Biology subjects

Chang, D.

Publications and source records attributed to Chang, D..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Reproducible Brain Entropy (BEN) Alterations During Rumination

Rumination, characterized by recurrent and repetitive thinking, is closely associated with mental disorders such as depression. However, the neural mechanisms underlying this mental state remain poorly understood. In this study, we use a relatively novel neuroimaging analysis method-Brain Entropy (BEN) to quantitatively assess the irregularity, disorder, and complexity of brain activity, providing new insights into the neural mechanisms of rumination. We utilized a publicly available MRI dataset from three different scanners. The dataset included 41 healthy adult participants who completed identical fMRI tasks on IPCASGE, PKUGE, and PKUSIEMENS scanners. The time interval between the two visits was 22.0 {+/-} 14.6 days. The fMRI session included four runs: resting state, sad memory, rumination, and distraction. Whole brain voxel-wise BEN differences of task state and resting state, rumination and sad memory, distraction and sad memory, and rumination and distraction were tested and overlap regions after thresholded (p<0.05) across the three scanners were identified as exhibiting significant differences. The results demonstrate distinct alterations in BEN across mental states. Compared to the sad memory condition, decreased BEN was found in the visual cortex (VC) during rumination and decreased BEN in the posterior cingulate cortex/precuneus (PCC/PCu) during distraction. However, when compared to distraction, rumination showed increased BEN in the PCC/PCu. These findings suggest that rumination involves heightened internal focus and reduced processing of external environmental information. This study highlights BEN as a valuable metric for elucidating the neural mechanisms underlying rumination and its role in depression.

neuroscience↗

bioRxiv2024

Older is Order: Entropy reduction in cortical spontaneous activity marks healthy aging

Entropy trajectories remain unclear for the aging process of human brain system due to the lacking of longitudinal neuroimaging resource. We used open data from an accelerated longitudinal cohort (PREVENT-AD) that included 24 healthy aging participants followed by 4 years with 5 visits per participant to establish cortical entropy aging curves and distinguish with the effects of age and cohort. This reveals that global cortical entropy decreased with aging, while a significant cohort effect was detectable that people who were born earlier showed higher cortical entropy. Such entropy reductions were also evident for large-scale cortical networks, although with different rates of reduction for different networks. Specifically, the primary and intermediate networks reduce their entropy faster than the higher-order association networks. We conclude two specific characteristics of the entropy of the human cortex with aging: the shift of the complexity hierarchy and the diversity of complexity strengthen.

neuroscience↗

bioRxiv2024

nSMase2-mediated exosome secretion shapes the tumor microenvironment to immunologically support pancreatic cancer

The pleiotropic roles of nSMase2-generated ceramide include regulation of intracellular ceramide signaling and exosome biogenesis. We investigated the effects of eliminating nSMase2 on early and advanced PDA, including its influence on the microenvironment. Employing the KPC mouse model of pancreatic cancer, we demonstrate that pancreatic epithelial nSMase2 ablation reduces neoplasia and promotes a PDA subtype switch from aggressive basal-like to classical. nSMase2 elimination prolongs survival of KPC mice, hinders vasculature development, and fosters a robust immune response. nSMase2 loss leads to recruitment of cytotoxic T cells, N1-like neutrophils, and abundant infiltration of anti-tumorigenic macrophages in the pancreatic preneoplastic microenvironment. Mechanistically, we demonstrate that nSMase2-expressing PDA cell small extracellular vesicles (sEVs) reduce survival of KPC mice; PDA cell sEVs generated independently of nSMase2 prolong survival of KPC mice and reprogram macrophages to a proinflammatory phenotype. Collectively, our study highlights previously unappreciated opposing roles for exosomes, based on biogenesis pathway, during PDA progression. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/614610v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@b6e6d1org.highwire.dtl.DTLVardef@1ebb41eorg.highwire.dtl.DTLVardef@17e4275org.highwire.dtl.DTLVardef@3d31f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Clonal evolutionary analysis reveals patterns of malignant transformation in pancreatic cancer from Intraductal Papillary Mucinous IPMN Neoplasms (IPMN)

Intraductal papillary mucinous neoplasms (IPMNs) are critical precursors to pancreatic ductal adenocarcinoma (PDAC), a highly lethal cancer due to late detection and rapid progression. Using multi-region whole-genome and transcriptome sequencing, we traced the evolution of PDAC from IPMN, constructing detailed phylogenetic trees to provide insights into subclonal architectures and progression pathways. Our analysis identified two distinct evolutionary trajectories: one driven by a single ancestral clone, and another involving multiple independent ancestral clones, potentially influencing the timing and nature of PDAC onset. We further explored the roles of mutational signatures and structural variants (SVs) in promoting clonal evolution. Complementing these genomic findings, our transcriptomic analysis revealed unique gene expression profiles and variations in the immune landscape, correlating with the different progression stages from IPMN to PDAC. These insights reveal the complex molecular dynamics of IPMN progression to PDAC, highlighting the need to refine early detection and treatment strategies.

cancer biology↗

bioRxiv2024

Altered resting-state brain entropy (BEN) by rTMS across the human cortex

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method effective in treating various neuropsychiatric disorders, yet its mechanisms are not fully understood. In general, rTMS protocols are categorized into excitatory protocols including high-frequency rTMS (HF-rTMS) and intermittent theta burst stimulation (iTBS), and inhibitory protocols including low-frequency rTMS (LF-rTMS) and continuous theta burst stimulation (cTBS). Brain entropy (BEN) measures irregularity, disorders, and complexity of brain activity, our previous studies have indicated that BEN affects excitatory rTMS, including HF-rTMS and iTBS. However, two important questions remain whether rTMS is equally sensitive to inhibitory rTMS and whether it can induce opposite brain activities, another question concerns whether rTMS can induce specific changes across brain regions. To address these issues, we utilized our own cTBS targeted on the left dorsal lateral prefrontal cortex (L-DLPFC) dataset and publicly available LF-rTMS dataset with stimulating sites including the L-DLPFC, left temporal parietal junction (L-TPJ), and left occipital cortex (L-OCC), from the OpenNeuro. BEN maps were calculated before and after stimulation. The results showed that L-DLPFC cTBS increased BEN in the MOFC and L-DLPFC LF-rTMS increased BEN in the MOFC, subgenual anterior cingulate cortex (MOFC/sgACC) and putamen, the regions are consistent with our previous findings with HF-rTMS and iTBS. Additionally, L-TPJ LF-rTMS resulted in increased BEN in the right TPJ, while L-OCC LF-rTMS led to decreased BEN in the posterior cingulate cortex (PCC). Our findings suggest that BEN is not only sensitive to excitatory rTMS but also to inhibitory rTMS. Moreover, LF-rTMS induces different effects across brain regions, as detected by BEN.

neuroscience↗

bioRxiv2024

The effects of L-carnitine and fructose in improved Ham's F10 on sperm culture in idiopathic severe asthenospermia within 24h

Trial designTo study the effects of L-carnitine and fructose on semen parameters of severe asthenospermia patients by sperm culturing in vitro within 24h. We optimized the energy composition and antioxidant substances of sperm culture medium in vitro (based on Hams F10 culture medium) by orthogonal test for preparing high quality culture medium. Sperms of 60 patients with idiopathic severe asthenospermia were collected, and cultured in vitro within 24h, by Hams F10 culture medium added to different concentrations of L-carnitine and fructose and culture temperature, whose effects on sperm motility were observed to determine which is the most appropriate concentration and temperature. MethodsFor determining the appropriate concentration of L-carnitine and fructose and the suitable culture temperature in Hams F10 culture medium, the orthogonal experiments were carried out to optimize above three factors, which had great influence on sperm viability, survival rate, deformity rate and DNA fragmentation index (DFI). ResultsThe final concentration of L-carnitine and fructose was determined in terms of initial tests to assess the effects of different concentrations (4, 8, 12, and 16 mg/ml L-carnitine and 0.125, 0.250, 0.375, and 0.50 mg/ml fructose) on sperm viability and motility in culture. During the operation of processing and culturing sperms in vitro within 24h, orthogonal test showed that sperm viability was better at the final concentration of 8 mg/ml L-carnitine and 0.375 mg/mL fructose in improved Hams F10 culture medium at 36.5 . ConclusionIdiopathic severe asthenospermia sperm can be effectively improved by the modified Hams F10 culture medium of the final concentration of 8 mg/ml L- carnitine and 0.375 mg/mL fructose in at 36.5 within 24h, which has shown better culture effect and is superior to Hams F10 basic medium.

biochemistry↗

bioRxiv2024

Transfer learning predicts species-specific drug interactions in emerging pathogens

Machine learning (ML) algorithms are necessary to efficiently identify potent drug combinations within a large candidate space to combat drug resistance. However, existing ML approaches cannot be applied to emerging and under-studied pathogens with limited training data. To address this, we developed a transfer learning and crowdsourcing framework (TACTIC) to train ML models on data from multiple bacteria. TACTIC was built using 2,965 drug interactions from 12 bacterial strains and outperformed traditional ML models in predicting drug interaction outcomes for species that lack training data. Top TACTIC model features revealed genetic and metabolic factors that influence cross- species and species-specific drug interaction outcomes. Upon analyzing [~]600,000 predicted drug interactions across 9 metabolic environments and 18 bacterial strains, we identified a small set of drug interactions that are selectively synergistic against Gram- negative (e.g., A. baumannii) and non-tuberculous mycobacteria (NTM) pathogens. We experimentally validated synergistic drug combinations containing clarithromycin, ampicillin, and mecillinam against M. abscessus, an emerging pathogen with growing levels of antibiotic resistance. Lastly, we leveraged TACTIC to propose selectively synergistic drug combinations to treat bacterial eye infections (endophthalmitis).

systems biology↗

bioRxiv2024

Molecular effects of indoor tanning

BackgroundTanning bed users have a significantly increased risk of melanoma, but it remains unclear how indoor tanning drives melanomagenesis. Tanning bed radiation is often thought of as a substitute for natural UV radiation despite differences in the maximum doses, UV content, body sites exposed, and patterns of melanoma that arise. MethodsTo better understand the epidemiologic trends and etiology of melanoma associated with tanning bed use, we described the patterns of melanoma in patients with quantifiable tanning bed usage and performed exome sequencing of 182 melanocytes from normal skin of a subset of these patients. ResultsTanning bed users were more likely than non-users to have melanoma on body sites with low cumulative levels of sun damage and were more likely to have multiple melanomas. The melanocytes in normal appearing skin from tanning bed users had higher mutation burdens, a higher proportion of melanocytes with pathogenic mutations, and distinct mutational signatures. These differences were most prominent over body sites that experience comparatively less exposure to natural sunlight. ConclusionsWe conclude that tanning bed radiation induces melanoma by increasing the mutation burden of melanocytes and by mutagenizing a broader field of melanocytes than are typically exposed to natural sunlight. The unique signatures of mutations in skin cells of tanning users may be attributable to the distinct spectra of radiation emitted from solariums.

genomics↗

bioRxiv2024

NCBP1 electrophilic-stress signaling in the nucleus promotes alternatively-spliced S6K1 that dominantly inhibits global translation

Subcellular stress profoundly influences protein synthesis. However, both the nature of spatiotemporally restricted chemical cues and local protein responders to these cues remain elusive. Unlocking these mechanisms requires the ability to functionally map in living systems locale-specific stress-responder proteins and interrogate how chemical modification of each responder impacts proteome synthesis. We resolved this problem by integrating precision localized electrophile generation and genetic code expansion tools. Upon examination of four distinct subcellular locales, only nuclear-targeted electrophile stress stalled translation. We discovered that NCBP1--a nuclear-resident protein with multifaceted roles in eukaryotic mRNA-biogenesis--propagated this nuclear stress signal through a single cysteine (C436) from among its 19 conserved cysteines. This NCBP1(C436)-specific modification elicited alternative splicing of >250 genes. Mechanistically, global protein-synthesis stall was choreographed by impaired association between electrophile-modified NCBP1(C436) and SF3A1, an essential component of spliceosome, triggering the production of alternatively-spliced S6-kinase, whose expression was sufficient to dominantly inhibit protein translation. SummaryNuclear reactive electrophile stress suppresses translation via an unprecedented gain of function mechanism. First NCBP1 is labeled at one of its 19 cysteines. This triggers alternative S6K1 splicing, which is dominant negative for translation.

biochemistry↗

bioRxiv2024

Self-Assembled Monolayer Transporters Enable Reagentless Analysis of Small Molecule Analytes

The detection of small molecules beyond glucose remains an ongoing challenge in the field of biomolecular sensing owing to their small size, diverse structures, and lack of alternative non-enzymatic sensing methods. Here, we present a new reagentless electrochemical approach for small molecule detection that involves directed movement of electroactive analytes through a self-assembled monolayer to an electrode surface. Using this method, we demonstrate detection of several physiologically relevant small molecules as well as the capacity for the system to operate in several biological fluids. We anticipate that this mechanism will further improve our capacity for small molecule measurement and provide a new generalizable monolayer-based technique for electrochemical assessment of various electroactive analytes.

bioengineering↗

bioRxiv2024

A high-continuity and annotated reference genome of allotetraploid Siberian wildrye (Elymus sibiricus L., Poaceae: Triticeae)

Elymus sibiricus L. (Siberian wildrye, Es), a species belonging to the wheat tribe, is extensively employed as forage and for the reclamation of degraded grasslands within the Qinghai-Tibet Plateau (QTP). This study provides a high-quality reference genome assembly for the allotetraploid Es, which is composed of 14 pseudomolecules with the total genome size of 6.57 Gb. Our finding suggest that large-scale bursts of retrotransposons are critical for the genome expansion of Es. We discovered a translocation event between the Es4H and Es6H chromosomes with a low frequency of combination. Phylogenetic analyses of 90 Es accessions and 25 diploid accessions representing proposed ancestors from various habitats revealed the existence of four distinct populations. We further provided support for the hypothesis that the QTP is the center of origin and genetic diversity for Es. Collectively, our study offers valuable insights into the evolution of Es, as well as providing genomic resources for genetic enhancement in the Elymus genus and wheat tribe.

genomics↗

bioRxiv2024

Structural insights into sphingosine 1-phosphate receptor 4 activation

S1PR4 is one of five subtypes of sphingosine 1-phosphate receptors (S1PRs) that regulate immune cell functioning, with functional distinctions to other subtypes. S1PR1-targeted modulators caused serious cardiac and vascular adverse effects because S1PR1 was expressed throughout the whole body. Since S1PR4 was only expressed in lung and lymphoid cells, S1PR4-targeted modulators might not trigger these side effects. However, the development of S1PR4-specific agonists is greatly hindered because of the lack of activated S1PR4 structure. Here, we resolved cryo-EM structures of activated S1PR4 and revealed the structural mechanism of ligand recognition, receptor activation, and Gi coupling. Our results offered structural templates for the development of selective S1PR4 agonists with improved safety profiles.

biochemistry↗

bioRxiv2023

Ridge regression baseline model outperforms deep learning method for cancer genetic dependency prediction

Accurately predicting genetic or other cellular vulnerabilities of unscreened, or difficult to screen, cancer samples will allow vast advancements in precision oncology. We re-analyzed a recently published deep learning method for predicting cancer genetic dependencies from their omics profiles. After implementing a ridge regression baseline model with an alternative, simplified problem setup, we achieved a model that outperforms the original deep learning method. Our study demonstrates the importance of problem formulation in machine learning applications and underscores the need for rigorous comparisons with baseline approaches.

bioinformatics↗

bioRxiv2023

Gut Microbiome Wellness Index 2 for Enhanced Health Status Prediction from Gut Microbiome Taxonomic Profiles

Recent advancements in human gut microbiome research have revealed its crucial role in shaping innovative predictive healthcare applications. We introduce Gut Microbiome Wellness Index 2 (GMWI2), an advanced iteration of our original GMWI prototype, designed as a robust, disease-agnostic health status indicator based on gut microbiome taxonomic profiles. Our analysis involved pooling existing 8069 stool shotgun metagenome data across a global demographic landscape to effectively capture biological signals linking gut taxonomies to health. GMWI2 achieves a cross-validation balanced accuracy of 80% in distinguishing healthy (no disease) from non-healthy (diseased) individuals and surpasses 90% accuracy for samples with higher confidence (i.e., outside the "reject option"). The enhanced classification accuracy of GMWI2 outperforms both the original GMWI model and traditional species-level -diversity indices, suggesting a more reliable tool for differentiating between healthy and non-healthy phenotypes using gut microbiome data. Furthermore, by reevaluating and reinterpreting previously published data, GMWI2 provides fresh insights into the established understanding of how diet, antibiotic exposure, and fecal microbiota transplantation influence gut health. Looking ahead, GMWI2 represents a timely pivotal tool for evaluating health based on an individuals unique gut microbial composition, paving the way for the early screening of adverse gut health shifts. GMWI2 is offered as an open-source command-line tool, ensuring it is both accessible to and adaptable for researchers interested in the translational applications of human gut microbiome science.

bioinformatics↗

bioRxiv2023

A resource for probing influences of perinatal factors on neurodevelopment in 3-10-years-old Chinese children

Adverse perinatal factors can disrupt the normal development of the brain, with potential long-term impacts on childrens overall development. Currently, the neuropathological mechanisms by which these factors lead to various neurodevelopmental disorders (NDDs) remain largely unknown. An open resource that integrate perinatal factors with brain and mental health development is essential for investigating NDD-related aetiology. In this Data Descriptor, we introduce a multicentre database containing information on perinatal factors that influence childrens brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors associated with a high incidence of NDDs at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development among children aged 3-10 years are associated with perinatal factors. Ultimately, our goal was to develop an early prediction and screening model for NDDs that leverages normative data to facilitate NDD aetiology research. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD and present preliminary brain-mind associations.

neuroscience↗

bioRxiv2023

SKIN REINNERVATION BY COLLATERAL SPROUTING FOLLOWING SPARED NERVE INJURY IN MICE

Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or via collateral sprouting of neighboring uninjured afferents into the denervated territory. While there has been substantial focus on mechanisms underlying regeneration, collateral sprouting has received relatively less attention. In this study, we used immunohistochemistry and genetic neuronal labeling to define the subtype specificity of sprouting-mediated reinnervation of plantar hind paw skin in the mouse spared nerve injury (SNI) model, in which productive regeneration cannot occur. Following an initial loss of cutaneous afferents in the tibial nerve territory, we observed progressive centripetal reinnervation by multiple subtypes of neighboring uninjured fibers into denervated glabrous and hairy plantar skin. In addition to dermal reinnervation, CGRP-expressing peptidergic fibers slowly but continuously repopulated the denervated epidermis, Interestingly, GFR2-expressing nonpeptidergic fibers exhibited a transient burst of epidermal reinnervation, followed by trend towards regression. Presumptive sympathetic nerve fibers also sprouted into the denervated territory, as did a population of myelinated TrkC lineage fibers, though the latter did so less efficiently. Conversely, rapidly adapting A{beta} fiber and C fiber low threshold mechanoreceptor (LTMR) subtypes failed to exhibit convincing collateral sprouting up to 8 weeks after nerve injury. Optogenetics and behavioral assays further demonstrated the functionality of collaterally sprouted fibers in hairy plantar skin with restoration of punctate mechanosensation without hypersensitivity. Our findings advance understanding of differential collateral sprouting among sensory neuron subpopulations and may guide strategies to promote the progression of sensory recovery or limit maladaptive sensory phenomena after peripheral nerve injury. Significance StatementFollowing nerve injury, whereas one mechanism for tissue reinnervation is regeneration of injured neurons, another, less well studied mechanism is collateral sprouting of nearby uninjured neurons. In this study, we examined collateral sprouting in denervated mouse skin and showed that it involves some, but not all neuronal subtypes. Despite such heterogeneity, a significant degree of restoration of punctate mechanical sensitivity is achieved. These findings highlight the diversity of collateral sprouting among peripheral neuron subtypes and reveal important differences between pre- and post-denervation skin that might be appealing targets for therapeutic correction to enhance functional recovery from denervation and prevent unwanted sensory phenomena such as pain or numbness.

neuroscience↗

bioRxiv2023

RAMZIS: a bioinformatic toolkit for rigorous assessment of the alterations to glycoprotein structure that occur during biological processes

MotivationGlycosylation elaborates the structures and functions of glycoproteins; glycoproteins are common post-translationally modified proteins and are heterogeneous and non-deterministically synthesized as an evolutionarily driven mechanism that elaborates the functions of glycosylated gene products. While glycoproteins account for approximately half of all proteins, their macro- and micro-heterogeneity requires specialized proteomics data analysis methods as a given glycosite can be divided into several glycosylated forms, each of which must be quantified. Sampling of heterogeneous glycopeptides is limited by mass spectrometer speed and sensitivity, resulting in missing values. In conjunction with the low sample size inherent to glycoproteomics, this necessitated specialized statistical metrics to identify if observed changes in glycopeptide abundances are biologically significant or due to data quality limitations. ResultsWe developed an R package, Relative Assessment of m/z Identifications by Similarity (RAMZIS), that uses similarity metrics to guide biomedical researchers to a more rigorous interpretation of glycoproteomics data. RAMZIS uses contextual similarity to assess the quality of mass spectral data and generates graphical output that demonstrates the likelihood of finding biologically significant differences in glycosylation abundance dataset. Investigators can assess dataset quality, holistically differentiate glycosites, and identify which glycopeptides are responsible for glycosylation pattern expression change. Herein RAMZIS approach is validated by theoretical cases and by a proof-of-concept application. RAMZIS enables comparison between datasets too stochastic, small, or sparse for interpolation while acknowledging these issues in its assessment. Using our tool, researchers will be able to rigorously define the role of glycosylation and the changes that occur during biological processes. Availabilityhttps://github.com/WillHackett22/RAMZIS ContactJoseph Zaia, Boston University Medical Campus, 670 Albany St., rm 509, Boston, MA 02118 USA, (e) jzaia@bu.edu, (v) 1-617-358-2429 Supplementary informationSupplementary data are available

bioinformatics↗

bioRxiv2023

A longitudinal resource for population neuroscience of school-age children and adolescents in China

During the past decade, cognitive neuroscience has been calling for population diversity to address the challenge of validity and generalizability, ushering in a new era of population neuroscience. The developing Chinese Color Nest Project (devCCNP, 2013-2022), a ten-year pilot stage of the lifespan CCNP (2013-2032), is an ongoing project focusing on brain-mind development. The project aims to create and share a large-scale, longitudinal and multimodal dataset of typically developing children and adolescents (ages 6.0-17.9 at enrolment) in the Chinese population. The devCCNP houses not only phenotypes measured by demographic, biophysical, psychological and behavioural, cognitive, affective, and ocular-tracking assessments but also neurotypes measured with magnetic resonance imaging (MRI) of brain morphometry, resting-state function, naturalistic viewing function and diffusion structure. This Data Descriptor introduces the first data release of devCCNP including a total of 864 visits from 479 participants. Herein, we provided details of the experimental design, sampling strategies, and technical validation of the devCCNP resource. We demonstrate and discuss the potential of a multicohort longitudinal design to depict normative brain growth curves from the perspective of developmental population neuroscience. The devCCNP resource is shared as part of the "Chinese Data-sharing Warehouse for In-vivo Imaging Brain" in the Chinese Color Nest Project (CCNP) - Lifespan Brain-Mind Development Data Community (https://www.scidb.cn/en/c/ccnp) at the Science Data Bank. Design TypesO_LIAccelerated longitudinal design C_LIO_LIBrain-mind development C_LIO_LIPopulation imaging C_LIO_LIBrain chart C_LIO_LIRepeated measure C_LI MeasurementsO_LIPsychological behaviours C_LIO_LIBiophysical and physical measures C_LIO_LIIntelligence quotient measure C_LIO_LINeuroimaging C_LI Sample Characteristic - OrganismO_LIHomo sapiens C_LI Sample Characteristic - EnvironmentO_LISchool- and community-based sample C_LI Sample Characteristic - LocationO_LIChongqing and Beijing, China C_LI DurationO_LI10 years (2013-2022) C_LI

neuroscience↗