Biology subjects

Liu, M.

Publications and source records attributed to Liu, M..

At least 19 recordsLinked to original sources

bioRxiv2018

Differential gene expression, including Sjfs800, in Schistosoma japonicum females before, during, and after male-female pairing

Schistosomiasis is a prevalent but neglected tropical disease caused by parasitic trematodes of the genus Schistosoma, with the primary disease-causing species being S. haematobium, S. mansoni, and S. japonicum. Male-female pairing of schistosomes is necessary for sexual maturity and the production of a large number of eggs, which are primarily responsible for schistosomiasis dissemination and pathology. Here, we used microarray hybridization, bioinformatics, quantitative PCR, in situ hybridization, and gene silencing assays to identify genes that play critical roles in S. japonicum reproduction biology, particularly in vitellarium development, a process that affects male-female pairing, sexual maturation, and subsequent egg production. Microarray hybridization analyses generated a comprehensive set of genes differentially transcribed before and after male-female pairing. Although the transcript profiles of females were similar 16 and 18 days after host infection, marked gene expression changes were observed at 24 days. The 30 most abundantly transcribed genes on day 24 included those associated with vitellarium development. Among these, genes for female-specific 800 (fs800), eggshell precursor protein, and superoxide dismutase (cu-zn-SOD) were substantially upregulated. Our in situ hybridization results in female S. japonicum indicated that cu-zn-SOD mRNA was highest in the ovary and vitellarium, eggshell precursor protein mRNA was expressed in the ovary, ootype, and vitellarium, and Sjfs800 mRNA was observed only in the vitellarium, localized in mature vitelline cells. Knocking down the Sjfs800 gene in female S. japonicum by approximately 60% reduced the number of mature vitelline cells, decreased rates of pairing and oviposition, and decreased the number of eggs produced in each male-female pairing by about 50%. These results indicate that Sjfs800 is essential for vitellarium development and egg production in S. japonicum and suggest that Sjfs800 regulation may provide a novel approach for the prevention or treatment of schistosomiasis.\n\nAuthor SummarySchistosomiasis is a common but largely unstudied tropical disease caused by parasitic trematodes of the genus Schistosoma. The eggs of schistosomes are responsible for schistosomiasis transmission and pathology, and the production of these eggs is dependent on the pairing of females and males. In this study, we determined which genes in Schistosoma japonicum females were differentially expressed before and after pairing with males, identifying the 30 most abundantly expressed of these genes. Among these 30 genes, we further characterized those in female S. japonicum that were upregulated after pairing and that were related to reproduction and vitellarium development, a process that affects male-female pairing, sexual maturation, and subsequent egg production. We identified three such genes, S. japonicum female-specific 800 (Sjfs800), eggshell precursor protein, and superoxide dismutase, and confirmed that the mRNAs for these genes were primarily localized in reproductive structures. By using gene silencing techniques to reduce the amount of Sjfs800 mRNA in females by about 60%, we determined that Sjfs800 plays a key role in development of the vitellarium and egg production. This finding suggests that regulation of Sjfs800 may provide a novel approach to reduce egg counts and thus aid in the prevention or treatment of schistosomiasis.

genomics↗

bioRxiv2018

Emotional Mirrors in the Rat’s Anterior Cingulate Cortex

AbstractHow do the emotions of others affect us? The human anterior cingulate cortex (ACC) responds while experiencing pain in the self and witnessing pain in others, but underlying cellular mechanisms remain poorly understood. Here we show the ACC (area 24) contains neurons responding when a rat experiences pain and while witnessing another receive footshocks. Most of these do not respond to a fear conditioned tone (CS). Deactivating this region reduces freezing while witnessing footshocks to others but not while hearing the CS. A decoder trained on spike counts while witnessing footshocks can decode the animals own pain intensity when experiencing pain. Mirror-like neurons thus exist in ACC that encode the pain of others in a code shared with pain but not fear in the self.\n\nOne Sentence SummaryACC contains neurons responding selectively when a rat witnesses anothers pain and experiences pain in the self.

neuroscience↗

bioRxiv2018

B1a cells protect against Schistosoma japonicum-induced liver inflammation and fibrosis by controlling monocyte infiltration

During Schistosoma infection, lack of B cells results in more severe granulomas, inflammation, and fibrosis in the liver, but the mechanisms underlying this pathology remain unclear. Thus, our aim was to clarify the mechanisms underpinning the immunomodulation of B cells in mice infected with Schistosoma japonicum. We found that B cell deficiency led to aggravated liver pathology, as demonstrated by increases in the size of the egg-associated granulomas, alanine transaminase levels, and collagen deposition. Compared with infected wild-type mice, infected B cell-deficient MT mice showed increased infiltration of Ly6Chi monocytes and higher levels of proinflammatory cytokines (tumor necrosis factor alpha, interleukin 6, and interleukin 12) and chemokines ([C-C motif] ligands (CCL)2, CCL3, CCL4, and CCL5). The results of flow cytometric analysis and cell transfer experiments showed that B1a cells increased significantly in the liver following S. japonicum infection, with some of those cells deriving from the peritoneal cavity. We also found that secretion of IL-10 from hepatic B cells increased significantly in infected wild-type mice and that this IL-10 was mainly derived from B1a cells. In addition, adoptively transferring peritoneal cavity B cells purified from wild-type, but not from IL-10-deficient mice, to MT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. These reductions were accompanied by decreases in the expression levels of chemokines and inflammatory cytokines. Taken together, these data indicated that after S. japonicum infection, an increased number of hepatic B1a cells secrete IL-10, which inhibits the expression of chemokines and cytokines and suppresses the infiltration of Ly6Chi monocytes into the liver thereby alleviating liver early inflammation and late fibrosis. Understanding this immunomodulatory role of B1a cells in schistosomiasis may lead to the development of therapeutic strategies for Schistosoma-induced liver disease.\n\nAuthor summaryInfection with Schistosoma, a waterborne parasitic flatworm (trematode) commonly called a blood fluke, results in strong granulomatous inflammation caused by the deposition of eggs in the liver. A granuloma is a substantial immune cell infiltration around the eggs intermixed with liver cells that can protect the host against liver damage. However, excessive infiltration and inflammation can lead to severe liver injury and fibrosis. Here, we found that B1a cells accumulate in the liver of mice after S. japonicum-induced infection and that these B1a cells release the anti-inflammatory cytokine interleukin 10 to regulate inflammation. The B1a cell-derived interleukin 10 inhibits the expression of chemokines (which attract cells such as monocytes to sites of infection or inflammation) and thus restrains excessive infiltration of Ly6Chi monocytes (which may have proinflammatory activity) into the liver, thereby alleviating early inflammation and later fibrosis. Our study provides insight into the immunomodulation of B1a cells in schistosomiasis and offers key information for the development of therapeutic strategies in Schistosoma-induced liver disease.

immunology↗

bioRxiv2018

Influenza incidence prediction for the United States: an update for the 2018-2019 season

IntroductionSeasonal influenza causes a high disease burden every year in the United States and worldwide. Anticipating epidemic size ahead of season can contribute to preparedness and more targetted control and prevention of seasonal influenza.\n\nMethodsA recently developed process-based epidemiological model that incorporates evolutionary change of the virus and generates incidence forecasts for the H3N2 subtype ahead of the season, was previously validated by several statistical criteria, including an accurate real-time prediction for the 2016-2017 influenza season. With this model, a new forecast is generated here for the upcoming 2018-2019 season. The accuracy of predictions published for the 2017-2018 season is also retrospectively evaluated.\n\nResultsFor 2017-2018, the model correctly predicted the dominance of the H3N2 subtype and its higher than average incidence. Based on surveillance and sequence data up to June 2018, the new forecast for the upcoming 2018-2019 season indicates low levels for H3N2, and suggests an H1N1 dominant season with low incidence of influenza B.\n\nDiscussionReal-time forecasts, those generated with a model that was parameterized based on data preceding the predicted season, allows valuable evaluation of the approach. Anticipating the dominant subtype and the size of the upcoming epidemic ahead of season informs disease control. Further studies are needed to promote more accurate ahead-of-season forecasts and extend the approach to multiple subtypes.

bioinformatics↗

bioRxiv2018

Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population

The strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the real or/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQ1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 x 10-36, OR=2.29). Further stepwise conditional analysis revealed that DR{beta}1:37N has an independent protective effect on ACPA-positive RA (P = 5.81 x 10-16, OR=0.49). The DQ1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 x 10-5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQ1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DR{beta}1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.\n\nIn this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

genetics↗

bioRxiv2018

A Chemically-triggered Transition from Conflict to Cooperation in Burying Beetles

Although interspecific competition has long been recognized as a major driver of trait divergence and adaptive evolution1-3, relatively little effort has focused on how it influences the evolution of intraspecific cooperation4-6. Here we identify the mechanism by which the perceived pressure of interspecific competition influences the transition from intraspecific conflict to cooperation in a facultative cooperatively breeding species, the Asian burying beetle Nicrophorus nepalensis. In their natural environment in central Taiwan, N. nepalensis are typically aggressive to conspecifics and only cooperate with others of their own species at critical carcass resources in the presence of blowflies, their primary competitors7. We demonstrate that beetles form larger groups and are more cooperative in carcass preparation in warmer environments where the pressure of interspecific competition with blowflies is highest8. To test the hypothesis that the presence of blowflies promotes beetle cooperation and to identify the mechanism by which this occurs, we manipulated blowfly larvae on carcasses in the lab. We not only found that beetles are more cooperative at carcasses when blowfly maggots have begun to digest the tissue, but that this social cooperation appears to be triggered by a single chemical cue-- dimethyl disulfide (DMDS)--emitted from carcasses consumed by blowflies but not from control carcasses lacking blowflies. Our results provide experimental evidence that interspecific competition promotes the transition from intraspecific conflict to cooperation in N. nepalensis via a surprisingly simple social chemical cue that is a reliable indicator of interspecific competition. This finding helps bridge the gap between the proximate and ultimate factors regulating the transition between cooperation and conflict and moves toward a more comprehensive understanding of the evolution of mechanisms governing intraspecific variation in social behaviour.

evolutionary biology↗

bioRxiv2018

Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

Under hypoxia, most of glucose is converted to secretory lactate, which leads to the lack of carbon source from glucose and thus the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid releasing potentially toxic ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate under hypoxia. We found that glutamine nitrogen is indispensable to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. The specific metabolic pathway occurs in vivo and is required for tumor growth. Such a metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.\n\nSignificanceTumor cells often addict to glutamine, and particularly utilize its carbon for lipogenesis under hypoxia. We reveal that tumor cells package the excessive glutamine-nitrogen into secretory dihydroorotate, instead of toxic ammonia. This specifically reprogrammed pathway supports in vivo tumor growth, and could offer diagnostic markers and therapeutic targets for cancers.

biochemistry↗

bioRxiv2018

Can we obtain in vivo transmural mean hoop stress of the aortic wall without knowing patient-specific material properties and residual deformations?

It is well known that residual deformations/stresses alter the mechanical behavior of arteries, e.g. the pressure-diameter curves. In an effort to enable personalized analysis of the aortic wall stress, approaches have been developed to incorporate experimentally-derived residual deformations into in vivo loaded geometries in finite element simulations using thick-walled models. Solid elements are typically used to account for \"bending-like\" residual deformations. Yet, the difficulty in obtaining patient-specific residual deformations and material properties has become one of the biggest challenges of these thick-walled models. In thin-walled models, fortunately, static determinacy offers an appealing prospect that allows for the calculation of the thin-walled membrane stress without patient-specific material properties. The membrane stress can be computed using forward analysis by enforcing an extremely stiff material property as penalty treatment, which is referred to as the forward penalty approach. However, thin-walled membrane elements, which have zero bending stiffness, are incompatible with the residual deformations, and therefore, it is often stated as a limitation of thin-walled models. In this paper, by comparing the predicted stresses from thin-walled models and thick-walled models, we demonstrate that the transmural mean hoop stress is the same for the two models and can be readily obtained from in vivo clinical images without knowing the patient-specific material properties and residual deformations. Computation of patient-specific mean hoop stress can be greatly simplified by using membrane model and the forward penalty approach, which may be clinically valuable.

bioengineering↗

bioRxiv2018

Estimation of in vivo constitutive parameters of the aortic wall: a machine learning approach

The patient-specific biomechanical analysis of the aorta demands the in vivo mechanical properties of individual patients. Current inverse approaches have shown the feasibility of estimating the nonlinear, anisotropic material parameters from in vivo image data using certain optimization schemes. However, since such inverse methods are dependent on iterative nonlinear optimization, these methods are highly computation-intensive, which may take weeks to complete for only a single patient, inhibiting rapid feedback for clinical use. Recently, machine learning (ML) techniques have led to revolutionary breakthroughs in many applications. A potential paradigm-changing solution to the bottleneck associated with patient-specific computational modeling is to incorporate ML algorithms to expedite the procedure of in vivo material parameter identification. In this paper, we developed a ML-based approach to identify the material parameters from three-dimensional aorta geometries obtained at two different blood pressure levels, namely systolic and diastolic geometries. The nonlinear relationship between the two loaded shapes and the constitutive parameters are established by a ML-model, which was trained and tested using finite element (FE) simulation datasets. Cross-validation was used to adjust the ML-model structure on a training/validation dataset. The accuracy of the ML-model was examined using a testing dataset.

bioengineering↗

bioRxiv2018

Sequencing of Panax notoginseng genome reveals genes involved in disease resistance and ginsenoside biosynthesis

Panax notoginseng is a traditional Chinese herb with high medicinal and economic value. There has been considerable research on the pharmacological activities of ginsenosides contained in Panax spp.; however, very little is known about the ginsenoside biosynthetic pathway. We reported the first de novo genome of 2.36 Gb of sequences from P. notoginseng with 35,451 protein-encoding genes. Compared to other plants, we found notable gene family contraction of disease-resistance genes in P. notoginseng, but notable expansion for several ATP-binding cassette (ABC) transporter subfamilies, such as the Gpdr subfamily, indicating that ABCs might be an additional mechanism for the plant to cope with biotic stress. Combining eight transcriptomes of roots and aerial parts, we identified several key genes, their transcription factor binding sites and all their family members involved in the synthesis pathway of ginsenosides in P. notoginseng, including dammarenediol synthase, CYP716 and UGT71. The complete genome analysis of P. notoginseng, the first in genus Panax, will serve as an important reference sequence for improving breeding and cultivation of this important nutraceutical and medicinal but vulnerable plant species.

genomics↗

bioRxiv2018

How do wind speed, release height, seed morphology interact to determine seed dispersal trajectory of Calligonum (Polygonaceae) species

How seed dispersal trajectory shifts with abiotic and biotic factors and what is the relationship between seed dispersal distance and dispersal trajectory are remain unclear. We used wind tunnel and video camera to track the seed dispersal trajectory of 7 Calligonum species with different appendages under the different wind speeds and the release heights. Dispersal trajectories and distances were determined by video analysis and spatial coordinate transformation. Based on perspective principle, 4 modes of trajectories were determined. Wind speed, seed mass and release height were the key factors determining seed dispersal trajectory modes. Release height and wind speed tended to have the strongest explanatory power on seeds with bristles and wings, respectively. Different trajectory modes lead to different dispersal distance, while the same dispersal distance can be the result of different trajectory modes. The proportion of species trajectory modes formed its trajectory spectrum. Wind speed tends to have strong influence on light and low-wind-loading seeds, release height tends to have that on heavy and high-wind-loading seeds. Species with high proportion of horizontal projectile and projectile have high dispersal capacity, vice versa. Therefore, trajectory spectrum of a species reveals its primary dispersal strategies and evolutionary consequences.

ecology↗

bioRxiv2018

The Mediator CDK8-Cyclin C complex modulates vein patterning in Drosophila by stimulating Mad-dependent transcription

Dysregulations of CDK8 and its regulatory partner CycC, two subunits of the conserved Mediator complex, have been linked to diverse human diseases such as cancer, thus it is essential to understand the regulatory network mobilizing the CDK8-CycC complex in both normal development and tumorigenesis. To identify upstream regulators or downstream effectors of CDK8, we performed a dominant modifier genetic screen in Drosophila based on the defects in vein patterning caused by specific depletion or overexpression of CDK8 or CycC in wing imaginal discs. We identified 26 genomic loci whose haploinsufficiency can modify these CDK8-specific phenotypes. Further analysis of two deficiency lines and mutant alleles led us to identify interactions between CDK8-CycC and the components of the Decapentaplegic (Dpp, the Drosophila homolog of TGF{beta}) signaling pathway. We observed that CDK8-CycC positively regulates transcription activated by Mad (Mothers against dpp), the primary transcription factor downstream of the Dpp/TGF{beta} signaling pathway. CDK8 can directly interact with Mad in vitro through the linker region between the DNA-binding MH1 (Mad homology 1) domain and the carboxy terminal MH2 transactivation domain. Besides CDK8 and CycC, further analyses of other subunits of the Mediator complex have revealed six additional Mediator subunits that are required for Mad-dependent transcription in the wing discs, including Med12, Med13, Med15, Med23, Med24, and Med31. Furthermore, CDK9 and Yorkie also positively regulate Mad-dependent gene expression in vivo. These results suggest that the Mediator complex may coordinate with other transcription cofactors in regulating Mad-dependent transcription during the wing vein patterning in Drosophila.\n\nSignificanceCDK8 is a conserved subunit of the transcription cofactor Mediator complex that bridges transcription factors with RNA Polymerase II in eukaryotes. Here we explore the role of CDK8 in Drosophila by performing a dominant modifier genetic screen based on vein patterning defects caused by alteration of CDK8-specific activities. We show that components of the Dpp/TGF{beta} signaling pathway genetically interact with CDK8; CDK8 positively regulates gene expression activated by Mad, the key transcription factor downstream of Dpp/TGF{beta} signaling, by directly interacting with the linker region of Mad protein. Given the fundamental roles of Dpp/TGF{beta} signaling in regulating development and its misregulation in various diseases, understanding how Mad/Smad interacts the Mediator complex may have broad implications in understanding and treating these diseases.

developmental biology↗

bioRxiv2018

Microbial coexistence through chemical-mediated interactions

Many microbial functions happen within communities of interacting species. Explaining how species with intrinsically disparate fitness can coexist is important for applications such as manipulating host-associated microbiota or engineering industrial communities. Previous coexistence studies have often neglected interaction mechanisms. Here, we formulate and experimentally constrain a model in which chemical mediators of microbial interactions (e.g. metabolites or waste-products) are explicitly incorporated. We construct many instances of coexistence by simulating community assembly through enrichment and ask how species interactions can explain coexistence. We show that growth-facilitating influences between members are favored in assembled communities. Among negative influences, self-restraint, such as production of self-inhibiting waste, contributes to coexistence, whereas inhibition of other species disrupts coexistence. Coexistence is also favored when interactions are mediated by depletable chemicals that get consumed or degraded, rather than by reusable chemicals that are unaffected by recipients. Our model creates null predictions for coexistence driven by chemical-mediated interactions.

ecology↗

bioRxiv2018

Neural Mechanisms Associated with Semantic and Basic Self-Oriented Memory Processes Interact to Modulate Self-Esteem.

Individuals constantly encounter feedback from others and process this feedback in various ways to maintain positive situational state self-esteem (SSE) in relation to semantic-based or trait self-esteem (TSE). Individuals may utilize a data-driven, or episodic-based process that encodes positive, but not negative, self-relevant information automatically, or employ a semantic-driven process that manipulates encoded negative feedback post-hoc. Its unclear, however, how these processes work either alone or in concert while individuals receive positive and negative feedback to modulate feedback encoding and subsequent SSE. Utilizing neural regions associated with semantic self-oriented and basic encoding processes (mPFC and PCC respectively), and time-frequency and Granger causality analyses to assess mPFC and PCC interactions, this study examined how encoding of positive and negative self-relevant feedback modulated individuals post-task SSE in relation to their TSE while continuous EEG was recorded. Among those with higher levels of TSE, the encoding of positive or negative feedback was not associated with SSE. Rather, higher SSE was associated with mPFC activity to all feedback and higher TSE. The relationship between TSE and SSE was moderated by mPFC-PCC communication such that increases in mPFC-PCC communication led to SSE levels that were consistent with TSE levels. Furthermore, Granger causality analyses indicated that individuals exhibited higher SSE to the extent mPFC influenced PCC in response to positive and negative feedback. Findings highlight the dynamic interplay between semantic self-oriented and basic encoding processes that modulate SSE in relation to TSE, to maintain more positive global selfperceptions in the moment and over time.

neuroscience↗

bioRxiv2018

Coupled Mixed Model for joint genetic analysis of complex disorders from independently collected data sets: application to Alzheimer’s disease and substance use disorder

In the last decade, Genome-wide Association studies (GWASs) have contributed to decoding the human genome by uncovering many genetic variations associated with various diseases. Many follow-up investigations involve joint analysis of multiple independently generated GWAS data sets. While most of the computational approaches developed for joint analysis are based on summary statistics, the joint analysis based on individual-level data with consideration of confounding factors remains to be a challenge. In this study, we propose a method, called Coupled Mixed Model (CMM), that enables a joint GWAS analysis on two independently collected sets of GWAS data with different phenotypes. The CMM method does not require the data sets to have the same phenotypes as it aims to infer the unknown phenotypes using a set of multivariate sparse mixed models. Moreover, CMM addresses the confounding variables due to population stratication, family structures, and cryptic relatedness, as well as those arising during data collection such as batch effects that frequently appear in joint genetic studies. We evaluate the performance of CMM using simulation experiments. In real data analysis, we illustrate the utility of CMM by an application to evaluating common genetic associations for Alzheimers disease and substance use disorder using datasets independently collected for the two complex human disorders. Comparison of the results with those from previous experiments and analyses supports the utility of our method and provides new insights into the diseases.\n\nThe software is available at https://github.com/HaohanWang/CMM

genetics↗

bioRxiv2018

The lysine demethylase dKDM2 is non-essential for viability, but regulates circadian rhythms in Drosophila

Post-translational modification of histones, such as histone methylation controlled by specific methyltransferases and demethylases, play critical roles in modulating chromatin dynamics and transcription in eukaryotes. Misregulation of histone methylation can lead to aberrant gene expression, thereby contributing to abnormal development and diseases such as cancer. As such, the mammalian lysine-specific demethylase 2 (KDM2) homologs, KDM2A and KDM2B, are either oncogenic or tumor suppressive, depending on specific pathological contexts. However, the role of KDM2 proteins during development in the whole organisms remains poorly understood. Unlike vertebrates, Drosophila has only one KDM2 homolog (dKDM2), but its functions in vivo remain elusive due to the complexities of the existing mutant alleles. To address this problem, we have generated two dKdm2 null alleles using the CRISPR/Cas9 technique. These dKdm2 homozygous mutants are fully viable and fertile, with no developmental defects observed under laboratory conditions. However, the dKdm2 null mutant adults display defects in circadian rhythms. Most of the dKdm2 mutants become arrhythmic under constant darkness, while the circadian period of the rhythmic mutant flies is approximately one hour shorter than the control. Interestingly, opposite defects are observed when dKDM2 is overexpressed in circadian pacemaker neurons. Taken together, these results demonstrate that dKdm2 is not essential for viability; instead, dKDM2 protein plays important roles in regulating circadian rhythms in Drosophila. Further analyses of the molecular mechanisms of how dKDM2 and its orthologs in vertebrates regulate circadian rhythms will advance our understanding of the epigenetic regulations of circadian clocks.

developmental biology↗

bioRxiv2018

Structure of the receptor-activated human TRPC6 ion channel

TRPC6 is a receptor-activated nonselective cation channel that belongs to the family of canonical transient receptor potential (TRPC) channels. It is activated by diacylglycerol, a lipid second messenger. TRPC6 is involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 [A] resolution. The structure shows a two-layer architecture, in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domain, including N terminal ankyrin repeats and C terminal coiled-coil, contribute to the tetramer assembly. The high affinity inhibitor BTDM wedges between S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structure uncovers the molecular architecture of TRPC channels and provides a structural basis for understanding the mechanism of these channels.

biophysics↗

bioRxiv2018

WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death

Mutations in the autophagy gene WDR45 cause {beta}-propeller protein-associated neurodegeneration (BPAN); however the molecular and cellular mechanism of the disease process is largely unknown. Here we generated constitutive Wdr45 knockout (KO) mice that displayed cognitive impairments, abnormal synaptic transmission and lesions in hippocampus and basal ganglia. Immunohistochemistry analysis shows loss of neurons in prefrontal cortex and basal ganglion in aged mice, and increased apoptosis in these regions, recapitulating a hallmark of neurodegeneration. Quantitative proteomic analysis shows accumulation of endoplasmic reticulum (ER) proteins in KO mouse. Furthermore, we show that a defect in autophagy results in impaired ER turnover and ER stress. The unfolded protein response (UPR) is elevated through IRE1 and possibly other kinase signaling pathways, and eventually leads to neuronal apoptosis. Suppression of ER stress, or activation of autophagy through inhibition of mTOR pathway rescues neuronal death. Thus, our study not only provides mechanistic insights for BPAN, but also suggests that a defect in macroautophagy machinery leads to impairment in selective organelle autophagy.

cell biology↗