Biology subjects

Lu, B.

Publications and source records attributed to Lu, B..

88 records · Page 5Linked to original sources

bioRxiv2020

Novel culture method to diagnose fungal infections with biopsy tissues

Biopsy tissue is a difficult sample to gain for the identification of potential pathogen in the clinical laboratory. At present, there are no effective culture methods for small-sized biopsy tissue. In this study, we propose a novel tissue biopsy culture method based on Myco/F lytic liquid culture system, namely, tissue was grinded before injected into culture bottles. More types and numbers of fungi are cultivated using this culture system than sputum or BALF culture. A few of mycobacteria were also detected with ground tissues. The method may be a promising alternative to or supplement for the traditional plate culture in clinical practice.

microbiology↗

bioRxiv2019

Acetylation is required for NLRP3 self-aggregation and full activation of the inflammasome

The full activation of NLRP3 inflammasome needs two sequential signals: the fist priming signal and the second assembly signal. Various stimuli including infections and stress signals can provide the assembly signal. However, how NLRP3 detects diverse stimuli and becomes fully activated remain largely unknown. In this study, we found the second signal specially triggers the acetylation of NLRP3, which facilitates the aggregation of NLRP3 and its interaction with ASC and NEK7, thus promoting the assembly of inflammasome. Meanwhile, by employing pharmacological and molecular approaches, we identified KAT5 as a regulator of NLRP3 acetylation and activation. Furthermore, KAT5 specific inhibitor-NU9056 exhibited a robust suppressive effect on NLRP3 inflammasome both in vitro and in vivo. Thus, our study reveals a new mechanism for NLRP3 full activation and suggests targeting NLRP3 acetylation may provide a new approach for treatment of NLRP3 associated diseases.

immunology↗

bioRxiv2019

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency, and delay growth of human prostate cancer xenografts by reducing the number of cancer propagating cells. In sum, our study provides a definitive proof of tumor suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer propagating cells in prostate cancers with MME downregulation.

cancer biology↗

bioRxiv2019

Reproducible observations revealing patterns of the default mode network underlie rumination

Rumination is a repetitive self-referential thinking style and posited to be an expression of abnormalities in the default mode network (DMN) in major depressive disorder (MDD). Recent evidences indicate DMN is not a unitary network but can be further divided into 3 functionally heterogenous subsystems. However, the subsystem mechanism through which DMN underlie rumination remain unclear. Here, with a modified continuous state-like paradigm, we induced healthy participants to ruminate or imagine objective scenarios (as a distraction control condition) on 3 different MRI scanners. We compared functional connectivities (FC) and inter-subject correlations (ISC) of the DMN and its 3 subsystems between rumination and distraction states. Results yielded a highly reproducible and dissociated pattern. During rumination, within-DMN FC was generally decreased compared to the distraction state. At the subsystem level, we found increased FC between the core and medial temporal lobe (MTL) subsystem and decreased FC between the core and dorsal medial prefrontal cortex (DMPFC) subsystem and within the MTL subsystem. Furthermore, we found decreased ISC within the MTL subsystem. These results suggest a specific and less synchronous activity pattern of DMN during rumination and shed new light on the association between rumination and DMN substrates regarding MDD.

neuroscience↗

bioRxiv2019

Tau Accumulation via Reduced BAG3-mediated Autophagy Is Required for GGGGCC Repeat Expansion-Induced Neurodegeneration

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders including Huntington disease (HD, caused by the expanded CAG repeats (CAGr) in the HTT gene) and amyotrophic lateral sclerosis (ALS, could be caused by the expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene), of which the molecular mechanisms remain unclear. Here we demonstrate that loss of the Drosophila orthologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and shortened life-span in Drosophila models expressing mutant HTT protein with expanded CAGr or the expanded G4C2r. Importantly, expression of human tau (htau4R) restored the disease-relevant phenotypes that were mitigated by the loss of dtau, suggesting a conserved role of tau in neurodegeneration. We further discovered that G4C2r expression increased dtau accumulation, possibly due to reduced activity of BAG3-mediated autophagy. Our study reveals a conserved role of tau in G4C2r-induced neurotoxicity in Drosophila models, providing mechanistic insights and potential therapeutic targets.

neuroscience↗

bioRxiv2019

Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.

physiology↗

bioRxiv2019

LonP1 Orchestrates UPRmt and UPRER and Mitochondrial Dynamics to Regulate Heart Function

Protein quality control is pivotal to cellular homeostasis and integrity of cardiomyocytes for maintenance of normal heart function. The unfolded protein response (UPR) is an adaptive process to modulate protein quality control in the endoplasmic reticulum (ER) and mitochondria, and is accordingly termed UPRER and UPRmt, respectively. Lon protease (LonP1) is a highly conserved mitochondrial protease to modulate UPRmt, which is involved in regulating metabolism, mitophagy, and stress response. However, whether LonP1 regulates UPRER remains elusive. To investigate the regulation of protein quality control in cardiomyocytes, we generated cardiac-specific LonP1 deletion mice. Our findings show that LonP1 deficiency caused impaired mitochondrial respiratory function and fragmentation. Surprisingly, both UPRER and UPRmt is substantially induced in LonP1-deletion heart suggesting of LonP1 as a novel regulator of UPRER; however, the activation of UPRER occurs earlier than UPRmt in response to LonP1 deletion. Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming of cardiomyocytes, pathological heart remodeling, as well as impeded heart function. Thus, we uncovered the novel function of LonP1 as an UPRmt mediator, and reciprocal orchestration of UPRmt and UPRER and mitochondrial dynamics regulated by LonP1 in the cardiomyocytes that is critical to maintain heart function, which offers exciting new insights into the potential therapeutic strategy for heart failure.

cell biology↗

bioRxiv2019

MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure

Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here we describe a phenomenon termed MISTERMINATE (mitochondrial stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs including complex-I 30kD subunit (C-I30) mRNA, occurring on mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C-terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally-extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinsons disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.

cell biology↗

bioRxiv2019

Stability of dynamic functional architecture differs between brain networks and states

Stable representation of information in distributed neural connectivity is critical to function effectively in the world. Despite the dynamic nature of the brains functional architecture, characterizing its temporal stability has been largely neglected. Here we characterized stability of functional architecture for each brain voxel by measuring the concordance of dynamic functional connectivity (DFC) over time, and explored how stability was modified by movie watching. High-order association regions, especially the default mode network, demonstrated high stability during resting state scans, while primary sensory-motor cortices revealed relatively lower stability. During movie watching, stability in the primary visual cortex was decreased, which was associated with larger DFC variation with neighboring regions. By contrast, higher-order regions in the ventral and dorsal visual stream demonstrated increased stability. The distribution of functional stability and its modification describes a profile of the brains stability property, which may be useful reference for examining distinct mental states and disorders.

neuroscience↗

bioRxiv2018

De novo aging-related meganeurites: alteration of NADPH diaphorase positivity in the sacral spinal cord of the aged dog

The aging-related changes of NADPH-diaphorase (NADPH-d) in the spinal cord were studied in aged dogs. At all levels of the spinal cord examined, NADPH-d activities were present in neurons and fibers in the superficial dorsal horn, dorsal commissure and in neurons around the central canal. In addition, the sympathetic autonomic nucleus in the thoracic and rostral lumbar segments exhibited prominent NADPH-d cellular staining whereas the sacral parasympathetic nucleus (SPN) in the sacral segments was not well stained. Interestingly, we found abundant NADPH-d positive enlarged-diameter fibers termed megaloneurite, which characteristically occurred in the aged sacral segments, distributed in the dorsal gray commissure (DGC), lateral collateral pathway (LCP) the lateral fasciculi and the central canal compared with the cervical, thoracic and lumbar segments. The dense, abnormal NADPH-d megaloneurites occurred in extending from dorsal entry zone through lamina I along with the lateral boundary of the dorsal horn to the region of the SPN. These fibers were prominent in the S1-S3 segments but not in adjacent segments L5-L7 and Cx1 or in thoracolumbar segments and cervical segments. Double staining with GFAP, NeuN, CGRP, MAP2 and Iba1, NADPH-d megaloneurite colocalized with vasoactive intestinal peptide. Presumably, the megaloneurites may represent, in part, visceral afferent projections to the SPN and/or DGC. The NADPH-d megaloneurites in the aged sacral spinal cord indicated some anomalous changes in the neurites, which might account for a disturbance in the aging pathway of the autonomic and sensory nerve in the pelvic visceral organs.

neuroscience↗

bioRxiv2018

Differential Susceptibility of Rat Retinal Ganglion Cell Subtypes Following Optic Nerve Crush

Retinal ganglion cells (RGCs) are a heterogeneous group of cells, comprised of numerous subpopulations, that work together to send visual information to the brain. In numerous blinding disorders termed optic neuropathies, RGCs are the main cell type affected leading to degeneration of these cells and eventual loss of vision. Previous studies have identified and characterized RGC subtypes in numerous animal systems, with only a handful of studies demonstrating their differential loss in response to disease and injury. Thus, efforts of the current study utilized an optic nerve crush (ONC) model to characterize the loss of RGCs and disease phenotypes associated with this injury. Additionally, the loss of RGC subtypes including direction selective-, alpha-, and ip-RGCs following ONC was explored. Results of this study demonstrated the differential loss of RGC subtypes with a high susceptibility for loss of alpha- and direction selective-RGCs and the preferential survival of ip-RGCs following ONC and allows for the establishment of additional studies focused on mechanisms and loss of these cells in optic neuropathies. Additionally, these results put important emphasis on the development of therapeutics targeted at the loss of specific subtypes as well as cellular replacement following injury and disease.

neuroscience↗

bioRxiv2018

High glucose-induced ubiquitylation of G6PD leads to the injury of podocyte

Oxidative stress contributes substantially to podocyte injury in diabetic kidney disease. The mechanism of hyperglycemia-induced oxidative stress in podocytes is not fully understood. Glucose-6-phosphate dehydrogenase is critical in maintaining NADPH, an important cofactor for antioxidant system. Here, we hypothesized that high glucose induces ubiquitylation and degradation of G6PD, which injures podocytes by reactive oxygen species (ROS) accumulation. We found that both G6PD protein expression and G6PD activity was decreased in kidneys of both diabetic patients and diabetic rodents. Overexpressing G6PD reversed redox imbalance and podocyte apoptosis induced by high glucose and palmitate. Inhibition of G6PD induced podocyte apoptosis. In G6PD deficient mice, podocyte apoptosis was also largely increased. High glucose had no effect on G6PD mRNA level but it caused decreased G6PD protein expression, which was mediated by the ubiquitin proteasome pathway. Furthermore, von Hippel-Lindau (VHL), an E3 ubiquitin ligase subunit, directly bound to G6PD and degraded G6PD through ubiquitylating G6PD on lysine residues 366/403. Our data suggest that high glucose induces ubiquitylation of G6PD by VHL, which leads to ROS accumulation and podocyte injury.

cell biology↗

bioRxiv2018

CLADES: A Classification-based Machine Learning Method for Species Delimitation from Population Genetic Data

Species are considered to be the basic unit of ecological and evolutionary studies. Since multi-locus genomic data are becoming increasingly available, there has been considerable interests in the use of DNA sequence data to delimit species. In this paper, we show that machine learning can be used for species delimitation. There exists no species delimitation methods that are based on machine learning. Our method treats the species delimitation problem as a classification problem. It is a problem of identifying the category of a new observation on the basis of training data. Extensive simulation is first conducted over a broad range of evolutionary parameters for training purpose. Each pair of known populations are combined to form training samples with a label of \"same species\" or \"different species\". We use Support Vector Machine (SVM) to train a classifier using a set of summary statistics computed from training samples as features. The trained classifier can classify a test sample to two outcomes: \"same species\" or \"different species\". Given multi-locus genomic data of multiple related organisms or populations, our method (called CLADES) performs species delimitation by first classifying pairs of populations. CLADES then delimits species by maximizing the likelihood of species assignment for multiple populations. CLADES is evaluated through extensive simulation and also tested on real genetic data. We show that CLADES is both accurate and efficient for species delimitation when compared with existing methods. CLADES can be useful especially when existing methods have difficulty in delimitation, e.g. with short species divergence time and gene flow.

evolutionary biology↗

bioRxiv2018

Physiological Significance of R-fMRI Indices in Detecting Structural Brain Lesions

Resting-state functional MRI (R-fMRI) research has recently entered the era of \"big data\", however, few studies have provided a rigorous validation of the physiological underpinnings of R-fMRI indices. Although studies have reported that various neuropsychiatric disorders exhibit abnormalities in R-fMRI measures, these \"biomarkers\" have not been validated in differentiating structural lesions (brain tumors) as a concept proof. We enrolled 60 patients with intracranial tumors located in the unilateral cranial cavity and 60 matched normal controls to test whether R-fMRI indices can differentiate tumors, which represents a prerequisite for adapting such indices as biomarkers for neuropsychiatric disorders. Common R-fMRI indices of tumors and their counterpart control regions, which were defined as the contralateral normal areas (for amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo) and degree centrality (DC)) and ipsilateral regions surrounding the tumors (for voxel-mirrored homotopic connectivity (VMHC)), were comprehensively assessed. According to paired t-tests with a Bonferroni correction, only ALFF (both with and without Z-standardization) and VMHC (Fishers r-to-z transformed) could successfully differentiate substantial tumors from their counterpart normal regions in patients. And DC was not able to differentiate tumor from normal unless employed Z-standardization. To validate the lower power in the between-subject design than in the within-subject design, each metric was calculated in a matched control group, and two-sample t-tests were used to compare the patient tumors and the normal controls at the same area. Only ALFF (and that with Z-standardization) along with VMHC succeeded in differentiating significant differences between tumors and the sham tumors areas of normal controls. This study tested the premise of R-fMRI biomarkers for differentiating lesions, and brings a new understanding to physical significance of the Z-standardization.

neuroscience↗

bioRxiv2017

Dynamics of a Form-Fitting Protein in a Nanopore: Avidin in ClyA

We probe the molecular dynamics of a protein, avidin, as it is captured and trapped in a nanopore, ClyA, with time-resolved single-molecule electrical conductance measurements, and we present a method for visualizing this process from the data. The case of avidin in ClyA has rich time-dependent conductance spectra of discrete levels that correlate with different configurations of the protein in the pore. One is very long-lasting, stable and noise-free, and portends the use of this system as a platform for more general studies of proteins and other molecules, where avidin acts as a shuttle that ferries analytes into the pore for probing. We demonstrate this by the sensitive detection of a biotin molecule attached to avidin captured by the pore. We also present an approach to determining the nanopore size based on a 3D printed model of the pore.

biophysics↗

bioRxiv2017

A Comprehensive Assessment Of Reproducibility Of R-fMRI Metrics On The Impact Of Different Strategies For Multiple Comparison Correction And Small Sample Size

Concerns regarding reproducibility of resting-state functional magnetic resonance imaging (R-fMRI) findings have been raised. Little is known about how to operationally define R-fMRI reproducibility and to what extent it is affected by multiple comparison correction strategies and sample size. We comprehensively assessed two aspects of reproducibility, test-retest reliability and replicability, on widely used R-fMRI metrics in both between-subject contrasts of sex differences and within-subject comparisons of eyes-open and eyes-closed (EOEC) conditions. We noted permutation test with Threshold-Free Cluster Enhancement (TFCE), a strict multiple comparison correction strategy, reached the best balance between family-wise error rate (under 5%) and test-retest reliability / replicability (e.g., 0.68 for test-retest reliability and 0.25 for replicability of amplitude of low-frequency fluctuations (ALFF) for between-subject sex differences, 0.49 for replicability of ALFF for within-subject EOEC differences). Although R-fMRI indices attained moderate reliabilities, they replicated poorly in distinct datasets (replicability < 0.3 for between-subject sex differences, < 0.5 for within-subject EOEC differences). By randomly drawing different sample sizes from a single site, we found reliability, sensitivity and positive predictive value (PPV) rose as sample size increased. Small sample sizes (e.g., < 80 (40 per group)) not only minimized power (sensitivity < 2%), but also decreased the likelihood that significant results reflect \"true\" effects (PPV < 0.26) in sex differences. Our findings have implications for how to select multiple comparison correction strategies and highlight the importance of sufficiently large sample sizes in R-fMRI studies to enhance reproducibility.

neuroscience↗