Biology subjects

Mai, K.

Publications and source records attributed to Mai, K..

12 recordsLinked to original sources

bioRxiv2026

Multimodal Connectome Markers of Disruptive Behavior Problems in Youth: Distinct Patterns of Concurrent Severity and Prospective Symptom Change

Disruptive behaviors problems, such as irritability/anger and maladaptive aggression, are associated with altered connectivity across networks supporting emotion regulation. However, multimodal connectome markers of concurrent severity and prospective symptom change, including sex-specific patterns, remain unclear. Using a large, sex-balanced sample from the Adolescent Brain Cognitive Development (ABCD) Study, we applied multimodal connectome-based predictive modelling (CPM) to test whether resting-state functional (n = 7,556; 49.3% female) and structural (N = 8,978; 48.4%) connectivity predicted baseline disruptive behavior severity (at ages 9-10) and 2-year symptom change (from ages 9-10 to 11-12). Models were adjusted for covariates, permutation-tested, and FDR corrected. Secondary analyses tested sex-stratified models separately in males and females. In models emerging as significant, follow-up analyses tested for distinct vs shared predictive edges. Functional and structural connectomes predicted baseline severity ({rho} = 0.087 and {rho} = 0.071, respectively). Functional connectivity also predicted prospective symptom change ({rho} = 0.038), whereas prospective structural prediction was predominately with negative edges ({rho} = 0.026). Functional connectivity models were significant in both sexes, while prospective structural connectivity models were significant in males, but not females. Frontoparietal, medial frontal, sensorimotor, salience, cerebellar, and visual networks contributed across models. Cross-sectional models showed a more distributed pattern while prospective models showed a more focal pattern. These findings identify complementary, largely distinct functional and structural connectome patterns associated with current disruptive behavior risk and subsequent symptom change, supporting the importance of developmental timing, sex, and imaging modality in developing brain-based biomarkers of disruptive behavior risk in youth.

neuroscience↗

bioRxiv2026

Partial sleep deprivation diminishes and uncouples neuronal activity and energy metabolism in the live mouse hippocampus

Sleep disorders and wakefulness constitute a pronounced and pervasive health risk that contributes to numerous cerebral pathologies such as stroke, depression, and neurodegenerative disorders. The hippocampus (HC) plays vital roles in learning and memory and is especially susceptible to the pathological insults imposed by sleep deprivation (SD). While SD disrupts neuronal network signaling and triggers inflammatory processes, the impact of SD on metabolism within the HC presently remains poorly understood. In this study, we assessed the progressive and cumulative effects of partial SD in the live mouse HC CA1 region using two-photon microscopy. Using a custom-designed implantable cannula enabling direct HC visualization and administration of dyes and pharmacological agents directly to HC tissue, we longitudinally monitored spontaneous neuronal activity and partial pressure of oxygen (pO2) within HC CA1 tissue before and during a 7-day period of partial SD and after a 7- day period of recovery. Our results revealed a progressive decline in spontaneous neural activity, alongside sustained elevation in tissue pO2; during the 7-day partial SD period. Notably, after 7 days of recovery, neuronal activity did not return to baseline, and tissue oxygenation continued to increase. Our findings emphasize chronic SD's cumulative and enduring impairments to neuronal function and metabolism in the HC and reveal uncoupling between metabolic and functional recovery that outlasts the sleep restriction period.

neuroscience↗

bioRxiv2026

A multifunctional polyketide synthase in nematodes produces divergent families of signaling molecules that control different developmental arrests

To improve their chances of reproductive success, nematodes not only must arrest their development in response to adverse growth conditions but also must quickly recover if conditions improve. A polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) hybrid assembly line that is expressed in the canal-associated neurons (CANs) of Caenorhabditis elegans promotes recovery from starvation-induced larval arrest. Here, we show that in the predatory nematode Pristionchus pacificus this assembly line produces a suite of secondary metabolites, including a family of hybrid polyketide-nonribosomal peptides known as the nemamides, the related nemaketides, and a family of ascarylose-modified polyketides named ascarenes. Depending on the starter unit that is loaded onto the PKS, the assembly line can produce dramatically different downstream products. Whereas the nemamides promote recovery from starvation-induced larval arrest, the ascarenes inhibit development of the dauer larval stage and promote recovery. This dichotomy suggests that the PKS-NRPS megasynthetase serves as a signaling hub in the CANs, controlling multiple developmental events. The PKS-NRPS assembly line is highly conserved across many nematode species, and identification of these chemical signals will help to elucidate the signaling pathways that control development in the worm and lead to novel anthelmintics.

biochemistry↗

bioRxiv2025

Robust non-invasive detection of hyperglycemia in mouse models of metabolic dysregulation: the novel Urination Index biomarker

Blood glucose is one of the most essential parameters in metabolic research. Yet, accurate blood glucose monitoring in mouse models of diabetes is challenging due to the significant stress associated with the measurements and the variability in diabetes development among experimental mouse models. This variability necessitates frequent blood glucose measurements, which only provide intermittent data and may not accurately reflect continuous metabolic changes. To address these issues, we have utilized the Tecniplast DVC system to monitor bedding moisture, enabling the detection of increased urination (polyuria), a primary symptom of diabetes. Polyuria is a hallmark of (undiagnosed/untreated) diabetes, and we revealed high correlations between bedding moisture and blood glucose during hyperglycemia. Thus, our developed algorithm enhances animal welfare by reducing the need for invasive blood glucose tests and enabling non-invasive, continuous assessment of hyperglycemia onset, progression, and severity directly within the mices home cage. Continuous monitoring of polyuria allows detailed analysis of temporal and circadian urination patterns and enables assessment of the efficacy of glucose-lowering interventions, which is crucial in developing new pharmacological treatments. We propose that this innovative approach of a novel digital biomarker, the Urination Index (UI), offers a significant advance in the methodology for diabetes research in mouse models, improves animal welfare by reducing the need for invasive blood glucose tests, and enhances the reliability of data and the quality of life for the animals involved.

physiology↗

bioRxiv2024

ConvexGating infers gating strategies from clusters in single cell cytometry data

Manual expert gating remains common practice for the definition of specific cell populations in the analysis of flow cytometry data. The increasing number of measured parameters per individual cell and high inter-rater variability makes manual gating inconsistent in many scenarios such as multi-center studies. Here, we propose ConvexGating, an AI tool that automatically learns gating strategies in an unbiased, fully data-driven, yet interpretable manner. ConvexGating scales efficiently with increasing parameter space, creating proficient strategies with low-contamination in the extracted population for previously known and so far unknown or ill-defined cell populations. The inferred strategies are independent of parent populations, for instance, plasmacytoid dendritic cells (pDCs) can be fully identified as CD45RA- CD123+. In addition to flow cytometry data, ConvexGating derives gating strategies for cyTOF (Cytometry by Time of Flight) and CITEseq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) data and supports optimal design of marker panels for cell sorting.

immunology↗

bioRxiv2023

Tip60-mediated Rheb acetylation links palmitic acid with mTORC1 activation and insulin resistance

Differences in dietary fatty acid saturation impact glucose homeostasis and insulin sensitivity in vertebrates. Excess dietary intake of saturated fatty acids (SFAs) induces glucose intolerance and metabolic disorders. In contrast, unsaturated fatty acids (UFAs) elicit beneficial effects on insulin sensitivity. However, it remains elusive how SFAs and UFAs signal differentially toward insulin signaling to influence glucose homeostasis. Here, using a croaker model, we report that dietary palmitic acid (PA), but not oleic acid or linoleic acid, leads to dysregulation of mTORC1 signaling which provokes systemic insulin resistance and glucose intolerance. Mechanistically, using croaker primary myocytes, mouse C2C12 myotubes and HEK293T cells, we show that PA-induced mTORC1 activation is dependent on mitochondrial fatty acid {beta} oxidation. Notably, PA profoundly elevates acetyl-CoA derived from mitochondrial fatty acid {beta} oxidation which intensifies Tip60-mediated Rheb acetylation. Subsequently, the induction of Rheb acetylation facilitates hyperactivation of mTORC1 which enhances serine phosphorylation of IRS1 and simultaneously inhibits transcription of IRS1 through impeding TFEB nuclear translocation, leading to impairment of insulin signaling. Furthermore, targeted abrogation of acetyl-CoA produced from fatty acid {beta} oxidation or Tip60-mediated Rheb acetylation by pharmacological inhibition and genetic knockdown rescues PA-induced insulin resistance. Collectively, this study reveals a conserved acetylation-dependent mechanistic insight for understanding the link between fatty acids and insulin resistance, which may provide a potential therapeutic avenue to intervene in the development of T2D.

cell biology↗

bioRxiv2023

Synergistic effects of dietary taurine and carbohydrates supplementation on skeleton muscle of juvenile turbot Scophthalmus maximus

The present study aims to investigate the effects of dietary taurine and carbohydrate levels on the skeleton muscle growth of turbot. Muscle samples of turbot were collected after 70 days of feeding trial by treatment groups of 0% (C), 0.4% (L1), 1.2% (L2) taurine with 15% dietary carbohydrate level, and 0.4% (H1), 1.2% (H2) taurine with 21% dietary carbohydrate level. Results showed that L2 and H2 treatment has given significantly higher hyperplasia with significantly high muscle fiber frequencies and muscle fiber density than that in the other groups. Hyperplastic muscle fiber generation was significantly stimulated by the high carbohydrate level (21%). Muscle density was not dependent on the level of carbohydrates. Aspartate, Threonine, Serine, Glutamine, Leucine, Phenylalanine, Isoleucine, Lysine, Histidine, and Arginine were significantly high in the H1 group than that in other all groups. H2 treatment was given a significantly higher amount of total collagen content than the other groups by increasing alkaline-soluble, alkaline-insoluble hydroxyproline, and total hydroxyproline levels. Hardness has significantly increased in all the treatment groups than that in the control group. And also, muscle hardness was significantly increased by the dietary carbohydrate levels. Intestine amylase, lipase, and trypsin enzyme activities were significantly increased in all the treatment groups than that in the control. Amylase and lipase activities were significantly highest in the H2 group. Taurine 1.2% with carbohydrates 21% treatment group (H2) was given significantly higher levels of cellular level muscle growth with more collagen in the skeletal muscle of Turbot.

cell biology↗

bioRxiv2022

Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

Autoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased activity of the DNA sensor cGAS and enhanced IFN-I signature. To identify potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients. Immunogenic DNA accumulated during disease onset, triggering cGAS/STING/IRF3-dependent IFN-I release that promoted endothelial damage, pulmonary hemorrhages, and lung dysfunction. Macrophage subsets played dichotomic roles in disease. While recruited monocyte-derived macrophages were major disease drivers by producing most IFN-{beta}, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-{beta}-producing macrophages. Moreover, pharmacological inhibition of STING, IFNAR-I or its downstream JAK/STAT signaling reduced disease severity and accelerated recovery. Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcome. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/493983v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@521964org.highwire.dtl.DTLVardef@13506org.highwire.dtl.DTLVardef@1403dbeorg.highwire.dtl.DTLVardef@958cc4_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryKessler et al. identify aberrant DNA recognition by cGAS/STING axis and IFN-I production by inflammatory macrophages as a major driver of severe ANCA-associated vasculitis (AAV). Pharmacological interventions blocking this pathway ameliorate disease and accelerate recovery, identifying potential targets for therapeutic intervention in patients.

immunology↗

bioRxiv2022

Predicting the pathogenicity of missense variants using features derived from AlphaFold2

Each individual genome harbors multiple missense variants, which can be systematically identified via genome or exome sequencing. This class of genetic variation can alter the functional properties of the respective protein, and thereby lead to clinically relevant phenotypes, such as cancer or Mendelian diseases. Despite advances in computational prediction scores, the classification of missense variants as clinically significant or benign remains a major challenge. Recently, the structure of the human proteome was derived with unprecedented accuracy using the artificial intelligence system AlphaFold2. However, the question of whether AlphaFold2 structures can improve the accuracy of computational pathogenicity prediction for missense variants remains unclear. To address this, we first engineered a set of features for each amino acid from these structures. We then trained a random forest to distinguish between proxy-benign and proxy-pathogenic missense variants derived from gnomAD. This yielded a novel AlphaFold2-based pathogenicity prediction score, termed AlphScore. Important feature classes used by AlphScore are solvent accessibility, amino acid network related features, features describing the physicochemical environment, and AlphaFold2s quality parameter (pLDDT). AlphScore alone showed lower performance than existing scores, such as CADD or REVEL. However, when AlphScore was added to those scores, the performance always increased, as measured by the approximation of deep mutational scan data, as well as the prediction of expert-curated missense variants from the ClinVar database. Overall, our data indicate that the integration of AlphaFold2 predicted structures can improve pathogenicity prediction of missense variants.

genetics↗

bioRxiv2021

SARS-CoV-2 bearing a mutation at the S1/S2 cleavage site exhibits attenuated virulence and confers protective immunity

Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) possesses a discriminative polybasic cleavage motif in its spike protein that is recognized by host furin protease. Proteolytic cleavage activates the spike protein and influences both the cellular entry pathway and cell tropism of SARS-CoV-2. Here, we investigated the impact of the furin cleavage site on viral growth and pathogensis using a hamster animal model infected with SARS-CoV-2 variants bearing mutations at the furin cleavage site (S gene mutants). In the airway tissues of hamsters, the S gene mutants exhibited a low growth property. In contrast to parental pathogenic SARS-CoV-2, hamsters infected with the S gene mutants showed no body weight loss and only a mild inflammatory response, indicating the attenuated variant nature of S gene mutants. We reproduced the attenuated growth of S gene mutants in primary differenciated human airway epithelial cells. This transient infection was enough to induce protective neutralizing antibodies crossreacting with different SARS-CoV-2 lineages. Consequently, hamsters inoculated with S gene mutants showed resistance to subsequent infection with both the parental strain and the currently emerging SARS-CoV-2 variants belonging to lineages B.1.1.7 and P.1. Together, our findings revealed that the loss of the furin cleavage site causes attenuation in the airway tissues of SARS-CoV-2 and highlights the potential benefits of S gene mutants as potential immunogens.

microbiology↗

bioRxiv2018

Distinct housing conditions reveal a major impact of adaptive immunity on the course of obesity-induced type 2 diabetes

Obesity is associated with adipose tissue inflammation, insulin resistance and the development of type 2 diabetes. However, our knowledge is mostly based on conventional murine models and promising pre-clinical studies rarely translated into successful therapies.\n\nThere is a growing awareness of the limitations of studies in laboratory mice, housed in abnormally hygienic specific pathogen-free (SPF) conditions, as relevant aspects of the human immune system remain unappreciated. Here, we assessed the impact of housing conditions on adaptive immunity and metabolic disease processes during high-fat diet. We therefore compared diet-induced obesity in SPF mice with those housed in non-SPF, so called \"antigen exposed\" (AE) conditions. Surprisingly, AE mice fed a high-fat diet maintained increased insulin levels to compensate for insulin resistance, which was reflected in islet hyperplasia and improved glucose tolerance compared to SPF mice. In contrast, we observed higher proportions of effector/memory T cell subsets in blood and liver of high-fat diet AE mice accompanied by the development of nonalcoholic steatohepatitis-like liver pathology. Thus, our data demonstrate the impact of housing conditions on metabolic alterations. Studies in AE mice, in which physiological microbial exposure was restored, could provide a tool for revealing therapeutic targets for immune-based interventions for type 2 diabetes patients.

immunology↗

bioRxiv2017

A negative feedback mechanism in the insulin-regulated glucose homeostasis in Japanese flounder Paralichthys olivaceus by two ways of glucose administration

The present study comparatively analyzed the blood glucose and insulin concentration, the temporal and spatial expression of brain-gut peptides and the key enzymes of glycolysis and gluconeogenesis in Japanese flounder by intraperitoneal (IP) injection and oral (OR) administration of glucose. Samples were collected at 0, 1, 3, 5, 7, 9, 12, 24 and 48h after IP and OR, respectively. Results showed that the hyperglycemia lasted 5 hours and 21 hours in OR and IP group, respectively. The serum insulin concentration significantly decreased (1.58{+/-}0.21mIU/L) at 3h after IP glucose. However, it significantly increased at 3h (3.37{+/-}0.34mIU/L) after OR glucose. The gene expressions of prosomatostatin, neuropeptide Y, cholecystokinin precursor and orexin precursor in the brain showed different profiles between the OR and IP group. The OR not IP administration of glucose had significant effects on the gene expressions of preprovasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide and gastrin in the intestine. When the blood glucose concentration peaked in both IP and OR group, the glucokinase expression in liver was stimulated, but the expression of fructose-1,6-bisphosphatase was depressed. In conclusion, brain-gut peptides were confirmed in the present study. And the serum insulin and the brain-gut peptides have different responses between the IP and OR administration of glucose. A negative feedback mechanism in the insulin-regulated glucose homeostasis was suggested in Japanese flounder. Furthermore, this regulation could be conducted by activating PI3k-Akt, and then lead to the pathway downstream changes in glycolysis and gluconeogenesis.

biochemistry↗