Biology subjects

Wang, C.-Y.

Publications and source records attributed to Wang, C.-Y..

26 records · Page 2Linked to original sources

bioRxiv2023

CK2α-dependent regulation of Wnt activity governs white matter development and repair

Wnt signaling plays an essential role in developmental and regenerative myelination in the CNS. The Wnt signaling pathway is comprised of multiple regulatory layers; thus, how these processes are coordinated to orchestrate oligodendrocyte development remains unclear. Here we show CK2, a Wnt/{beta}-catenin signaling Ser/Thr kinase, phosphorylates Daam2, inhibiting its function and Wnt-activity during oligodendrocyte development. Intriguingly, we found Daam2 phosphorylation differentially impacts distinct stages of oligodendrocyte development, accelerating early differentiation followed by decelerating maturation and myelination. Application towards white matter injury revealed CK2-mediated Daam2 phosphorylation plays a protective role for developmental and behavioral recovery after neonatal hypoxia, while promoting myelin repair following adult demyelination. Together, our findings identify a novel regulatory node in the Wnt pathway that regulates oligodendrocyte development via protein phosphorylation-induced signaling complex instability and highlights a new biological mechanism for myelin restoration. SignificanceWnt signaling plays a vital role in OL development and has been implicated as an adverse event for myelin repair after white matter injury. Emerging studies have shed light on multi-modal roles of Wnt effectors in the OL lineage, but the underlying molecular mechanisms and modifiable targets in OL remyelination remain unclear. Using genetic mouse development and injury model systems, we delineate a novel stage-specific function of Daam2 in Wnt signaling and OL development via a S704/T7-5 phosphorylation mechanism, and determine a new role of the kinase CK2 in contributing to OL development. In-depth understanding of CK2-Daam2 pathway regulation will allow us to precisely modulate its activity in conjunction with Wnt signaling and harness its biology for white matter pathology.

neuroscience↗

bioRxiv2023

Genomics-Driven Discovery of Myxopyromides, a Class of Polyketidic Amides Associated with Predation of Myxococcus sp. SDU36

Myxobacteria are renowned for their genuine prowess to deliver multifarious bioactive natural products. Genome mining of Myxococcus sp. SDU36 identified a hybrid PKS-NRPS BGC (mpd) that presumably specified previously uncharacterized molecules. The expression of mpd was activated by exchanging the innate promoter of core PKS-NRPS genes with our recently characterized strong constitutive promoter BBa_J23104. Comparative metabolic profiling allowed facile isolation of the elicited compounds 1-5 designated myxopyromides A-E, a group of structurally related polyketidic amides. Especially, myxopyromides D was appended with an uncommon pyrrolinone warhead at the carboxylic terminus, whereas myxopyromide C was instead decorated with a rare structural unit of aminobutanone. Although myxopyromides basically follow a textbook modular PKS-NRPS biosynthetic trajectory, an anteriorly unappreciated flexible chain release strategy is adopted to enrich the chemical repertoire of mpd BGC. Interestingly, myxopyromides were associated with the predation of Myxococcus sp. SDU36. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/535179v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@29d791org.highwire.dtl.DTLVardef@1079fdcorg.highwire.dtl.DTLVardef@19044d8org.highwire.dtl.DTLVardef@97c7dc_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a NO-CCL2-CCR2 pathway

Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests pH homeostasis is a new cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates BBB disruption and reactive gliosis, which were both rescued by pharmacological or genetic inhibition of the NO-CCL2 pathway in vivo. Together, our study identifies the astrocytic Slc4a4-NO-CCL2 axis as a pivotal mechanism controlling BBB integrity and repair, while providing insights for a novel therapeutic approach against BBB-related CNS disorders.

neuroscience↗

bioRxiv2023

The Complexity of Functional Connectivity Profiles of the Subgenual Anterior Cingulate Cortex and Dorsal Lateral Prefrontal Cortex in Major Depressive Disorder: a DIRECT Consortium Study

BackgroundThe subgenual anterior cingulate cortex (sgACC) plays a central role in the pathophysiology of major depressive disorder (MDD), and its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Nevertheless, previous research on sgACC functional connectivity (FC) in MDD has yielded inconsistent results, partly due to small sample sizes and limited statistical power. Furthermore, calculating sgACC-FC to target TMS individually is challenging. MethodsLeveraging a large multi-site cross-sectional sample (1660 MDD patients vs. 1341 healthy controls) from Phase II of the Depression Imaging REsearch ConsorTium (DIRECT), we systematically delineated case-control difference maps of sgACC-FC. Then, we explored the potential impact of such group-level abnormality profiles on the TMS target localization and clinical efficacy. Next, we developed an MDD big data-guided individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to localize TMS targets individually. ResultsWe found an enhanced sgACC-DLPFC FC in MDD patients compared to healthy controls (HC). Such group differences altered the position of the sgACC anti-correlation peak in the left DLPFC. In two independent clinical samples, we showed that the magnitude of TMS targets case-control differences in sgACC FC was related to clinical improvement. The MDD big data-guided individualized TMS targeting algorithm may generate individualized TMS targets that are clinically superior to group-level targets. InterpretationWe reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large, independently ascertained sample and demonstrated the potential impact of such case-control differences on FC-guided localization of TMS targets. FundingMinistry of Science and Technology of the Peoples Republic of China, National Natural Science Foundation of China, and Chinese Academy of Sciences

neuroscience↗

bioRxiv2021

4D chromosome reconstruction elucidates the spatial reorganization of the mammalian X-chromosome

Chromosomes are segmented into domains and compartments; yet, how these structures are spatially related in 3D is unclear. Here, by directly integrating Hi-C capture experiments and 3D modeling, we use X-inactivation as a model to examine the time evolution of 3D chromosome architecture during substantial changes in gene expression. First, we show that gene expression A/B compartments are consistent with phase separation in 3D space. Second, we show that residuals of smaller scale structures persist through transitions, despite further large-scale reorganization into the final inactive configuration, comprising two "megadomains". Interestingly, these previously hidden residual structures were not detectable in 2D Hi-C maps or principal component analyses. Third, time-dependent reaction-diffusion simulations reveal how Xist RNA particles diffuse across the 3D X-superstructure as it reorganizes. Our 4DHiC pipeline helps satisfy the growing demand for methodologies that produce 3D chromosome reconstructions directly from 2D datasets, which are consistent with the empirical data.

biophysics↗

bioRxiv2018

Unique unfoldase/aggregase activity of a molecular chaperone that dysregulates a translational elongation factor

The various chaperone activities of heat shock proteins contribute to ensuring cellular proteostasis. Here, we demonstrate the non-canonical unfoldase activity as an inherent functionality of the prokaryotic molecular chaperone Hsp33. The holding-inactive, reduced form of Hsp33 (RHsp33) strongly bound to the translational elongation factor, EF-Tu, and catalyzed the EF-Tu aggregation via evoking its aberrant folding, resulting in its susceptibility to proteolytic degradation by Lon. This interaction was critically mediated by the redox-switch domain of RHsp33 and the guanine nucleotide-binding domain of EF-Tu. The RHsp33-induced in vivo aggregation of EF-Tu upon heat shock was evident in a Lon-deficient strain and inhibited cell growth. Unlike wild-type Escherichia coli, the strain lacking both Hsp33 and Lon showed a non-reduced level of EF-Tu and diminished capability of counteracting heat shock. These findings suggest that the unique unfoldase/aggregase activity of Hsp33 potentially involved in protein turnover confers a cellular survival advantage under heat-stressed conditions.

biochemistry↗

bioRxiv2018

Effect of NaCl-Stressed Bt Cotton on the Feeding Behaviors and Nutritional Parameters of Helicoverpa armigera

Saline-alkali soil is an arable land resource on which transgenic Bt cotton has been planted on a large scale in accordance with food security strategies, but there are concerns about the insecticidal effects of Bt cotton on target insect pests. In this study, a Bacillus thuringiensis (Bt) cotton variety, GK19, and its nontransgenic parent variety, Simian-3, were used as experimental materials to study the effect of the expression of exogenous insecticidal proteins in Bt cotton under NaCl stress on the feeding behavior and nutritional parameters of Helicoverpa armigera. The results showed that the expression of exogenous insecticidal proteins in GK19 was significantly inhibited under NaCl stress. However, on GK19 Bt cotton, the feeding, crawling, resting and spinning down of the 5th instar H. armigera larvae, as well as the food consumption and feces amount of these larvae, did not markedly differ under different NaCl concentrations. In contrast, the mean relative growth rate (MRGR), relative growth rate (RGR), approximate digestibility (AD), efficiency of conversion of ingested food (ECI) and efficiency of conversion of digested food (ECD) of the larvae decreased markedly in response to NaCl stress. Under the same concentration of NaCl, the nutritional parameters of the bollworm larvae on GK19 Bt cotton or Simian-3 nontransgenic cotton were different. However, the interaction between salt stress and cotton variety had no significant effect on the feeding behavior or nutritional parameters of H. armigera larvae. These results may provide a scientific basis for determining the effect of exogenous insecticidal protein expression in Bt cotton under NaCl stress on H. armigera and can therefore be useful for the effective application of Bt cotton in saline-alkali soils to prevent and control H. armigera.

ecology↗

bioRxiv2018

Reduced but not Enhanced Default Mode Network Functional Connectivity in Major Depressive Disorder: Evidence from 25 Cohorts in the REST-meta-MDD Project

Major Depressive Disorder (MDD) is common and disabling, but its neural pathophysiology remains unclear. Functional brain network studies in MDD have largely had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. The 25 research groups in China composing the REST-meta-MDD Project contributed R-fMRI data of 1,300 patients with MDD and 1,128 normal controls (NCs). The data were preprocessed locally with a standardized protocol prior to aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to show increased FC in MDD. We found decreased instead of increased DMN FC when comparing 848 MDDs with 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naive MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDDs. Exploratory analyses also revealed alterations of local intrinsic activity in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates treatment response. This manuscript announces the publicly available resting-state fMRI indices of the REST-meta-MDD consortium shared via the R-fMRI Maps Project.\n\nSIGNIFICANCE STATEMENTFunctional connectivity within the default mode network in major depressive disorder patients has been frequently reported abnormal but with contradicting directions in previous small sample size studies. By creating the REST-meta-MDD consortium containing neuroimaging data of 1,300 depressed patients and 1,128 normal controls from 25 research groups in China, we found decreased default mode network functional connectivity in depressed patients, driven by patients with recurrent depression, and associated with current medication treatment but not with disease duration. These findings suggest that default mode network functional connectivity remains a prime target for understanding the pathophysiology of depression, with particular relevance to revealing mechanisms of effective treatments.

neuroscience↗