bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimer’s Disease
Authors: Jin Mengmeng , Ma Ziyuan , Dang Rui , Zhang Haiwei , Kim Rachael , Xue Haipeng , Pascual Jesse , Finkbeiner Steven , Head Elizabeth , Liu Ying , Jiang Peng 
Published: March 2024

SUMMARYWhile challenging, identifying individuals displaying resilience to Alzheimer’s disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline. Furthermore, DS individuals are at an increased risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Recent studies indicate that somatic mutations in hematopoietic cells may lead to resilience to neurodegeneration. Microglia, derived from hematopoietic lineages, play a central role in AD etiology. We therefore hypothesize that microglia carrying the somatic mutations associated with DS myeloid leukemia may impart resilience to AD. Using CRISPR-Cas9 gene editing, we introduce a trisomy 21-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-basedin vitromicroglia culture andin vivohuman microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses microglial type-1 interferon signaling, independent of trisomy 21 genetic background. This mutation reduces neuroinflammation and enhances phagocytic and autophagic functions, thereby ameliorating senescent and dystrophic phenotypes in human microglia. Moreover, the CSF2RB A455D mutation promotes the development of a unique microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity in chimeric mouse brains where human microglia largely repopulate the hippocampus. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize and replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest that hPSC-derived CSF2RB A455D microglia could be employed to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need to deplete endogenous diseased microglia prior to cell transplantation.
Investigating the Role and Regulation of GPNMB in Progranulin-deficient Macrophages
Authors: Gillett Drew A. , Neighbarger Noelle K. , Cole Cassandra , Wallings Rebecca L. , Tansey Malú Gámez 
Published: March 2024

ABSTRACTProgranulin is a holoprotein that is critical for successful aging, and insufficient levels of progranulin are associated with increased risk for developing age-related neurodegenerative diseases like AD, PD, and FTD. Symptoms can vary widely, but a uniting feature among these different neurodegenerative diseases is prodromal peripheral immune cell phenotypes. However, there remains considerable gaps in the understanding of the function(s) of progranulin in immune cells, and recent work has identified a novel target candidate called GPNMB. We addressed this gap by investigating the peritoneal macrophages of 5-6-month-oldGrnKO mice, and we discovered that GPNMB is actively increased as a result of insufficient progranulin and that MITF, a transcription factor, is also dysregulated in progranulin-deficient macrophages. These findings highlight the importance of early-stage disease mechanism(s) in peripheral cell populations that may lead to viable treatment strategies to delay disease progression at an early, prodromal timepoint and extend therapeutic windows.
Changes in the senescence profile and immune checkpoints in HIV-infected individuals after COVID-19
Authors: Crespo-Bermejo Celia , Brochado-Kith Óscar , Grande-García Sergio , Lara-Aguilar Violeta , Llamas-Adán Manuel , Arca-Lafuente Sonia , Martín-Carbonero Luz , de los Santos Ignacio , Jiménez Sousa M Ángeles , Resino Salvador , Berenguer Juan , Madrid Ricardo , Fernández-Rodríguez Amanda , Briz Verónica 
Published: March 2024

ABSTRACTBackgroundBoth SARS-CoV-2 and HIV infection exhibit alterations in the senescence profile and immune checkpoint (IC) molecules. However, the midterm impact of SARS-CoV-2 on these profiles in people with HIV (PWH) remains unclear. This study aimed to evaluate differences in plasma biomarker levels related to ICs, the senescence-associated secretory phenotype (SASP), and pro- and anti-inflammatory cytokines in PWH following recovery from SARS-CoV-2 infection.MethodsWe conducted a cross-sectional study of 95 PWH receiving antiretroviral therapy, stratified by SARS-CoV-2 infection status: a) 48 previously infected (HIV/SARS) and b) 47 controls without previous infection (HIV). Plasma biomarkers (n=44) were assessed using Procartaplex Multiplex Immunoassays. Differences were analyzed using a generalized linear model adjusted for sex and ethnicity and corrected for the false discovery rate. Significant values were defined as an adjusted arithmetic mean ratio ≥1.2 or ≤0.8 and a qvalue<0.1. Spearman correlation evaluated relationships between plasma biomarkers (significant correlations, rho≥0.3 and q value<0.1).ResultsThe median age of the PWH was 45 years, and 80% were men. All SARS-CoV-2-infected PWH experienced symptomatic infection; 83.3% had mild symptomatic infection, and sample collection occurred at a median of 12 weeks postdiagnosis. The HIV/SARS group showed higher levels of ICs (CD80, PDCD1LG2, CD276, PDCD1, CD47, HAVCR2, TIMD4, TNFRSF9, TNFRSF18, and TNFRSF14), SASP (LTA, CXCL8, and IL13), and inflammatory plasma biomarkers (IL4, IL12B, IL17A, CCL3, CCL4, and INF1A) than did the HIV group.ConclusionsSARS-CoV-2 infection in PWH causes significant midterm disruptions in plasma ICs and inflammatory cytokine levels, highlighting SASP-related factors, which could be risk factors for the emergence of complications in PWH.
Distinct changes to hippocampal and medial entorhinal circuits emerge across the progression of cognitive deficits in epilepsy
Authors: Feng Yu , Diego Keziah S. , Dong Zhe , Wick Zoé Christenson , Page-Harley Lucia , Page-Harley Veronica , Schnipper Julia , Lamsifer Sophia I. , Pennington Zachary T. , Vetere Lauren M. , Philipsberg Paul A. , Soler Ivan , Jurkowski Albert , Rosado Christin J. , Khan Nadia N. , Cai Denise J. , Shuman Tristan 
Published: March 2024

SUMMARYTemporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneousin vivoelectrophysiology in hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within MEC and between HPC-MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.
Development and application of GlycanDIA workflow for glycomic analysis
Authors: Xie Yixuan , Liu Xingyu , Zhao Chenfeng , Chen Siyu , Wang Shunyang , Lin Zongtao , Robison Faith M. , George Benson M. , Flynn Ryan A. , Lebrilla Carlito B. , Garcia Benjamin A. 
Published: March 2024

AbstractGlycans modify protein, lipid, and even RNA molecules to form the regulatory outer coat on cells called the glycocalyx. The changes in glycosylation have been linked to the initiation and progression of many diseases. Thus, while the significance of glycosylation is well established, a lack of accessible methods to characterize glycans has hindered the ability to understand their biological functions. Mass spectrometry (MS)-based methods have generally been at the core of most glycan profiling efforts; however, modern data-independent acquisition (DIA), which could increase sensitivity and simplify workflows, has not been benchmarked for analyzing glycans. Herein, we developed a DIA-based glycomic workflow, termed GlycanDIA, to identify and quantify glycans with high sensitivity and accuracy. The GlycanDIA workflow combined higher energy collisional dissociation (HCD)-MS/MS and staggered windows for glycomic analysis, which facilitates the sensitivity in identification and the accuracy in quantification compared to conventional data-dependent acquisition (DDA)-based glycomics. To facilitate its use, we also developed a generic search engine, GlycanDIA Finder, incorporating an iterative decoy searching for confident glycan identification and quantification from DIA data. The results showed that GlycanDIA can distinguish glycan composition and isomers fromN-glycans,O-glycans, and human milk oligosaccharides (HMOs), while it also reveals information on low-abundant modified glycans. With the improved sensitivity, we performed experiments to profileN-glycans from RNA samples, which have been underrepresented due to their low abundance. Using this integrative workflow to unravel theN-glycan profile in cellular and tissue glycoRNA samples, we found that RNA-glycans have specific forms as compared to protein-glycans and are also tissue-specific differences, suggesting distinct functions in biological processes. Overall, GlycanDIA can provide comprehensive information for glycan identification and quantification, enabling researchers to obtain in-depth and refined details on the biological roles of glycosylation.Graphical Abstract
Detection of oat crown rust disease in Taiwan (2019-2021)
Authors: Ho Chung-Ying , Henningsen Eva C , Chen Ssu-Tung , Ariyawansa Hiran A. , Nazareno Eric S. , Sperschneider Jana , Dodds Peter N. , Riddle Jakob , Kianian Shahryar F. , Figueroa Melania , Huang Yung-Fen 
Published: March 2024

AbstractOat is a minor forage crop grown in Taiwan. Only a few historical records of oat rust disease have been reported in the country, therefore the pathogen population remains poorly characterized. A rust-like disease outbreak was detected at the Experimental Farm of National Taiwan University in 2019, which caused significant damage to the field experiments. To determine the identity of the pathogen responsible for this disease outbreak, we collected infected foliar material. Disease signs suggested infection by the oat crown rust fungus. Hence, common procedures in rust pathology were applied to confirm the identity of the pathogen with phenotypic and molecular diagnostic techniques. A total of 50 field samples from infected oat cultivars were collected in 2019 and five rust isolates were purified in 2020 and 2021. Phylogenetic analysis based on ITS sequences indicated that the pathogen was likelyPuccinia coronataf. sp.avenae(Pca), which was further supported by the placement of Taiwanese isolate NTU-01 with otherPcarepresentatives in a phylogenetic tree of Basidiomycete fungi. Phenotyping assays across 36 oat differential lines demonstrated that Taiwanese isolates are phenotypically similar with relatively limited virulence. This study presents the first molecular confirmation ofPcain Taiwan and reports the virulence profiles of TaiwanesePcapopulation.
Automated high-throughput profiling of single-cell total transcriptome with scComplete-seq
Authors: Dinçaslan Fatma Betül , Ngang Shaun Wei Yang , Tan Rui Zhen , Cheow Lih Feng 
Published: March 2024

ABSTRACTDetecting the complete portrait of the transcriptome is essential to understanding the roles of both polyadenylated and non-polyadenylated RNA species. However, current efforts to investigate the heterogeneity of the total cellular transcriptome in single cells are limited by the lack of an automated, high-throughput assay that can be carried out on existing platforms. To address this issue, we developed scComplete-seq, a method that can easily augment existing high-throughput droplet-based single-cell mRNA sequencing to provide additional information on the non-polyadenylated transcriptome. Using scComplete-seq, we have successfully detected long and short non-polyadenylated RNAs at single-cell resolution, including cell-cycle-specific histone RNAs, cell-type-specific short non-coding RNA, as well as enhancer RNAs in cancer cells and PBMCs. By applying scComplete-seq, we have identified changes in both coding and non-coding transcriptome in PBMCs during different stimulations. Measuring the enhancer RNA expression also revealed the activation of specific biological processes and the transcription factors regulating such changes.
Interoceptive disruption in functional neurological disorder: a multimodal brain imaging study
Authors: Sojka Petr , Serranová Tereza , Khalsa Sahib S. , Perez David L. , Diez Ibai 
Published: March 2024

ABSTRACTThis multimodal brain imaging study investigated functional MRI (fMRI) neural processing of cardiac interoceptive signals in 38 patients with functional neurological disorder (FND) compared to 38 healthy controls (HCs). Additionally, we characterized how brain fMRI responses during heartbeat counting (interoception) vs. tone counting (exteroception) or rest related to grey matter volume, interoceptive awareness, and psychopathology scores. For both interoception vs. rest and interoception vs. exteroception contrasts, principal component analyses showed that principal component 1 (PC1) as derived from all study participants was comprised primarily of salience, ventral attention and sensorimotor network co-activations, along with default mode and visual processing network co-deactivations. Compared to HCs, patients with FND showed reduced contribution to these PC1 co-activation/co-deactivations patterns in both interoception vs. exteroception and interoception vs. rest contrasts; only the interoception vs. exteroception between-group fMRI findings held adjusting for depression/anxiety scores, antidepressant use and FND subtype. For the interoception vs. rest contrast, increasingly negative PC1 contribution scores positively correlated with decreased cingulate gyrus volumes and increased psychopathology scores. This multimodal brain imaging study underscores a role for salience and default-mode networks in the pathophysiology of FND, and sets the stage for comprehensive research efforts further contextualizing the mechanistic importance of altered interoception in patients with FND.
Flies tune the sensitivity of their multifunctional gyroscope
Authors: Verbe Anna , Lea Kristianna M. , Fox Jessica L. , Dickerson Bradley H. 
Published: March 2024

AbstractLocomotion requires navigating unpredictable and complex environments, demanding both stability and maneuverability within short timeframes. This is particularly important for flying insects, and the true flies (Diptera) stand out among this group for their impressive flight capabilities. Flies’ aerial abilities are partially attributed to halteres, tiny club-shaped structures that evolved from the hindwings and play a crucial role in flight control. Halteres oscillate during flight, in antiphase with the wings, providing rhythmic input to the wing steering systemviaarrays of embedded mechanosensors called campaniform sensilla. These sensor arrays convey timing information to the wing steering muscles, but linking haltere sensor location to sensor activity and the functional organization of the wing steering system remains a central challenge. Here, we usein vivocalcium imaging during tethered flight to obtain population-level recordings of the haltere sensory afferents in specific fields of sensilla. We find that haltere feedback is continuously modulated by visual stimuli to stabilize flight. Additionally, this feedback is present during saccades and help flies actively maneuver. We also find that the haltere’s multifaceted role arises from the steering muscles of the haltere itself, regulating haltere stroke amplitude to modulate campaniform activity. Taken together, our results underscore the crucial role of biomechanics in regulating the dynamic range of sensors and provide insight into how the sensory and motor systems of flies coevolved.Abstract Figure
Electrophysiological signatures of a developmental delay in a stem cell model ofKCNQ2developmental and epileptic encephalopathy
Authors: Rosa Filip , Theiss Stephan , Krepp Susanne , Loeffler Heidi , Mendes Dulini , Klingenstein Stefanie , Liebau Stefan , Weckhuysen Sarah , Alber Michael , Petrou Steven , Lerche Holger , Maljevic Snezana , Wuttke Thomas V 
Published: March 2024

AbstractBackgroundKCNQ2, encoding KV7.2 ion channels, has emerged as one of the prominent genes causing early onset seizures with developmental delay (KCNQ2developmental and epileptic encephalopathy;KCNQ2-DEE).KCNQ2 de novoloss-of-function (LOF) and associated neuronal hyperexcitability have been accepted as mechanisms contributing to seizures. To investigate the developmental impact ofKCNQ2LOF, we generated patient iPSC-derived models for two previously reportedde novovariants, p.(Arg325Gly) and p.(Gly315Arg), linked to severe congenital DEE.MethodsFunctional investigation of the two variants was initially performed inXenopus laevisoocyte system. Patient-derived iPSC lines were differentiated using NGN2- and embryoid body-based protocols yielding neurons roughly corresponding to mid- and mid-late gestational stages, respectively. KV7- mediated M-current, passive neuronal properties, action potential generation and spontaneous oscillatory network activities were analysed with whole-cell patch clamping.FindingsStudied KCNQ2 variants showed LOF with a dominant-negative effect in the heterologous system. Reduced M-currents in patient iPSC-derived neurons corroborated a LOF as the main pathomechanism. Interestingly, this led to the reduced neuronal firing of the early neurons and to a disruption of complex oscillatory activity, with significantly reduced duration and amplitude of these events in patient iPSC-derived neurons.InterpretationWe provide experimental evidence for changing roles of the M-current throughout development and place disease variant-mediated M-current reduction in the context of the neuronal maturation in the prenatal brain. Based on the reduced neuronal firing and disrupted oscillatory activity seen in patient iPSC-derived neurons, we propose that a delayed/impaired maturation of neuronal and network properties underliesKCNQ-DEE caused by LOF variants.
A vector system for single and tandem expression of cloned genes and multi-colour fluorescent tagging inHaloferax volcanii
Authors: Ithurbide Solenne , de Silva Roshali T. , Brown Hannah J. , Shinde Vinaya , Duggin Iain G. 
Published: March 2024

AbstractArchaeal cell biology is an emerging field expected to identify fundamental cellular processes, help resolve the deep evolutionary history of cellular life, and contribute new components and functions in biotechnology and synthetic biology. To facilitate these, we have developed plasmid vectors that allow convenient cloning and production of proteins and fusion proteins with flexible, rigid, or semi-rigid linkers in the model archaeonHaloferax volcanii. For protein subcellular localization studies using fluorescent protein (FP) tags, we created vectors incorporating a range of codon-optimized fluorescent proteins for N- or C-terminal tagging, including GFP, mNeonGreen, mCherry, YPet, mTurquoise2 and mScarlet-I. Obtaining functional fusion proteins can be challenging with proteins involved in multiple interactions, mainly due to steric interference. We demonstrated the use of the new vector system to screen for improved function in cytoskeletal protein FP fusions, and identified FtsZ1-FPs that are functional in cell division and CetZ1-FPs that are functional in motility and rod cell development. Both the type of linker and the type of FP influenced the functionality of the resulting fusions. The vector design also facilitates convenient cloning and tandem expression of two genes or fusion genes, controlled by a modified tryptophan-inducible promoter, and we demonstrated its use for dual-colour imaging of tagged proteins inH. volcaniicells. These tools should promote further development and applications of archaeal molecular and cellular biology and biotechnology.
Scalable design of repeat protein structural dynamics via probabilistic coarse-grained models
Authors: Sarvaharman Seeralan , Neary Timon E. , Gorochowski Thomas E. , Parmeggiani Fabio 
Published: March 2024

ABSTRACTComputational protein design has emerged as a powerful tool for creating proteins with novel functionalities. However, most existing methods ignore structural dynamics even though they are known to play a central role in many protein functions. Furthermore, methods like molecular dynamics that are able to simulate protein movements are computationally demanding and do not scale for the design of even moderately sized proteins. Here, we develop a probabilistic coarse-grained model to overcome these limitations and support the design of the structural dynamics of modular repeat proteins. Our model allows us to rapidly calculate the probability distribution of structural conformations of large modular proteins, enabling efficient screening of design candidates based on features of their dynamics. We demonstrate this capability by exploring the design landscape of 4–6 module repeat proteins. We assess the flexibility, curvature and multi-state potential of over 65,000 protein variants and identify the roles that particular modules play in controlling these features. Although our focus here is on protein design, the methods developed are easily generalised to any modular structure (e.g., DNA origami), offering a means to incorporate dynamics into diverse biological design workflows.
Convergent gene expression in endometrial epithelial cells illuminates the evolution of uterine receptivity
Authors: Brulport Axelle , Gazda Małgorzata Anna , Liorzou Eulalie , Daunesse Maëlle , Raquillet Bruno , Lepelletier Anthony , Sopena-Rios Maria , Raliou Mariam , Regnard Pierrick , Fellmann Lyne , Faccin Lucie , Garbit Slaveia , Cermolacce Alexia , Kondova Ivanela , Marcellin Louis , Abo Carole , Doridot Ludivine , Berthelot Camille 
Published: March 2024

AbstractThe epithelium of the uterine endometrium is the first maternal interface encountered by the embryo, and plays crucial roles in the maternal-embryonic crosstalk necessary to embryo implantation. Mechanisms of embryo implantation are highly variable between mammals: humans and mice have convergently evolved similar embryo implantation phenotypes, where the embryo embeds in the maternal mucosa, which differs from the ancestral mammalian and primate phenotypes. This phenomenon is thought to be partly controlled by maternal epithelial receptivity signals during the window of implantation. Here, we combined endometrial epithelial organoid models and single-cell transcriptomics to investigate how gene expression has evolved in endometrial epithelial cells between human, non-human primates and mouse at key time points in the hormonal cycle. We discovered that many maternal genes involved in uterine receptivity and embryo implantation exhibit more similar expression patterns between human and mouse compared to macaque and marmoset. In particular, we show that the endometrial expression ofLIF, a crucial actor of endometrial receptivity in both human and mouse, is likely an evolutionary convergence rather than a conserved feature as previously hypothesised.