bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell proteomics by mass spectrometry reveals deep epigenetic insight into the actions of an orphan histone deacetylase inhibitor
Authors: Orsburn Benjamin C. 
Published: January 2024

AbstractEpigenetic programming has been shown to play a role in nearly every human system and disease where anyone has thought to look. However, the levels of heterogeneity at which epigenetic or epiproteomic modifications occur at single cell resolution across a population remains elusive. While recent advances in sequencing technology have allowed between 1 and 3 histone post-translational modifications to be analyzed in each single cell, over twenty separate chemical PTMs are known to exist, allowing thousands of possible combinations. Single cell proteomics by mass spectrometry (SCP) is an emerging technology in which hundreds or thousands of proteins can be directly quantified in typical human cells. As the proteins detected and quantified by SCP are heavily biased toward proteins of highest abundance, chromatin proteins are an attractive target for analysis. To this end, I applied SCP to the analysis of cancer cells treated with mocetinostat, a class specific histone deacetylase inhibitor. I find that 16 PTMs can be confidently identified and localized with high site specificity in single cells. In addition, the high abundance of histone proteins allows higher throughput methods to be utilized for SCP than previously described. While quantitative accuracy suffers when analyzing more than 700 cells per day, 9 histone proteins can be measured in single cells analyzed at even 3,500 cells per day, a throughput 10-fold greater than any previous report. In addition, the unbiased global approach utilized herein identifies a previously uncharacterized response to this drug through the S100-A8/S100-A9 protein complex partners. This response is observed in nearly every cell of the over 1,000 analyzed in this study, regardless of the relative throughput of the method utilized. While limitations exist in the methods described herein, current technologies can easily improve upon the results presented here to allow comprehensive analysis of histone PTMs to be performed in any mass spectrometry lab. All raw and processed data described in this study has been made publicly available through the ProteomeXchange/MASSIVE repository system as MSV000093434Abstract graphic
A Survey of theDesulfuromonadiacytochromome provides a glimpse of the unexplored diversity of multiheme cytochromes in nature
Authors: Soares Ricardo , Fonseca Bruno M. , Nash Benjamin W. , Paquete Catarina M. , Louro Ricardo O. 
Published: January 2024

AbstractMultiheme cytochromes (MHC) provide prokaryotes with a broad metabolic versatility that contributes to their role in the biogeochemical cycling of the elements. However, MHC were isolated and studied in detail only from a limited number of species. To obtain a broader view of the diversity of MHC, we employed bioinformatics tools to study the cytochromome encoded in the genomes of theDesulfuromonadiaclass. We found that MHC predicted to be extracellular are the least conserved and present higher diversity. Although the most prevalent MHC have homologues already characterized, nearly half of the MHC families in theDesulforomonadiaclass have no known homologues and AlphaFold2 was employed to predict their 3D structures. This work illuminates for the first time the universe of experimentally uncharacterized cytochromes that are likely to contribute to the metabolic versatility and to the fitness ofDesulfuromonadiain diverse environmental conditions and to drive biotechnological applications.
COFFEE: Consensus Single Cell-Type Specific Inference for Gene Regulatory Networks
Authors: Lodi Musaddiq K , Chernikov Anna , Ghosh Preetam 
Published: January 2024

AbstractThe inference of gene regulatory networks (GRNs) is crucial to understanding the regulatory mechanisms that govern biological processes. GRNs may be represented as edges in a graph, and hence have been inferred computationally for scRNA-seq data. A wisdom of crowds approach to integrate edges from several GRNs to create one composite GRN has demonstrated improved performance when compared to individual algorithm implementations on bulk RNA-seq and microarray data. In an effort to extend this approach to scRNA-seq data, we present COFFEE (COnsensus single cell-type speciFic inFerence for gEnE regulatory networks), a Borda voting based consensus algorithm that integrates information from 10 established GRN inference methods. We conclude that COFFEE has improved performance across synthetic, curated and experimental datasets when compared to baseline methods. Additionally, we show that a modified version of COFFEE can be leveraged to improve performance on newer cell-type specific GRN inference methods. Overall, our results demonstrate that consensus based methods with pertinent modifications continue to be valuable for GRN inference at the single cell level.
Identification of Novel Biomarkers for Alzheimer’s Disease and Related Dementias Using Unbiased Plasma Proteomics
Authors: Lacar Benjamin , Ferdosi Shadi , Alavi Amir , Stukalov Alexey , Venkataraman Guhan R. , de Geus Matthijs , Dodge Hiroko , Wu Chao-Yi , Kivisakk Pia , Das Sudeshna , Guturu Harendra , Hyman Brad , Batzoglou Serafim , Arnold Steven E. , Siddiqui Asim 
Published: January 2024

AbstractAlzheimer’s disease (AD) and related dementias (ADRD) is a complex disease with multiple pathophysiological drivers that determine clinical symptomology and disease progression. These diseases develop insidiously over time, through many pathways and disease mechanisms and continue to have a huge societal impact for affected individuals and their families. While emerging blood-based biomarkers, such as plasma p-tau181 and p-tau217, accurately detect Alzheimer neuropthology and are associated with faster cognitive decline, the full extension of plasma proteomic changes in ADRD remains unknown. Earlier detection and better classification of the different subtypes may provide opportunities for earlier, more targeted interventions, and perhaps a higher likelihood of successful therapeutic development. In this study, we aim to leverage unbiased mass spectrometry proteomics to identify novel, blood-based biomarkers associated with cognitive decline. 1,786 plasma samples from 1,005 patients were collected over 12 years from partcipants in the Massachusetts Alzheimer’s Disease Research Center Longitudinal Cohort Study. Patient metadata includes demographics, final diagnoses, and clinical dementia rating (CDR) scores taken concurrently. The ProteographTMProduct Suite (Seer, Inc.) and liquid-chromatography mass-spectrometry (LC-MS) analysis were used to process the plasma samples in this cohort and generate unbiased proteomics data. Data-independent acquisition (DIA) mass spectrometry results yielded 36,259 peptides and 4,007 protein groups. Linear mixed effects models revealed 138 differentially abundant proteins between AD and healthy controls. Machine learning classification models for AD diagnosis identified potential candidate biomarkers including MBP, BGLAP, and APoD. Cox regression models were created to determine the association of proteins with disease progression and suggest CLNS1A, CRISPLD2, and GOLPH3 as targets of further investigation as potential biomarkers. The Proteograph workflow provided deep, unbiased coverage of the plasma proteome at a speed that enabled a cohort study of almost 1,800 samples, which is the largest, deep, unbiased proteomics study of ADRD conducted to date.
Small Intestinal Goblet Cells Control Humoral Immune Responses and Mobilization During Enteric Infection
Authors: Kulkarni Devesha H. , Talati Khushi , Joyce Elisabeth L. , Kousik Hrishi , Harris Dalia L. , Floyd Alexandria N. , Vavrinyuk Vitaly , Barrios Bibianna , Udayan Sreeram , McDonald Keely , John Vini , Hsieh Chyi-Song , Newberry Rodney D. 
Published: January 2024

ABSTRACTHumoral immune responses within the gut play diverse roles including pathogen clearance during enteric infections, maintaining tolerance, and facilitating the assemblage and stability of the gut microbiota. How these humoral immune responses are initiated and contribute to these processes are well studied. However, the signals promoting the expansion of these responses and their rapid mobilization to the gut mucosa are less well understood. Intestinal goblet cells form goblet cell-associated antigen passages (GAPs) to deliver luminal antigens to the underlying immune system and facilitate tolerance. GAPs are rapidly inhibited during enteric infection to prevent inflammatory responses to innocuous luminal antigens. Here we interrogate GAP inhibition as a key physiological response required for effective humoral immunity. Independent of infection, GAP inhibition resulted in enrichment of transcripts representing B cell recruitment, expansion, and differentiation into plasma cells in the small intestine (SI), which were confirmed by flow cytometry and ELISpot assays. Further we observed an expansion of isolated lymphoid follicles within the SI, as well as expansion of plasma cells in the bone marrow upon GAP inhibition. S1PR1-induced blockade of leukocyte trafficking during GAP inhibition resulted in a blunting of SI plasma cell expansion, suggesting that mobilization of plasma cells from the bone marrow contributes to their expansion in the gut. However, luminal IgA secretion was only observed in the presence ofS. typhimuriuminfection, suggesting that although GAP inhibition mobilizes a mucosal humoral immune response, a second signal is required for full effector function. Overriding GAP inhibition during enteric infection abrogated the expansion of laminar propria IgA+ plasma cells. We conclude that GAP inhibition is a required physiological response for efficiently mobilizing mucosal humoral immunity in response to enteric infection.
A Novel Mouse Model forLAMA2-Related Muscular Dystrophy: Analysis of Molecular Pathogenesis and Clinical Phenotype
Authors: Tan Dandan , Liu Yidan , Luo Huaxia , Shen Qiang , Long Xingbo , Xu Luzheng , Liu Jieyu , Zhong Nanbert , Zhang Hong , Xiong Hui 
Published: January 2024

AbstractOur understanding of the molecular pathogenesis ofLAMA2-related muscular dystrophy (LAMA2-MD) requires improving. Here, we report the phenotype, neuropathology and transcriptomics data (scRNA-seq and bulk RNA-seq) of a newLama2knockout mouse (dyH/dyH) which was created based on the humanLAMA2-MD mutation hotspot region using CRISPR-Cas9. The dyH/dyHmice presented severe phenotype with muscular dystrophy. Mouse brain scRNA-seq showed thatLama2gene was expressed predominantly and specifically in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells, and weakly in astrocytes in wild-type mouse. Laminin α2 expression on the cortical surface was observed with immunofluorescence. In dyH/dyH,Lama2expression was decreased in those cell types, which might be associated with the disruption of gliovascular basal lamina assembly. Additionally, transcriptomic investigation of muscles showed 2020 differentially expressed genes, mainly associated with the impaired muscle cytoskeleton and development. In summary, this study provided potentially useful information for understanding the molecular pathogenesis ofLAMA2-MD.
Morphological Reprogramming of Primary Cilia Length Mitigates the Fibrotic Phenotype in Fibroblasts Across Diverse Fibrotic Conditions
Authors: Verma Priyanka , Yalavarthi Bharat , Bhattacharyya Swati , Khanna Dinesh , Gudjonsson Johann E. , Tsoi Lam C. , Wells Rebecca , Ross Rebecca L , Galdo Natalia Riobo-Del , Galdo Francesco Del , Fortier Sean M. , Teves Maria E. , Varga John , Bhattacharyya Dibyendu 
Published: January 2024

ABSTRACTFibrosis is a hallmark of systemic sclerosis (SSc) and many diverse and incurable diseases. Myofibroblast activation, a common cellular phenomenon shared across fibrotic diseases, is marked by actin polymerization known to affect primary cilia (PC) length. We discovered that fibroblasts from diverse fibrotic conditions display significantly reduced PC lengthex vivo.Treatment of healthy fibroblasts with profibrotic TGF-β1 induced PC shortening, while silencingACTA2in SSc skin fibroblasts caused PC elongation. Importantly, we found that PC length is negatively correlated with cellular expression of α-SMA in TGF-β1-stimulated healthy fibroblasts, or pharmacologically de-differentiated myofibroblasts. PC elongation by microtubule polymerization induction in SSc skin fibroblasts using LiCl or the HDAC6 inhibitor tubacin, reversed and mitigated fibrotic responses. Our results implicate a key role for microtubule polymerization in restraining fibrotic responses and suggest that modulation of PC dynamics may represent a potential therapeutic strategy for SSc and other treatment-resistant diseases associated with fibrosis.Teaser.PC length shortening is a hallmark of fibrosis.
Dynamic parallel transmit diffusion MRI at 7T
Authors: Zhang Minghao , Ding Belinda , Dragonu Iulius , Liebig Patrick , Rodgers Christopher T. 
Published: January 2024

AbstractDiffusion MRI (dMRI) is inherently limited by SNR. Scanning at 7T increases intrinsic SNR but 7T MRI scans suffer from regions of signal dropout, especially in the temporal lobes and cerebellum. We applied dynamic parallel transmit (pTx) to allow whole-brain 7T dMRI and compared with circularly polarized (CP) pulses in 6 subjects.Subject-specific 2-spoke dynamic pTx pulses were designed offline for 8 slabs covering the brain. We used vendor-provided B0and B1+mapping. Spokes positions were set using the Fourier difference approach, and RF coefficients optimized with a Jacobi-matrix high-flip-angle optimizer. Diffusion data were analyzed with FSL.Comparing whole-brain averages for pTx against CP scans: mean flip angle error improved by 15% for excitation (2-spoke-VERSE 15.7°vsCP 18.4°,P=0.012) and improved by 14% for refocusing (2-spoke-VERSE 39.7°vsCP 46.2°,P=0.008). Computed spin-echo signal standard deviation improved by 14% (2-spoke-VERSE 0.185 vs 0.214 CP,P=0.025). Temporal SNR increased by 5.4% (2-spoke-VERSE 8.47vsCP 8.04, P=0.004) especially in the inferior temporal lobes. Diffusion fitting uncertainty decreased by 6.2% for first fibres (2-spoke VERSE 0.0655 vs CP 0.0703,P<0.001) and 1.3% for second fibers (2-spoke VERSE 0.139vsCP 0.141,P=0.01). In conclusion, dynamic parallel transmit improves the uniformity of 7T diffusion-weighted imaging. In future, less restrictive SAR limits for parallel transmit scans are expected to allow further improvements.
Neural and behavioral dynamics of encoding, production and synchronization with external rhythms in subcortical lesion patients
Authors: Criscuolo Antonio , Schwartze Michael , Nozaradan Sylvie , Kotz Sonja A. 
Published: January 2024

AbstractActing in and adapting to a dynamically changing environment necessitates precise encoding of thetimingof unfolding sensory events in our environment, and totimeof our own (re-)actions to them. Cerebellar (CE) and basal ganglia (BG) circuitries play fundamental and complementary roles in timing processes. While the CE seems to encode the precise timing of sensory events (whenan event occurs), the BG engage in generating temporal predictions (whena next event occurs). However, their contributions are rarely investigated in combination, as it is generally difficult to record data from respective patient groups in parallel.Here we investigated the causal roles of CE and BG in sensory and sensorimotor timing processes. Healthy controls and patients with CE or BG lesions listened to isochronous auditory sequences while their EEG was recorded and later performed a tapping synchronization task. We assessed intra- and inter-individual variabilities, as well as group differences, using event-related responses, delta-band inter-trial phase-coherence and acceleration dynamics while tuning to the stimulation frequency (Sf). CE and BG lesions increased variability in ERP latency and reduced the coherence of delta-band activity. CE but not BG lesions further impacted the stability of delta-band oscillations while tuning to theSf. These findings show a causal link between subcortical lesions and the capacity to encode and synchronize ongoing neural activity with temporal regularities in the acoustic environment, but do not fully dissociate the specific contributions of the BG and the CE to processing sound in isochronous contexts.
The cervical and meningeal lymphatic network as a pathway for retrograde nanoparticle transport to the brain
Authors: Ramos-Zaldívar Héctor M , Polakovicova Iva , Salas-Huenuleo Edison , Yefi Claudia P , Silva David , Jara-Guajardo Pedro , Oyarzún Juan Esteban , Neira-Troncoso Álvaro , Burgos Patricia V. , Cavieres Viviana A. , Arias-Muñoz Eloisa , Martínez Carlos , Riveros Ana L. , Corvalán Alejandro H , Kogan Marcelo J , Andia Marcelo E 
Published: January 2024

AbstractThe meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain. Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within deep cervical lymph nodesin vivo,exclusively through lymphatic structures. Since the functional anatomy of dural lymphatics has been found to be conserved between mice and humans, we expect that our results will encourage further research into the retrograde motion of nanoparticles towards the brain for pharmacological purposes in nanomedicine, as well as to better understand the fluid dynamics in different physiological or neuropathological conditions.
Impact of perinatal maternal docosahexaenoic acid-containing phospholipid synthesis on offspring growth and neurological symptoms
Authors: Kanatani Ayumi , Hishikawa Daisuke , Nagata Katsuyuki , Hamano Fumie , Nakano Kenta , Okamura Tadashi , Shimizu Takao , Shindou Hideo , Nagamatsu Takeshi , Yanagida Keisuke 
Published: January 2024

AbstractMothers provide essential nutrients, including docosahexaenoic acid (DHA), an omega-3 fatty acid, during the perinatal period. DHA deficiency in perinatal mothers is linked to developmental abnormalities, especially in the central nervous system of the offspring; however, its specific impact on distinct events in fetal and neonatal brain development and prospective brain functions remains incompletely understood. We demonstrated using mice lackingAgpat3, a gene encoding the enzyme that synthesizes DHA-containing phospholipids (DHA-PLs), that maternal DHA-PL synthesis significantly contributes to the maternal– offspring DHA supply during the fetal period but not in infancy. Selective modulation of DHA-PL levels during fetal and postnatal periods inAgpat3-knockout mice showed that fetal stage-specific insufficiency in maternal DHA-PL supply potentially influences the neuropsychiatric phenotype in adult mice without affecting postnatal tissue DHA-PL levels, weight gain, and brain expansion. Collectively, enhancing maternal DHA-PL synthesis during pregnancy may help prevent prospective neuropsychiatric abnormalities in the offspring.
Psilocybin Promotes Cell-Type-Specific Changes in the Orbitofrontal Cortex Revealed by Single-Nucleus RNA-seq
Authors: Huang Ziran , Wei Xiaoyan , Wang Yihui , Tian Jing , Dong Jihui , Liang Bo , Lu Lin , Zhang Wen 
Published: January 2024

AbstractRecent clinical breakthroughs hold great promise for the application of psilocybin in the treatments of psychological disorders, such as depression, addiction, and obsessive-compulsive disorder. Psilocybin is a psychedelic whose metabolite, psilocin, is a 5-HT2Areceptor agonist. Nevertheless, the underlying mechanisms for the effects of psilocybin on the brain are not fully illustrated, and cell type-specific and circuit effects of psilocybin are not fully understood. Here, we combined single-nucleus RNA-seq with functional assays to study the long-term effects of psilocybin on the orbitofrontal cortex (OFC), a brain region vulnerable to psychological disorders such as depression. We showed that a single dose of psilocybin induced long-term genetic and functional changes in neurons of the OFC, and excitatory and inhibitory neurons collectively reduced circuit activity of the brain region. Knockdown of 5-HT2Areceptor in deep layer excitatory neurons abated psilocybin-induced functional changes and the anti-depressant effect. Together, these results showed the cell type-specific mechanisms of psilocybin and shed light on the brain region difference in the effect of psychedelics.
Tolerance thresholds underlie responses to DNA damage during germline development
Authors: Jansen Gloria , Gebert Daniel , Kumar Tharini Ravindra , Simmons Emily , Murphy Sarah , Teixeira Felipe Karam 
Published: January 2024

AbstractSelfish DNA modules like transposable elements (TEs) are particularly active in the germline, the lineage that passes genetic information across generations. New TE insertions can disrupt genes and impair the functionality and viability of germ cells. However, we find that inP-Mhybrid dysgenesis inDrosophila, a sterility syndrome triggered by theP-element DNA transposon, germ cells harbour unexpectedly few new TE insertions, despite accumulating DNA double-strand breaks (DSBs) and inducing cell cycle arrest. Using an engineered CRISPR-Cas9 system, we show that generating DSBs at silencedP-elements or other non-coding sequences is sufficient to induce germ cell loss independently of gene disruption. Indeed, we demonstrate that both developing and adult mitotic germ cells are sensitive to DSBs in a dosage-dependent manner. Following the mitotic-to-meiotic transition, however, germ cells become more tolerant to DSBs, completing oogenesis regardless of the accumulated genome damage. Our findings establish DNA damage tolerance thresholds as crucial safeguards of genome integrity during germline development.
Strata use in a canopy-beetle community of a lowland Neotropical rainforest in southern Venezuela
Authors: Kirmse Susan 
Published: January 2024

AbstractThe stratification in tropical rainforests is well pronounced. This strongly impacts the distribution of arthropods. As part of a larger beetle survey in the northern part of the Amazonian rainforest, I analyze the characteristics of beetle species shared between the canopy and the understory. Linking the strata use of adult beetles in the complex structure of tropical rainforests with their ecological characteristics may uncover causes of the differences in diversity between vertical layers. Seventy out of a total of 862 beetle species in 45 families sampled on 23 canopy-tree species were collected also in the understory. Beetle families represented with most species in the canopy and ground samples comprise Curculionidae, Chrysomelidae, and Carabidae. In Elateridae and Scarabaeidae, the proportion of shared species between both strata amounted to ≥ 20%. In contrast, the species-rich families (≥ 20 canopy species) Cerambycidae, Mordellidae, and Buprestidae did not comprise species sampled in both strata. Adult feeding requirements and larval substrates are discussed as main reasons for the differences in strata use between these beetle families. In addition, different climatic conditions between the exposed canopy and the more uniform understory might cause a migration of adult beetles between both strata and thus, result in intermixing of beetle species from different strata within the forest.