Biology subjects

Zhang, J. J.

Publications and source records attributed to Zhang, J. J..

11 recordsLinked to original sources

bioRxiv2025

The Adipomyokine Follistatin-like-1 Restores Cardiovascular Function in a Swine Model of Diabetic Myocardial Infarction

Obesity, diabetes, and metabolic syndrome increase the incidence and complicate the management of myocardial infarction (MI). Current treatments do not adequately blunt the progression to chronic ischemic heart disease and heart failure, making these diseases the largest cause of mortality worldwide. Insulin resistance and metabolic syndrome were induced in obese Ossabaw swine prior to ischemia/reperfusion injury-induced MI. Subcutaneous administration of the adipomyokine Follistatin-like-1 (recombinant non-glycosylated human FSTL1, ngFSTL1) for two weeks, beginning one month following myocardial infarction, decreased infarct necrosis, increased blood flow, and increased cardiomyocyte proliferation within the infarct region, leading to improved systolic and diastolic function. ngFSTL-1 also enhanced coronary and peripheral vascular function by increasing BKCa channel-dependent vasodilatory capacity. We conclude that subcutaneous ngFSTL1 ameliorated clinically relevant parameters of cardiac and vascular dysfunction in a preclinical swine model of diabetic MI, and suggest FSTL1 treatment may be broadly efficacious in humans. ARTICLE HIGHLIGHTSO_LISubcutaneous administration of recombinant human non-glycosylated FSTL1 (ngFSTL1) for 2 weeks, 1 month after infarction/reperfusion injury, improved cardiac function in a preclinical obese swine model of diabetic MI. C_LIO_LIngFSTL1 treatment induced cardiomyocyte proliferation and improved coronary perfusion, resulting in reduced necrosis of the infarct region. C_LIO_LIngFSTL1 treatment increased blood flow through peripheral arterioles, including cerebral and skeletal muscle, in addition to cardiac arterioles. C_LIO_LISystemic delivery of the non-glycosylated form of the adipomyokine FSTL1 might be an effective treatment for diabetic MI. C_LI

physiology↗

bioRxiv2024

Chemosensory modulation of eye-body coordination in larval zebrafish

Coordinated eye-body movements are essential for adaptive behavior, yet little is known about how multisensory input, particularly chemosensory cues, shapes this coordination. Using our enhanced Fish-on-Chips optofluidic platform, we uncovered complex dynamics in how larval zebrafish coordinate saccadic eye movements with tail flips. Under baseline conditions, spontaneous tail flips dynamically align with saccades in frequency and direction for coordinated turns. Chemosensory valence further modulates this coordination: death-associated cues intensify both the strength and relative frequency of coupled saccade-tail flips during turns, whereas food-related cues promote forward gliding without altering saccade coupling. Concurrent brain-wide neuronal imaging reveals that the zebrafish pallium represents the mapping between aversive valence and enhanced saccade-tail coordination, with stronger coupling associated with higher pallium activation. These findings uncover the neural representations and behavioral strategies by which chemosensory inputs of different valences are associated with amplified eye-body coordination and adaptive locomotion in a developing vertebrate, offering insights into principles of sensory-motor integration.

neuroscience↗

bioRxiv2024

An asymmetric nautilus-like HflK/C assembly controls FtsH proteolysis of membrane proteins

FtsH, a AAA protease, associates with HflK/C subunits to form a megadalton complex that spans the inner membrane and extends into the periplasm of E. coli. How this complex and homologous assemblies in eukaryotic organelles recruit, extract, and degrade membrane-embedded substrates is unclear. Following overproduction of protein components, recent cryo-EM structures reveal symmetric HflK/C cages surrounding FtsH in a manner proposed to inhibit degradation of membrane-embedded substrates. Here, we present structures of native complexes in which HflK/C instead forms an asymmetric nautilus-like assembly with an entryway for membrane-embedded substrates to reach and be engaged by FtsH. Consistent with this nautilus-like structure, proteomic assays suggest that HflK/C enhances FtsH degradation of certain membrane-embedded substrates. The membrane curvature in our FtsH{middle dot}HflK/C complexes is opposite that of surrounding membrane regions, a property that correlates with lipid-scramblase activity and possibly with FtsHs function in the degradation of membrane-embedded proteins.

biochemistry↗

bioRxiv2022

Mechanism of repression of the glycerol utilization operon in Borrelia burgdorferi

Lyme disease pathogen Borrelia burgdorferi, switches carbohydrate utilization while transmitting between two disparate hosts, an Ixodes tick vector and a mammalian host. The ability to use glycerol is important for B. burgdorferi to colonize and persist in the tick vector, and expression of the glpFKD (glp) operon for glycerol uptake/utilization is tightly regulated during the enzootic cycle of B. burgdorferi between ticks and mammals. In present study, we identified a cis element within the 5 untranslated region of glp that negatively regulates the glp expression. This repression of glp is independent of RpoS. We further show that BadR directly binds to this cis element and represses glp. The efficiency of BadR binding in the presence of c-di-GMP and various carbohydrates were also assessed. This finding, along with previous findings of positive regulation of glp expression by the c-di-GMP signaling pathway and negative regulation by the alternative sigma factor RpoS, demonstrates that B. burgdorferi employs multi-layer regulatory mechanisms to coordinate glp expression during its enzootic cycle.

microbiology↗

bioRxiv2021

Balanced, Orientation-Dependent Dichoptic Masking in Cortex of Visually Normal Humans Measured Using Electroencephalography (EEG)

In the human visual system, cerebral cortex combines left- and right-eye retinal inputs, enabling single, comfortable binocular vision. In visual cortex, the signals from each eye inhibit one another (interocular suppression). While this mechanism may be disrupted by e.g. traumatic brain injury, clinical assessments of interocular suppression are subjective, qualitative, and lack reliability. EEG is a potentially useful clinical tool for objective, quantitative assessment of binocular vision. In a cohort of normal participants, we measured occipital, visual evoked potentials (VEPs) in response to dichoptically-presented vertical and/or horizontal sine-wave gratings. Response amplitudes to orthogonal gratings were greater than that of parallel gratings, which were in turn greater than that of monocular gratings. Our results indicate that interocular suppression is (normally) balanced, orientation-tuned, and that suppression per se is reduced for orthogonal gratings. This objective measure of suppression may have application in clinical settings.

neuroscience↗

bioRxiv2021

A Novel Optical Design Enabling Lightweight and Large Field-Of-View Head-Mounted Microscopes

We present a novel fluorescence microscope light path that enables imaging, during free behavior, of thousands of neurons in mice and hundreds of neurons in juvenile songbirds. The light path eliminates traditional illumination optics, allowing for head-mounted microscopes that have both a lower weight and a larger field-of-view (FOV) than previously possible. Using this light path, we designed two microscopes: one optimized for field-of-view ([~]4 mm FOV; 1.4 g), and the other optimized for weight (1.0 mm FOV; 1.0 g).

neuroscience↗

bioRxiv2021

Genome wide association studies define minimal set of loci for prediction of penicillin and tetracycline susceptibility in Neisseria gonorrhoeae

BackgroundWhile Neisseria gonorrhoeae poses an urgent public health threat because of increasing antimicrobial resistance, much of the circulating population remains susceptible to historical treatment regimens. Point-of-care diagnostics that report susceptibility could allow for reintroduction of these regimens, but development of such diagnostics has been limited to ciprofloxacin, for which susceptibility can be predicted from a single locus. MethodsWe assembled a dataset of 12,045 N. gonorrhoeae genomes with phenotypic resistance data for tetracycline (n = 3,611) and penicillin (n = 6,935). Using conditional genome wide association studies (GWAS), we sought to define genetic variants associated with susceptibility to penicillin and tetracycline. We evaluated the sensitivity and specificity of these variants for predicting susceptibility and non-resistance in our collection of gonococcal genomes. FindingsIn our conditional penicillin GWAS, the presence of a genetic variant defined by a non-mosaic penA allele without an insertion at codon 345 was significantly associated with penicillin susceptibility and had the highest negative effect size of significant variants (p = 5.0 x 10-14, {beta} = -2.5). In combination with the absence of blaTEM, this variant predicted penicillin susceptibility with high specificity (99.8%) and modest sensitivity (36.7%). For tetracycline, the wild type allele at rpsJ codon 57, encoding valine, was significantly associated with tetracycline susceptibility (p = 5.6 x 10-16, {beta} = -1.6) after conditioning on the presence of tetM. The combination of rpsJ codon 57 allele and tetM absence predicted tetracycline susceptibility with high specificity (97.2%) and sensitivity (88.7%). InterpretationAs few as two genetic loci can predict susceptibility to penicillin and tetracycline in N. gonorrhoeae with high specificity. Molecular point-of-care diagnostics targeting these loci have the potential to increase available treatments for gonorrhea. FundingNational Institute of Allergy and Infectious Diseases, the National Science Foundation, and the Smith Family Foundation Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed with the terms "Neisseria gonorrhoeae" and "diagnostic" or "assay" plus "penicillin" or "tetracycline" for reports in any language published up to July 1, 2021. We additionally searched for "Neisseria gonorrhoeae" and "genome wide association study". We found that previously proposed molecular diagnostics for penicillin and tetracycline susceptibility either exclusively focused on plasmid-mediated resistance (i.e., targeting blaTEM or tetM) or did not include variants in genes encoding antibiotic targets (e.g., did not include penA or rpsJ). Targets for molecular surveillance have focused on resistance-associated alleles rather than susceptibility-associated alleles. We did not find any previous penicillin or tetracycline conditional genome wide association studies (GWAS) in N. gonorrhoeae. Added value of this studyTo identify targets for molecular diagnostics that predict penicillin and tetracycline susceptibility, we conducted GWAS conditioning on the presence of plasmid-mediated resistance determinants to detect chromosomal loci with the highest association with susceptibility. We discovered a sequence (penA_01) that differentiates susceptible isolates from those with a resistance-associated insertion at codon 345 and from those with mosaic penA alleles, which is associated with penicillin susceptibility. We also found that rpsJ codon 57 was the chromosomal locus contributing the most to tetracycline susceptibility. The combination of these chromosomal loci and the absence of plasmid encoded determinants predicts penicillin and tetracycline susceptibility with high specificity in both a large global collection of N. gonorrhoeae and a validation dataset consisting of recently published genomes from CDCs Gonococcal Isolate Surveillance Program (GISP) surveillance collected in 2018. Implications of all the available evidenceThe chromosomal loci penA_01 and rpsJ codon 57 in combination with plasmid loci blaTEM and tetM are candidates for the development of point-of-care molecular diagnostics for penicillin and tetracycline susceptibility. The loci may be combined with the currently available ciprofloxacin susceptibility diagnostics to predict susceptibility to multiple antibiotics. Additionally, our study suggests that conditional GWAS focused on variants associated with susceptibility may be a promising approach to identify minimal sets of loci for molecular diagnostics and surveillance.

microbiology↗

bioRxiv2021

Th17 immunity in the colon is controlled by two novel subsets of colon-specific mononuclear phagocytes

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.

immunology↗

bioRxiv2020

Auranofin resistance in Toxoplasma gondii decreases the accumulation of reactive oxygen species but does not target parasite thioredoxin reductase

Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, including Toxoplasma gondii. We generated auranofin resistant T. gondii lines through chemical mutagenesis in order to identify the molecular target of this drug. Resistant clones were confirmed with a competition assay using wild-type T. gondii expressing yellow fluorescence protein (YFP) as a reference strain. The predicted auranofin target, thioredoxin reductase, was not mutated in any of our resistant lines. Subsequent whole genomic sequencing analysis (WGS) did not reveal a consensus resistance locus, although many have point mutations in genes encoding redox-relevant proteins such as superoxide dismutase (TgSOD2) and ribonucleotide reductase. We investigated the SOD2 L201P mutation and found that it was not sufficient to confer resistance when introduced into wild-type parasites. Resistant clones accumulated less ROS than their wild type counterparts. Our results demonstrate that resistance to auranofin in T. gondii enhances its ability to abate oxidative stress through diverse mechanisms. This evidence supports a hypothesized mechanism of auranofin anti-parasitic activity as disruption of redox homeostasis.

microbiology↗

bioRxiv2020

Latent learning drives sleep-dependent plasticity in distinct CA1 subpopulations

Latent learning allows the brain the transform experiences into cognitive maps, a form of implicit memory, without reinforced training. Its mechanism is unclear. We tracked the internal states of the hippocampal neural ensembles and discovered that during latent learning of a spatial map, the state space evolved into a low-dimensional manifold that topologically resembled the physical environment. This process requires repeated experiences and sleep in-between. Further investigations revealed that a subset of hippocampal neurons, instead of rapidly forming place fields in a novel environment, remained weakly tuned but gradually developed correlated activity with other neurons. These weakly spatial neurons bond activity of neurons with stronger spatial tuning, linking discrete place fields into a map that supports flexible navigation.

neuroscience↗

bioRxiv2019

Avant-garde assembly-line biosynthesis expands diversity of cyclic lipodepsipeptide products

Modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzymatic assembly lines are large and dynamic protein machines that generally undergo a linear progression of catalytic cycles via a series of enzymatic domains organized into independent modules. Here we report the heterologous reconstitution and comprehensive characterization of two hybrid NRPS-PKS assembly lines that defy many standard rules of assembly-line biosynthesis to generate a large combinatorial library of cyclic lipodepsipeptide protease inhibitors called thalassospiramides. We generate a series of precise domain-inactivating mutations in thalassospiramide assembly lines and present compelling evidence for an unprecedented biosynthetic model that invokes inter-module substrate activation and tailoring, module skipping, and pass-back chain extension, whereby the ability to pass the growing chain back to a preceding module is flexible and substrate-driven. Expanding bidirectional inter-module domain interactions could represent a viable mechanism for generating chemical diversity without increasing the size of biosynthetic assembly lines and raises new questions regarding our understanding of the structural features of multi-modular megaenzymes.

molecular biology↗