Biology subjects

Cheng, B.

Publications and source records attributed to Cheng, B..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Reconstruction of TrkB complex assemblies and localizing an-tidepressant targets using Artificial Intelligence

Since Major Depressive Disorder (MDD) represents a neurological pathology caused by inter-synaptic messaging errors, membrane receptors, the source of signal cascades, constitute appealing drugs targets. G protein-coupled receptors (GPCRs) and ion channel receptors chelated antidepressants (ADs) high-resolution architectures were reported to realize receptors physical mechanism and design prototype compounds with minimal side effects. Tyrosine kinase receptor 2 (TrkB), a receptor that directly modulates synaptic plasticity, has a finite three-dimensional chart due to its high molecular mass and intrinsically disordered regions (IDRs). Leveraging breakthroughs in deep learning, the meticulous architecture of TrkB was projected employing Alphfold 2 (AF2). Furthermore, the Alphafold Multimer algorithm (AF-M) models the coupling of intra- and extra-membrane topologies to chaperones: mBDNF, SHP2, Etc. Conjugating firmly dimeric transmembrane helix with novel compounds like 2R,6R-hydroxynorketamine (2R,6R-HNK) expands scopes of drug screening to encompass all coding sequences throughout genomes. The operational implementation of TrkB kinase-SHP2, PLC{gamma}1, and SHC1 ensembles has paved the path for machine learning in which it can forecast structural transitions in the self-assembly and self-dissociation of molecules during trillions of cellular mechanisms. In silicon, the cornerstone of the alteration will be artificial intelligence (AI), empowering signal networks to operate at the atomic level and picosecond timescales.

bioinformatics↗

bioRxiv2023

A Latent Clinical-anatomical Dimension Relating Metabolic Syndrome to Brain Morphology - Evidence from a Multivariate Imaging Analysis of 40,087 Individuals

The link between metabolic syndrome (MetS) and neurodegenerative as well cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, cortical morphology, and cognitive function in 40,087 individuals. Multivariate, data-driven statistics identified a latent dimension linking more severe MetS to widespread brain morphological abnormalities, accounting for up to 71% of shared variance in the data. This dimension was replicable across sub-samples. In a mediation analysis we could demonstrate that MetS-related brain morphological abnormalities mediated the link between MetS severity and cognitive performance in multiple domains. Employing imaging transcriptomics and connectomics, our results also suggest that MetS-related morphological abnormalities are linked to the regional cellular composition and macroscopic brain network organization. By leveraging extensive, multi-domain data combined with a dimensional stratification approach, our analysis provides profound insights into the association of MetS and brain health. These findings can inform effective therapeutic and risk mitigation strategies aimed at maintaining brain integrity.

neuroscience↗

bioRxiv2023

Is resting state fMRI better than individual characteristics at predicting cognition?

Changes in spontaneous brain activity at rest provide rich information about behavior and cognition. The mathematical properties of resting-state functional magnetic resonance imaging (rsfMRI) are a depiction of brain function and are frequently used to predict cognitive phenotypes. Individual characteristics such as age, gender, and total intracranial volume (TIV) play an important role in predictive modeling of rsfMRI (for example, as "confounders" in many cases). It is unclear, however, to what extent rsfMRI carries independent information from the individual characteristics that is able to predict cognitive phenotypes. Here, we used predictive modeling to thoroughly examine the predictability of four cognitive phenotypes in 20,000 healthy UK Biobank subjects. We extracted common rsfMRI features of functional brain connectivity (FC) and temporal complexity (TC). We assessed the ability of these features to predict outcomes in the presence and absence of age, gender, and TIV. Additionally, we assessed the predictiveness of age, gender, and TIV only. We find TC and FC features to perform comparably with regard to predicting cognitive phenotypes. As compared to rsfMRI features, individual characteristics provide systematically better predictions with smaller sample sizes and, to some extent, in larger cohorts. It is also consistent across different levels of inherent temporal noise in rsfMRI. Our results suggest that when the objective is to perform cognitive predictions as opposed to understanding the relationship between brain and behavior, individual characteristics are more applicable than rsfMRI features.

neuroscience↗

bioRxiv2023

Secretion encoded single-cell sequencing (SEC-seq) uncovers gene expression signatures associated with high VEGF-A secretion in mesenchymal stromal cells

Cells secrete numerous bioactive molecules essential for the function of healthy organisms. However, there are no scalable methods to link individual cell secretions to their transcriptional state. By developing and using secretion encoded single-cell sequencing (SEC-seq), which exploits hydrogel nanovials to capture individual cells and their secretions, we simultaneously measured the secretion of vascular endothelial growth factor A (VEGF-A) and the transcriptome for thousands of individual mesenchymal stromal cells (MSCs). We found that VEGF-A secretion is heterogeneous across the cell population and lowly correlated with the VEGFA transcript level. While there is a modest population-wide increase in VEGF-A secretion by hypoxic induction, highest VEGF-A secretion across normoxic and hypoxic culture conditions occurs in a subpopulation of MSCs characterized by a unique gene expression signature. Taken together, SEC-seq enables the identification of specific genes involved in the control of secretory states, which may be exploited for developing means to modulate cellular secretion for disease treatment.

bioengineering↗

bioRxiv2022

Targeting TR4-induced RCC cells-derived exosomally initiated signaling increases Sunitinib efficacy

Sunitinib is the first-line therapy for metastatic clear cell renal cell carcinoma (RCC) via suppressing neoangiogenesis and tumor growth. The detailed mechanisms, especially whether and how RCC cells can impact endothelial cells sensitivity to Sunitinib, remain unclear. Here, we found that TR4 was commonly upregulated in RCC tissue and relative to tumor angiogenesis. Tube formation and Mouse aortic ring assay showed that the overexpression or knockdown of TR4 in RCC cells enhanced or reduced the angiogenesis of endothelial cells and their resistance to Sunitinib in vitro. Mechanistically, We found that TR4 transcriptionally increase ADAM15 expression, as a consequence, exosomes carrying relatively large amounts of ADAM15 secreted from RCC cell resulted in activating the EGFR phosphorylation and reducing the efficacy of Sunitinib in endothelial cells. Targeting the TR4-induced renal cancers-derived exosomelly initiated signaling with a small molecular, CRM197, increases sunitinib efficacy in vitro and xenograft tumor models. Taken together, our findings indicate a novel function of TR4 in RCC blunted the efficacy of sunitinib via exosomal ADAM15-induced activation of EGFR signaling pathway in endothelial cells.

cancer biology↗

bioRxiv2022

The effects of ethnoracial-related stressors during pregnancy on the developing offspring brain.

We are increasingly aware of the effects of ethnoracial stress on health, with emerging interest in the potential for intergenerational transmission before birth. Here, we investigate the effect of maternal prenatal discrimination and acculturation experiences on fetal growth, birth outcomes, and functional connectivity in the infant brain. In pregnant adolescent women, we collected self-report measures of acculturation (tailored to an adolescent and Latinx population), discrimination, and maternal distress (i.e., stress and depressive symptoms; n=165). Fetal growth were obtained via electronic health records (n=92), and infant amygdala seed connectivity was assessed using functional magnetic resonance imaging (n=38). We found that greater maternal prenatal assimilation to the host culture was associated with slower fetal growth, lower gestational age at birth, and weaker amygdala-fusiform connectivity. Maternal prenatal discrimination was associated with weaker amygdala-prefrontal connectivity. Together, these results suggest intergenerational effects of ethnoracial stressors on the growth and neural development of future generations.

neuroscience↗

bioRxiv2022

Brain Network Architecture Constrains Age-related Cortical Thinning

Age-related cortical atrophy, approximated by cortical thickness measurements from magnetic resonance imaging, follows a characteristic pattern over the lifespan. Although its determinants remain unknown, mounting evidence demonstrates correspondence between the connectivity profiles of structural and functional brain networks and cortical atrophy in health and neurological disease. Here, we performed a cross-sectional multimodal neuroimaging analysis of 2633 individuals from a large population-based cohort to characterize the association between age-related differences in cortical thickness and functional as well as structural brain network topology. We identified a widespread pattern of age-related cortical thickness differences including "hotspots" of strong age effects located in brain areas with high centrality (structural network hubs). Regional age-related differences were furthermore strongly correlated within the structurally defined node neighborhood. The overall pattern of thickness differences as well as its change throughout the later lifespan was found to be anchored in the functional network hierarchy as encoded by macroscale functional connectivity gradients. Lastly, the identified difference pattern covaried significantly with cognitive and motor performance. Our findings indicate that connectivity profiles of functional and structural brain networks might act as organizing principles behind age-related cortical thinning as an imaging surrogate of cortical atrophy.

neuroscience↗

bioRxiv2022

Lifting the ban on nuclear import activates Gdown1-mediated modulation of global transcription and facilitates adaptation to cellular stresses

Dynamic regulation of transcription is crucial for cellular response to various environmental or developmental cues. Gdown1 is a ubiquitously expressed, RNA polymerase II (Pol II) interacting protein, essential for embryonic development. It tightly binds Pol II in vitro and competitively blocks binding of TFIIF and other transcriptional regulatory factors, yet its cellular functions and regulatory circuits remain unclear. Here, we show that Gdown1 strictly localizes in the cytoplasm of mammalian somatic cells and exhibits potent resistance to the imposed driving force for nuclear localization. Combined with genetic and microscope-based approaches, two types of functionally coupled and evolutionally conserved localization regulatory motifs are identified, including the CRM1-dependent nucleus export signal (NES) and a novel Cytoplasm Anchoring Signal (CAS) which mediates nuclear pore retention. Mutagenesis of CAS alleviates the cytoplasmic retention activity thus unlocks its nucleocytoplasmic shuttling properties, and increased nuclear import of Gdown1 causes drastic reduction of Pol II levels and global transcription. Importantly, nuclear translocation of Gdown1 occurs in a stress-responsive manner and ablation of GDOWN1 significantly weakens cellular tolerance. Collectively, our work uncovers the molecular basis of the localization of Gdown1 and highlights that its controlled nuclear translocation serves as a key strategy in modulating global transcription and stress-adaptation.

cell biology↗

bioRxiv2022

Three-dimensional actuation of hummingbird wings requires diverse effects from the primary flight muscles

Hummingbirds have evolved to hover and maneuver with exceptional flight control. This is directly enabled by their musculoskeletal system that successfully exploits the agile motion of flapping wings. Here, we reveal novel principles of hummingbird wing actuation that provide insights into the evolution and robotic emulation of hummingbird flight. We develop a functional model of hummingbird musculoskeletal system, which predicts instantaneous, three-dimensional torque produced by primary (pectoralis and supracoracoideus) and combined secondary muscles. It also reveals primary muscle contractile behavior, including stress, strain, elasticity, and work. Results show that the primary muscles (i.e., the flight "engine") function as diverse effectors, as they do not simply power the stroke, but also actively deviate and pitch the wing. The secondary muscles produce controlled-tightening effects, by acting against primary muscles in deviation and pitching. The diverse effector capacity of pectoralis is associated with the evolution of a comparatively enormous bicipital crest on humerus.

biophysics↗

bioRxiv2021

The first transchromosomic rat model with human chromosome 21 shows robust Down syndrome features

Progress in earlier detection and symptom management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available due to technical challenges. We developed the first transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein coding genes. RNA-Seq of neonatal forebrains demonstrates that TcHSA21rat not only expresses HSA21 genes but also has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a "Down syndrome karyotype" in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, a prominent feature of DS that is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.

genetics↗

bioRxiv2021

The noncoding RNA PRANCR regulates splicing of Fibronectin-1 to control keratinocyte proliferation and migration

Most human genes undergo alternative splicing (AS), but the regulation and functional consequences of most splicing events remain unknown. Long noncoding RNAs (lncRNAs) have recently been discovered to have novel roles in the regulation of AS. Here we investigate whether PRANCR, a lncRNA recently identified to be essential for epidermis formation, functions by controlling AS of cell fate genes. Using transcriptome-wide analysis, we identified 238 exonic splicing events regulated by PRANCR. Among these is alternative splicing of an exon containing the extra domain A (EDA) in the gene fibronectin-1 (FN1). Expression of the FN1-EDA+ isoform is enriched in proliferating keratinocytes. We find that PRANCR regulates EDA inclusion by controlling expression of the serine/arginine-rich splicing factors (SRSFs) 1 and 7. Depletion of PRANCR or FN1-EDA resulted in decreased proliferation, increased CDKN1A/p21, and inhibition of keratinocyte migration. We find that these cellular phenotypes can be explained by reduced phosphorylation of focal adhesion kinase (FAK). Collectively, these results identify a lncRNA regulating skin function through alternative splicing of a cell fate gene.

cell biology↗

bioRxiv2021

Counting of Enzymatically Amplified Affinity Reactions in Hydrogel Particle-Templated Drops

Counting of numerous compartmentalized enzymatic reactions underlies quantitative and high sensitivity immunodiagnostic assays. However, digital enzyme-linked immunosorbent assays (ELISA) require specialized instruments which have slowed adoption in research and clinical labs. We present a lab-on-a-particle solution to digital counting of thousands of single enzymatic reactions. Hydrogel particles are used to bind enzymes and template the formation of droplets that compartmentalize reactions with simple pipetting steps. These hydrogel particles can be made at a high throughput, stored, and used during the assay to create ~500,000 compartments within 2 minutes. These particles can also be dried and rehydrated with sample, amplifying the sensitivity of the assay by driving affinity interactions on the hydrogel surface. We demonstrate digital counting of {beta}-galactosidase enzyme at a femtomolar detection limit with a dynamic range of 3 orders of magnitude using standard benchtop equipment and experiment techniques. This approach can faciliate the development of digital ELISAs with reduced need for specialized microfluidic devices, instruments, or imaging systems.

bioengineering↗

bioRxiv2021

Efficient Inhibition of SARS-CoV-2 Using Chimeric Antisense Oligonucleotides through RNase L Activation

There is an urgent need for effective antiviral drugs to alleviate the current COVID-19 pandemic. Here, we rationally designed and developed chimeric antisense oligonucleotides to degrade envelope and spike RNAs of SARS-CoV-2. Each oligonucleotide comprises a 3 antisense sequence for target recognition and a 5-phosphorylated 2-5 poly(A)4 for guided ribonuclease L (RNase L) activation. Since RNase L can potently cleave single strand RNA during innate antiviral response, the improved degradation efficiency of chimeric oligonucleotides was twice as much as classic antisense oligonucleotides in Vero cells, for both SARS-CoV-2 RNA targets. In pseudovirus infection models, one of chimeric oligonucleotides targeting spike RNA achieved potent and broad-spectrum inhibition of both SARS-CoV-2 and its recently reported N501Y and/or {Delta}H69/{Delta}V70 mutants. These results showed that the constructed chimeric oligonucleotides could efficiently degrade pathogenic RNA of SARS-CoV-2 facilitated by immune activation, showing promising potentials as antiviral nucleic acid drugs for COVID-19.

microbiology↗

bioRxiv2021

Forebrain Shh overexpression improves cognitive function in a Down syndrome mouse model and euploid littermates

People with Down syndrome (DS) have intellectual disability, early-onset dementia, and cerebellar hypoplasia. Trisomic cerebellar granule cell precursors from Ts65Dn, a mouse model of DS, had a deficit in mitogenic response to Sonic hedgehog (Shh) in vitro, and newborn Ts65Dn mice received a single subcutaneous injection of the Shh signaling agonist SAG had normalized cerebellar morphology and improved spatial learning and hippocampal synaptic plasticity at adult. However, cognitive effects of Shh overexpression in vivo and where SAG acts to improve cognitive outcomes of trisomy are unknown. Here, we created an inducible human Shh (hShh) knock-in mouse, TRE-bi-hShh-Zsgreen1 (TRE-hShh), expressing dually-lipidated Shh-Np in the presence of transactivator (tTA). Double transgenic mice, Camk2a-tTA;TRE-hShh (Camk2a-hShh) and Pcp2-tTA;TRE-hShh (Pcp2-hShh), increased Shh signaling in forebrain and cerebellum, respectively. Forebrain Shh overexpression normalized hyperactivity, and spatial learning and memory deficits in 3-month-old Ts65Dn, while Shh overexpression in cerebellum had no effect. Further, Camk2a-hShh delayed early-onset severe cognitive impairment in 7-month-old Ts65Dn and enhanced spatial cognition in euploid (Eu) and showed no effect on the longevity of Eu or Ts65Dn, and MRI demonstrated that Pcp2-hShh mitigated disproportionately small cerebellum in Ts65Dn. Finally, Ts65Dn at postnatal day 6 had reduced Gli1 levels in hippocampus and cerebellum, which could be at least partially rescued by Camk2a-hShh and Pcp2-hShh, respectively. Our findings suggest restoration of impaired Shh signaling in forebrain from the perinatal and early postnatal period improves cognitive function.

neuroscience↗

bioRxiv2020

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, has been found to negatively regulate the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role of GSTZ1 in sorafenib-induced ferroptosis in HCC cell lines and determine the involved molecular mechanisms. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1 deficient cell viability and promoted ferroptosis, accompanied with ectopic increases of iron and lipid peroxides. An in vivo experiment showed that the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1-/- mice. In conclusion, GSTZ1 was significantly downregulated in sorafenib resistant hepatoma cells. GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. GSTZ1 deficiency was resistant to sorafenib-induced ferroptosis and is, therefore, a potential therapeutic approach for treating HCC by synergizing sorafenib and RSL3 to induce ferroptosis.

cancer biology↗

bioRxiv2020

Using Engineered Escherichia coli to Synthesize Squalene with Optimized Manipulation of Squalene Synthase and Mevalonate Pathway

Squalene is the metabolic precursor of sterols and naturally synthesized in the deep-dea shark liver and human sebum. The utilization of squalene is wide such as food, cosmetical, and pharmaceutical industries. This experiment used engineered Escherichia coli to construct the gene circuit for the biosynthesis of squalene. Human squalene synthase (hSQS) efficiently catalyzes the synthesis of squalene. Also, mevalonate (MVA) pathway would increase the yield of the precursor of squalene, farnesyl diphosphate, which then increased the yield of squalene. Meanwhile, the regulation of MVA pathway via different inducer IPTG concentrations and creation of selection pressure by antibiotics were investigated.

synthetic biology↗

bioRxiv2020

Recombinant SARS-CoV-2 RBD molecule with a T helper epitope as a built in adjuvant induces strong neutralization antibody response

Without approved vaccines and specific treatment, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading around the world with above 20 million COVID-19 cases and approximately 700 thousand deaths until now. An efficacious and affordable vaccine is urgently needed. The Val308 - Gly548 of Spike protein of SARS-CoV-2 linked with Gln830 - Glu843 of Tetanus toxoid (TT peptide) (designated as S1-4) and without TT peptide (designated as S1-5), and prokaryotic expression, chromatography purification and the rational renaturation of the protein were performed. The antigenicity and immunogenicity of S1-4 protein was evaluated by Western Blotting (WB) in vitro and immune responses in mice, respectively. The protective efficiency of it was measured by virus neutralization test in Vero E6 cells with SARS-CoV-2. S1-4 protein was prepared to high homogeneity and purity by prokaryotic expression and chromatography purification. Adjuvanted with Alum, S1-4 protein stimulated a strong antibody response in immunized mice and caused a major Th2-type cellular immunity compared with S1-5 protein. Furthermore, the immunized sera could protect the Vero E6 cells from SARS-CoV-2 infection with neutralization antibody GMT 256. The candidate subunit vaccine molecule could stimulate strong humoral and Th1 and Th2-type cellular immune response in mice, giving us solid evidence that S1-4 protein could be a promising subunit vaccine candidate.

bioengineering↗

bioRxiv2020

Glycoengineering of NK cells with glycan ligands of CD22 and selectins for B-cell lymphoma therapy

CD22, a member of Siglec family of sialic acid binding proteins, has restricted expression on B cells. Antibody-based agents targeting CD22 or CD20 (Rituxan) on B lymphoma and leukemia cells exhibit clinical efficacy for treating these malignancies, but also attack normal B cells leading to immune deficiency. Here, we report a chemoenzymatic glycocalyx editing strategy to introduce high-affinity and specific CD22 ligands onto NK-92MI and cytokine-induced killer (CIK) cells to achieve tumor-specific CD22 targeting. These CD22-ligand modified cells exhibited significantly enhanced tumor cell binding and killing in vitro without harming healthy B cells. For effective lymphoma cell killing in vivo we further functionalized CD22 ligand-modified NK-92MI cells with the E-selectin ligand sialyl Lewis X to promote trafficking to bone marrow. The cells containing the ligands of both CD22 and selectins resulted in the efficient suppression of B lymphoma in a xenograft model. Our results suggest that NK cells modified with glycan ligands to CD22 and selectins promote both targeted killing of B lymphoma cells and improved trafficking to sites where the cancer cells reside, respectively.

bioengineering↗