Biology subjects

Fu, X.

Publications and source records attributed to Fu, X..

At least 109 records · Page 6Linked to original sources

bioRxiv2023

Multi-Scale Label-free Human Brain Imaging with Integrated Serial Sectioning Polarization Sensitive Optical Coherence Tomography and Two-Photon Microscopy

The study of neurodegenerative processes in the human brain requires a comprehensive understanding of cytoarchitectonic, myeloarchitectonic, and vascular structures. Recent computational advances have enabled volumetric reconstruction of the human brain using thousands of stained slices, however, tissue distortions and loss resulting from standard histological processing have hindered deformation-free reconstruction of the human brain. The development of a multi-scale and volumetric human brain imaging technique that can measure intact brain structure would be a major technical advance. Here, we describe the development of integrated serial sectioning Polarization Sensitive Optical Coherence Tomography (PSOCT) and Two Photon Microscopy (2PM) to provide label-free multi-contrast imaging, including scattering, birefringence and autofluorescence of human brain tissue. We demonstrate that high-throughput reconstruction of 4x4x2cm3 sample blocks and simple registration of PSOCT and 2PM images enable comprehensive analysis of myelin content, vascular structure, and cellular information. We show that 2 m in-plane resolution 2PM images provide microscopic validation and enrichment of the cellular information provided by the PSOCT optical property maps on the same sample, revealing the sophisticated capillary networks and lipofuscin filled cell bodies across the cortical layers. Our method is applicable to the study of a variety of pathological processes, including demyelination, cell loss, and microvascular changes in neurodegenerative diseases such as Alzheimers disease (AD) and Chronic Traumatic Encephalopathy (CTE).

neuroscience↗

bioRxiv2023

Lipase-mediated detoxification of host-derived antimicrobial fatty acids by Staphylococcus aureus

Long-chain fatty acids with antimicrobial properties are abundant on the skin and mucosal surfaces, where they are essential to restrict the proliferation of opportunistic pathogens such as Staphylococcus aureus. These antimicrobial fatty acids (AFAs) elicit bacterial adaptation strategies, which have yet to be fully elucidated. Characterizing the pervasive mechanisms used by S. aureus to resist AFAs could open new avenues to prevent pathogen colonization. Here, we identify the S. aureus lipase Lip2 as a novel resistance factor against AFAs. Lip2 detoxifies AFAs via esterification with cholesterol. This is reminiscent of the activity of the fatty acid-modifying enzyme (FAME), whose identity has remained elusive for over three decades. In vitro, Lip2-dependent AFA-detoxification was apparent during planktonic growth and biofilm formation. Our genomic analysis revealed that prophage-mediated inactivation of Lip2 was more common in blood and nose isolates than in skin strains, suggesting a particularly important role of Lip2 for skin colonization. Accordingly, in a mouse model of S. aureus skin colonization, bacteria were protected from sapienic acid - a human-specific AFA - in a cholesterol- and lipase-dependent manner. These results suggest Lip2 is the long-sought FAME that exquisitely manipulates environmental lipids to promote bacterial growth. Our data support a model in which S. aureus exploits and/or exacerbates lipid disorders to colonize otherwise inhospitable niches.

microbiology↗

bioRxiv2023

A parabrachial-hypothalamic parallel circuit governs cold defense in mice

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Remarkable advances have been made in understanding how neurocircuits centered in the hypothalamic preoptic area (POA), the brains thermoregulation center, control warm defense, whereas mechanisms by which the POA regulates cold defense remain unclear. Here, we confirmed that the pathway from the lateral parabrachial nucleus (LPB) to the POA, is critical for cold defense. Parallel to this pathway, we uncovered that a pathway from the LPB to the dorsomedial hypothalamus (DMH), namely the LPB[->]DMH pathway, is also essential for cold defense. Projection-specific blockings revealed that both pathways provide an equivalent and cumulative contribution to cold defense, forming a parallel circuit. Specifically, activation of the LPB[->]DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and physical activity. Further, we identified a subpopulation of somatostatin+ neurons in the LPB that target the DMH to promote BAT thermogenesis. Therefore, we reveal a parabrachial-hypothalamic parallel circuit in governing cold defense in mice. This not only enables resilience to hypothermia but also provides a scalable and robust network in heat production, reshaping our understanding of how neural circuits regulate essential homeostatic behaviors.

neuroscience↗

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↗

bioRxiv2023

Computational Scoring and Experimental Evaluation of Enzymes Generated by Neural Networks

In recent years, generative protein sequence models have been developed to sample novel sequences. However, predicting whether generated proteins will fold and function remains challenging. We evaluate computational metrics to assess the quality of enzyme sequences produced by three contrasting generative models: ancestral sequence reconstruction, a generative adversarial network, and a protein language model. Focusing on two enzyme families, we expressed and purified over 440 natural and generated sequences with 70-90% identity to the most similar natural sequences to benchmark computational metrics for predicting in vitro enzyme activity. Over three rounds of experiments, we developed a computational filter that improved experimental success rates by 44-100%. Surprisingly, neither sequence identity to natural sequences nor AlphaFold2 residue-confidence scores were predictive of enzyme activity. The proposed metrics and models will drive protein engineering research by serving as a benchmark for generative protein sequence models and helping to select active variants to test experimentally.

biochemistry↗

bioRxiv2023

Efficient and scalable prediction of spatio-temporal stochastic gene expression in cells and tissues using graph neural networks

The simulation of spatial stochastic models is highly computationally expensive, an issue that has severely limited our understanding of the spatial nature of gene expression. Here we devise a graph neural network based method to learn, from stochastic trajectories in a small region of space, an effective master equation for the time-dependent marginal probability distributions of mRNA and protein numbers at sub-cellular resolution for every cell in a tissue. Numerical solution of this equation leads to accurate results in a small fraction of the computation time of standard simulation methods. Moreover its predictions can be extrapolated to a spatial organisation (a cell network topology) and regions of parameter space unseen in its neural network training. The scalability and accuracy of the method suggest it is a promising approach for whole cell modelling and for detailed comparisons of stochastic models with spatial genomics data.

systems biology↗

bioRxiv2023

Epigenetic modifications mediate cultivar-specific root development and metabolic adaptation to nitrogen availability in wheat

The breeding of crops with improved nitrogen use efficiency (NUE) is crucial for sustainable agriculture. However, the role of epigenetic modification in the regulation of cultivar-specific responses to low nitrogen (LN) constraint is not well understood. Here, we analyzed the chromatin landscapes in roots, leaves, and seeds in two wheat cultivars (KN9204 and J411) that differ radically in NUE under normal and nitrogen-limited conditions. Transcriptional regulatory chromatin regions exhibited a clear cultivar-specificity between KN9204 and J411. Cultivar-specific regulation of nitrogen metabolism genes (NMGs) is linked to variation in histone modification levels, rather than differences in DNA sequence. Cultivar-specific histone modification regions were found to contribute to the genetic regulation of NUE-related traits, such as QTL locus of maximum root length of qMRL-7B. Furthermore, LN-induced H3K27ac and H3K27me3 dynamics enhanced root growth more in KN9204, while strengthened the nitrogen uptake system more in J411. Evidence from histone deacetylase inhibitor treatment and transgenic plants with loss-of-function of the H3K27me3 methyltransferase further showed that changes in epigenetic modifications can alter the strategy for root development and nitrogen uptake in response to LN constraint. Taken together, the results of our study highlight the importance of epigenetic regulation in mediating cultivar-specific root development and metabolic adaptation to LN in wheat.

plant biology↗

bioRxiv2023

Ubiquinone deficiency drives reverse electron transport to disrupt hepatic metabolic homeostasis in obesity

Mitochondrial reactive oxygen species (mROS) are central to physiology. While excess mROS production has been associated with several disease states, its precise sources, regulation, and mechanism of generation in vivo remain unknown, limiting translational efforts. Here we show that in obesity, hepatic ubiquinone (Q) synthesis is impaired, which raises the QH2/Q ratio, driving excessive mROS production via reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo we demonstrated that RET is critical for metabolic health. In patients with steatosis, the hepatic Q biosynthetic program is also suppressed, and the QH2/Q ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.

biochemistry↗

bioRxiv2023

Augmentation of Histone Deacetylase 6 Activity Impairs Mitochondrial Respiratory Complex I in Ischemic/Reperfused Diabetic Hearts

BACKGROUNDDiabetes augments activity of histone deacetylase 6 (HDAC6) and generation of tumor necrosis factor (TNF) and impairs the physiological function of mitochondrial complex I (mCI) which oxidizes reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide to sustain the tricarboxylic acid cycle and {beta}-oxidation. Here we examined how HDAC6 regulates TNF production, mCI activity, mitochondrial morphology and NADH levels, and cardiac function in ischemic/reperfused diabetic hearts. METHODSHDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent myocardial ischemia/reperfusion injury in vivo or ex vivo in a Langendorff-perfused system. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. We compared the activities of HDAC6 and mCI, TNF and mitochondrial NADH levels, mitochondrial morphology, myocardial infarct size, and cardiac function between groups. RESULTSMyocardial ischemia/reperfusion injury and diabetes synergistically augmented myocardial HDCA6 activity, myocardial TNF levels, and mitochondrial fission and inhibited mCI activity. Interestingly, neutralization of TNF with an anti-TNF monoclonal antibody augmented myocardial mCI activity. Importantly, genetic disruption or inhibition of HDAC6 with tubastatin A decreased TNF levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and ameliorated cardiac dysfunction. In H9c2 cardiomyocytes cultured in high glucose, hypoxia/reoxygenation augmented HDAC6 activity and TNF levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. CONCLUSIONSAugmenting HDAC6 activity inhibits mCI activity by increasing TNF levels in ischemic/reperfused diabetic hearts. The HDAC6 inhibitor, tubastatin A, has high therapeutic potential for acute myocardial infarction in diabetes. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIIschemic heart disease (IHS) is a leading cause of death globally, and its presence in diabetic patients is a grievous combination, leading to high mortality and heart failure. C_LIO_LIDiabetes impairs assembly of mitochondrial complex I (mCI), complex III dimer, and complex IV monomer into the respiratory chain supercomplexes, resulting in electron leak and the formation of reactive oxygen species (ROS). C_LIO_LIBy oxidizing reduced nicotinamide adenine dinucleotide (NADH) and reducing ubiquinone, mCI physiologically regenerates NAD+ to sustain the tricarboxylic acid cycle and {beta}-oxidation. C_LI What New Information Does This Article Contribute?O_LIMyocardial ischemia/reperfusion injury (MIRI) and diabetes as comorbidities augment myocardial HDCA6 activity and generation of tumor necrosis factor (TNF), which inhibit myocardial mCI activity. C_LIO_LIGenetic disruption of histone deacetylase 6 (HDAC6) decreases mitochondrial NADH levels and augments mCI activity in type 1 diabetic mice undergoing MIRI via decreasing TNF production, leading to decreases in MIRI. C_LIO_LIPretreatment of type 2 diabetic db/db mice with a HDAC6 inhibitor, tubastatin A (TSA), decreases mitochondrial NADH levels and augments mCI activity by decreasing TNF levels, leading to improvements in cardiac function. C_LI Patients with diabetes are more susceptible to MIRI than non-diabetics with greater mortality and resultant heart failure. There is an unmet medical need in diabetic patients for the treatment of IHS. Our biochemical studies find that MIRI and diabetes synergistically augment myocardial HDAC6 activity and generation of TNF, along with cardiac mitochondrial fission and low bioactivity of mCI. Intriguingly, genetic disruption of HDAC6 decreases the MIRI-induced increases in TNF levels, concomitant with augmented mCI activity, decreased myocardial infarct size, and ameliorated cardiac dysfunction in T1D mice. Importantly, treatment of obese T2D db/db mice with TSA reduces the generation of TNF and mitochondrial fission and enhances mCI activity during reperfusion after ischemia. Our isolated heart studies revealed that genetic disruption or pharmacological inhibition of HDAC6 reduces mitochondrial NADH release during ischemia and ameliorates dysfunction of diabetic hearts undergoing MIRI. Furthermore, HDAC6 knockdown in cardiomyocytes blocks high glucose- and exogenous TNF-induced suppression of mCI activity in vitro, implying that HDAC6 knockdown can preserve mCI activity in high glucose and hypoxia/reoxygenation. These results demonstrate that HDAC6 is an important mediator in MIRI and cardiac function in diabetes. Selective inhibition of HDAC6 has high therapeutic potential for acute IHS in diabetes.

pharmacology and toxicology↗

bioRxiv2023

Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and glycerol-mediated gluconeogenesis in mice

The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by liver MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway essentially reversing glycolysis and an indirect mitochondrial pathway requiring the MPC. MPC deletion reduced the incorporation of 13C-glycerol into TCA cycle metabolites but not into newly synthesized glucose. However, suppression of glycerol metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice. Thus, glucose production by kidney and intestine may compensate for MPC deficiency in hepatocytes.

physiology↗

bioRxiv2022

Mutation divergence over space in tumour expansion

Mutation accumulation in tumour evolution is one major cause of intra-tumour heterogeneity (ITH), which often leads to drug resistance during treatment. Previous studies with multi-region sequencing have shown that mutation divergence among samples within the patient is common, and the importance of spatial sampling to obtain a complete picture in tumour measurements. However, quantitative comparisons of the relationship between mutation heterogeneity and tumour expansion modes, sampling distances as well as the sampling methods are still few. Here, we investigate how mutations diverge over space by varying the sampling distance and tumour expansion modes using individual based simulations. We measure ITH by the Jaccard index between samples and quantify how ITH increases with sampling distance, the pattern of which holds in various sampling methods and sizes. We also compare the inferred mutation rates based on the distributions of Variant Allele Frequencies (VAF) under different tumour expansion modes and sampling sizes. In exponentially fast expanding tumours, a mutation rate can always be inferred in any sampling size. However, the accuracy compared to the true value decreases when the sampling size decreases, where small sampling sizes result in a high estimate of the mutation rate. In addition, such an inference becomes unreliable when the tumour expansion is slower such as in surface growth.

cancer biology↗

bioRxiv2022

Effects of continuous tactile stimulation on auditory-evoked cortical responses depend on the audio-tactile phase

Auditory perception can benefit from stimuli in non-auditory sensory modalities, as for example in lip-reading. Compared with such visual influences, tactile influences are still poorly understood. It has been shown that single tactile pulses can enhance the perception of auditory stimuli depending on their relative timing, but whether and how such brief auditory enhancements can be stretched in time with more sustained, phase-specific periodic tactile stimulation is still unclear. To address this question, we presented tactile stimulation that fluctuated coherently and continuously at 4Hz with an auditory noise (either in-phase or anti-phase) and assessed its effect on the cortical processing and perception of an auditory signal embedded in that noise. Scalp-electroencephalography recordings revealed an enhancing effect of in-phase tactile stimulation on cortical responses phase-locked to the noise and a suppressive effect of anti-phase tactile stimulation on responses evoked by the auditory signal. Although these effects appeared to follow well-known principles of multisensory integration of discrete audio-tactile events, they were not accompanied by corresponding effects on behavioral measures of auditory signal perception. Our results indicate that continuous periodic tactile stimulation can enhance cortical processing of acoustically-induced fluctuations and mask cortical responses to an ongoing auditory signal. They further suggest that such sustained cortical effects can be insufficient for inducing sustained bottom-up auditory benefits.

neuroscience↗

bioRxiv2022

Modulating the epigenetic state promotes the reprogramming of transformed cells to pluripotency in a line-specific manner

Somatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are highly resistant to reprogramming. There must be barriers that block transformed cells from reprogramming, but the nature of those barriers is unclear. In this study, we generated a systematic panel of transformed mouse embryonic fibroblasts (MEFs) using a variety of oncogenic transgenes, and discovered transformed cell lines that remain compatible with reprogramming when transfected with Oct4/Sox2/Klf4/Myc. By comparing the reprogramming-capable and incapable transformed lines we identified multiple stages of failure in the reprogramming process. Some transformed lines failed very early, whilst other lines seemed to progress through a normal-looking reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperactive epigenetic state in some of the transformed cells. This study reveals that the barriers underlying resistance to reprogramming vary between the different transformation methods. Key findingsO_LISomatic cell reprogramming of transformed cells is context-specific C_LIO_LIInhibition of MEK converts some cell lines to reprogramming-capable C_LIO_LITransformed cell lines are characterized by a hyperactive chromatin state C_LIO_LIMEK inhibition indirectly affects chromatin to enable reprogramming C_LI

cell biology↗

bioRxiv2022

Computational structure prediction methods enable the systematic identification of oncogenic mutations

Oncogenic mutations are associated with the activation of key pathways necessary for the initiation, progression and treatment-evasion of tumors. While large genomic studies provide the opportunity of identifying these mutations, the vast majority of variants have unclear functional roles presenting a challenge for the use of genomic studies in the clinical/therapeutic setting. Recent developments in predicting protein structures enable the systematic large-scale characterization of structures providing a link from genomic data to functional impact. Here, we observed that most oncogenic mutations tend to occur in protein regions that undergo conformation changes in the presence of the activating mutation or when interacting with a protein partner. By combining evolutionary information and protein structure prediction, we introduce the Evolutionary and Structure (ES) score, a computational approach that enables the systematic identification of hotspot somatic mutations in cancer. The predicted sites tend to occur in Short Linear Motifs and protein-protein interfaces. We test the use of ES-scores in genomic studies in pediatric leukemias that easily recapitulates the main mechanisms of resistance to targeted and chemotherapy drugs. To experimentally test the functional role of the predictions, we performed saturated mutagenesis in NT5C2, a protein commonly mutated in relapsed pediatric lymphocytic leukemias. The approach was able to capture both commonly mutated sites and identify previously uncharacterized functionally relevant regions that are not frequently mutated in these cancers. This work shows that the characterization of protein structures provides a link between large genomic studies, with mostly variants of unknown significance, to functional systematic characterization, prioritizing variants of interest in the therapeutic setting and informing on their possible mechanisms of action.

cancer biology↗

bioRxiv2022

VR-based real-time imaging reveals abnormal cortical dynamics during behavioral transitions in a mouse model of autism

Functional connectivity (FC) can provide insight into cortical circuit dysfunction in neuropsychiatric disorders. However, dynamic changes in FC related to locomotion with sensory feedback remain unexplored. To investigate FC dynamics in locomoting mice, we developed mesoscopic Ca2+ imaging with a virtual reality (VR) environment. We find rapid reorganization of cortical FC in response to changing behavioral states. Using machine learning classification, behavioral states are accurately decoded. We then use our VR-based imaging system to study cortical FC in a mouse model of autism and find that locomotion states are associated with altered FC dynamics. Furthermore, we identify FC patterns involving the motor area as the most distinguishing features of the autism mice from wild-type mice during behavioral transitions, which might correlate with motor clumsiness in patients with autism. Our VR-based real-time imaging system provides invaluable information to understand FC dynamics linked to a behavioral abnormality of neuropsychiatric disorders.

neuroscience↗

bioRxiv2022

Systematic mining and genetic characterization of regulatory factors for wheat spike development

The spike architecture of wheat plays a crucial role in determining grain number, making it a key trait to optimize in wheat breeding programs. In this study, through a multi-omic approach, we analyzed the transcriptome and epigenome profiles of the shoot apex at eight developmental stages, revealing coordinated changes in chromatin accessibility and H3K27me3 abundance during the flowering transition. We constructed a core transcriptional regulatory network (TRN) that drives wheat spike formation, and experimentally validated a multi-layer regulatory module involving TaSPL15, TaAGLG1, and TaFUL2. By integrating the TRN with genome-wide association analysis (GWAS), we identified 227 transcription factors (TFs), including 42 with known functions and 185 with unknown functions. Further investigation of 61 novel TFs using multiple homozygous mutant lines uncovered 36 TFs with altered spike architecture or flowering time, such as TaMYC2-A1, TaMYB30-A1, and TaWRKY37-A1. Of particular interest, TaMYB30-A1, downstream and repressed by WFZP, was found to regulate fertile spikelet number. Notably, during the domestication and breeding process in China, the excellent haplotype of TaMYB30-A1 containing a C allele at the WFZP binding site was enriched, leading to improved agronomic traits. Our study presents novel and high-confidence regulators and offers an effective strategy for understanding the genetic basis of wheat spike development, with practical impact for wheat breeding applications.

plant biology↗

bioRxiv2022

A Unified Modular Framework to Incorporate Structural Dependency in Spatial Omics Data

Spatial omics technologies can help identify spatially organized biological processes, but existing computational approaches often overlook structural dependencies in the data. Here, we introduce Smoother, a unified framework that integrates positional information into non-spatial models via modular priors and losses. In simulated and real datasets, Smoother enables accurate data imputation, cell-type deconvolution, and dimensionality reduction with remarkable efficiency. In colorectal cancer, Smoother-guided deconvolution revealed plasma cell and fibroblast subtype localizations linked to tumor microenvironment restructuring. Additionally, joint modeling of spatial and single-cell human prostate data with Smoother allowed for spatial mapping of reference populations with significantly reduced ambiguity.

bioinformatics↗

bioRxiv2022

The metabolite alpha-ketobutyrate increases health and life spans by activating AMPK

Aging is a complex process that is directly related to human health and disease. The extraordinary finding that aging is malleable, as shown in model organisms whose life and health spans are extended by specific gene mutations or dietary or pharmacological perturbations 1-3, has offered enormous hope for our understanding and treatment of aging and related diseases. Although many molecules have been identified that can extend the lifespan of model organisms, few have been shown to alleviate age-related symptoms or illness in mammals 4. Here we show that supplementation with the endogenous metabolite -ketobutyrate (-KB) increases the lifespan of adult C. elegans. Using Gelfree DARTS-PROTOMAP, we identified microtubule-actin cross-linking factor (MACF1) that was protected against proteolysis in the presence of -KB. MACF1 belongs to the spectraplakin family of giant, evolutionarily conserved proteins with versatile functions 5, but their link to longevity regulation has not been explored. -KBs longevity effect in C. elegans is abrogated by loss-of-function mutation in vab-10, encoding the worm ortholog of mammalian MACF1 6. Like -KB treatment, vab-10 knockdown activates AMP-activated protein kinase (AMPK), and AMPK is required for -KB effects on longevity. The findings suggest a model in which -KB increases longevity by activating AMPK via VAB-10/MACF1 modulation. -KB also delays aging in mammals, increasing the lifespan of aged male mice and the healthspan of both male and female animals. Targeting of broadly expressed scaffolding proteins in connection to cellular energy homeostasis seems to be a clever way that nature has devised for metabolite signals to impinge upon multiple organ and tissue systems, which may have utility for controlling aging and related diseases.

physiology↗