda and GitHub (github.com/rrwick/Polypolish). All code and data required to reproduce analyses and figures are available atgithub.com/gbouras13/depth_vs_polishing_analysis. All FASTQ sequencing reads are available at BioProjectPRJNA1042815. A detailed list of accessions can be found in Table S1.
Targeting Maternal Gut Microbiome to Improve Mental Health Outcomes-A Pilot Feasibility Trial
Authors: Gallant Faith , Cooley Kieran , Grigoriadis Sophie , Ebrahimi Neda 
Published: March 2024

AbstractBackgroundPerinatal Depression and anxiety (PDA) is prevalent in new and expectant mothers affecting millions of women worldwide. Those with a history of mood and anxiety disorders are at the greatest risk of experiencing PDA at a subsequent pregnancy. Current safety concerns with pharmacological treatments have led to a greater need for adjunctive treatment options for PDA. Changes in the composition of the microbiome have been associated with various diseases during pregnancy and these changes are thought to be at least partially at play in perinatal mood disorders. While the relation between PDA and the microbiome has not been explored, evidence suggests that nutritional interventions, with fiber, fish oils, and probiotics, may play a favorable role in neuropsychiatric outcomes during and after pregnancy. The primary objective of the present study is to assess the feasibility and acceptability of a combination of non-pharmacological interventions in currently stable and pregnant women with a history of anxiety and/or depression. This study will also aim to understand ease of recruitment, treatment compliance, and protocol adherence in this cohort.MethodsThis a single centered, partially randomized-placebo controlled-double blind feasibility trial. 100 pregnant women, with a history of depression and/or anxiety/PDA will be recruited and randomized into one of four arms which could include: receiving a daily dose of both investigational products and dietary counselling on increasing dietary fiber, receiving a daily dose of both investigational drugs only, receiving fish oil investigational product and placebo, and a control arm with no intervention. The study involves six study visits, all of which can be conducted virtually every 3 months from the time of enrollment. At all study visits, information on diet, mental health, physical activity, and sleep quality will be collected. Additionally, all participants will provide a stool sample at each visit.DiscussionIt is anticipated that pregnant women with a history of depression and anxiety will be particularly interested in partaking in this trial, resulting in favourable recruitment rates. Given the positive findings of O3FA and probiotic supplements on mental health symptoms in non-pregnant adults, we expect a similar trend in PDA symptoms, with a low likelihood of adverse events. This study will build the foundation for larger powered studied to further contribute evidence for the efficacy of this potential treatment option.Trial RegistrationThis trial was registered at ClinicalTrials/gov on October 6, 2023;NCT06074250. Trial Sponsor: The Canadian College of Naturopathic Medicine, 1255 Sheppard Ave E, Toronto, ON M2K 1E2, 416-498-1255.
Glial activation mediates phenotypic effects ofAPOEε4and sex in Alzheimer’s disease
Authors: Lane Roger M. , Li Dan , Darreh-Shori Taher 
Published: March 2024

ABSTRACTINTRODUCTIONThis study examined the impact ofapolipoprotein ɛ4(APOEɛ4) allele frequency and sex on the phenotype of Alzheimer’s disease (AD).METHODSThe baseline characteristics, CSF, and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50-74 years with confirmed early AD from clinical trialNCT03186989were evaluated in a post-hoc study.RESULTSA phenotypic spectrum was observed from a predominant amyloid and limbic-amnestic phenotype in maleAPOEɛ4homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in femaleAPOEɛ4noncarriers. Amyloid pathology inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest correlations observed in maleAPOEɛ4carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in femaleAPOEɛ4noncarriers.DISCUSSIONGlial activation is influenced by apoE isoform and sex, which explains much of the phenotypic heterogeneity in early AD below age 75 years.HIGHLIGHTSAPOEɛ4homozygotes displayed a predominantly amyloid and limbic-amnestic phenotype.FemaleAPOEɛ4noncarriers displayed a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype.In maleAPOEɛ4carriers, amyloid pathology was inversely correlated with tau pathophysiology, synaptic injury, and glial activationFemales displayed a non-APOEɛ4allele frequency-dependent increase in glial activation and synaptic injuryIn femaleAPOEɛ4noncarriers, tau pathophysiology was strongly correlated with glial activation, synaptic injury, and neuroaxonal damageRESEARCH IN CONTEXTSystematic reviewThe impact ofAPOEɛ4alleles and sex on phenotypic features was examined in 45 patients, aged 50-74 years, with early AD.InterpretationFindings were consistent with prior reports and suggest that glial activation, influenced by apoE isoform and sex, explains much of the phenotypic heterogeneity in early AD below age 75 years. Lower glial activation inAPOEɛ4homozygotes associated with the highest levels of amyloid and the lowest levels of tau pathology, and a limbic-amnestic phenotype, suggesting degeneration of basal forebrain cholinergic neurons. Higher glial activation in femaleAPOEɛ4noncarriers was associated with the highest tau pathology and synaptic injury, the lowest amyloid pathology, greater ventricular expansion, and multi-domain cognitive deficits.Future directionsThis work defined a combined sex, genotype, and age framework that delineates multiple pathways to end-stage AD. Confirmation is required, followed by optimization of therapeutic approaches to amyloid, tau, and glial activation pathologies along the disease stage continuum.
T cell cholesterol transport is a metabolic checkpoint that links intestinal immune responses to dietary lipid absorption
Authors: Gao Yajing , Kennelly John P. , Xiao Xu , Whang Emily , Ferrari Alessandra , Bedard Alexander H. , Mack Julia J. , Nguyen Alexander H. , Weston Thomas , Uchiyama Lauren F. , Lee Min Sub , Young Stephen G. , Bensinger Steven J. , Tontonoz Peter 
Published: March 2024

AbstractThe intrinsic pathways that control membrane organization in immune cells and the impact of such pathways on cellular function are not well defined. Here we report that the non-vesicular cholesterol transporter Aster-A links plasma membrane (PM) cholesterol availability in T cells to immune signaling and systemic metabolism. Aster-A is recruited to the PM during T-cell receptor (TCR) activation, where it facilitates the removal of newly generated “accessible” membrane cholesterol. Loss of Aster-A leads to excess PM cholesterol accumulation, resulting in enhanced TCR nano-clustering and signaling, and Th17 cytokine production. Finally, we show that the mucosal Th17 response is restrained by PM cholesterol remodeling. Ablation of Aster-A in T cells leads to enhanced IL-22 production, reduced intestinal fatty acid absorption, and resistance to diet-induced obesity. These findings delineate a multi-tiered regulatory scheme linking immune cell lipid flux to nutrient absorption and systemic physiology.