Biology subjects

Shen, G.

Publications and source records attributed to Shen, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Multiple routes to red-shifted chlorophyll d-based photosynthesis

Strains of the cyanobacterium Acaryochloris marina exhibit diverse far-red light-harvesting properties during chlorophyll d-based photosynthesis. Here, we show that differences in light absorption among A. marina strains arise exclusively from Photosystem I (PSI) and reflect variation in multiple low-energy chlorophyll states. Time-resolved fluorescence reveals different combinations of low-energy states among strains, generating a continuum of spectral phenotypes. Cryo-EM structures of PSI at [~]1.8 [A] resolution reveal similar low-energy states arising from distinct pigment environments, demonstrating that red-shifted absorption is not governed by a single conserved motif. Phylogenetic analyses show that spectral tuning evolved through modular variation and reassortment of PSI components. These results indicate that distinct pigment configurations can converge on similar low-energy states, extending light harvesting near the energetic limit of oxygenic photosynthesis.

biophysics↗

bioRxiv2025

The pro-, but not anti-nociceptive effects of Cannabidiol depend on Trpa1b in larval Zebrafish

The promiscuous ligand cannabidiol (CBD) shows promise as an analgesic, but its complex pharmacodynamics has made it difficult to identify its mechanism(s) of action. Numerous putative CBD receptors including cannabinoid receptors CB1 and CB2, as well as Trpv1 and Trpa1--the receptors for capsaicin and mustard-oil (AITC) respectively--have been proposed to contribute to CBD-mediated analgesia. Larval zebrafish have several attributes that lend themselves to inquiries into the biology of nociception. The neural circuits underlying nociception in zebrafish larvae are highly analogous to those found in higher vertebrates. Notably, the small size and optical clarity of zebrafish enable holistic evaluation of analgesic function utilizing behavioral and imaging platforms. Here we report that in larval zebrafish CBD serves both anti- and pro-nociceptive functions. Utilizing place aversion assays as a proxy for nociception, we found that low concentrations of CBD inhibit aversion to noxious chemical stimuli including AITC and acetic acid. Counterintuitively, we found that higher concentrations of CBD potentiated nocifensive behavior as measured by enhanced thermal aversion and increased locomotion. Knockdown of Trpa1b eliminated the algogenic effects of CBD while having no effect on its analgesic properties, as it abolished trpa1b+ sensory neuron responses to CBD, CBD-evoked thermal hypersensitivity, and increased locomotion in Trpa1b-null animals. Strikingly, CBD profoundly inhibited thermal aversion to noxious heat in Trpa1b-null animals but not in wildtype animals, indicating that CBD-mediated Trpa1b activation can oppose the analgesic properties of CBD. These studies provide a framework to investigate the genetic and neural substrates of CBD-mediated analgesia and nociception. Significance statementWhile Cannabis and its component compounds such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have long been used to alleviate pain, little is known about their mechanisms of action. Our study provides a framework for investigating the effects of cannabinoids on nociception in a vertebrate, by utilizing behavioral experiments in combination with neuroimaging and in-vitro studies. Together, these approaches allowed us to define the role of one molecular target, Trpa1b, involved in the effects of CBD upon nociception. Critically, activation of this receptor by CBD masks a separate, analgesic effect upon temperature sensation, which suggests a possible explanation for CBDs inconsistent efficacy across different models of pain.

neuroscience↗

bioRxiv2024

Adaptation to cystine limitation stress promotes PDAC tumor growth and metastasis through translational upregulation of OxPPP

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.

cancer biology↗

bioRxiv2024

Assessment of DNA methylation from a single genomic region of ELOV2 is sufficient to predict chronological age

Estimation of chronological age is particularly informative in forensic contexts. Assessment of DNA methylation status allows for the prediction of age, though the accuracy and ease of manipulation may vary across different models. In this study, we started with a carefully designed discovery cohort recruiting more elderly subjects than other age categories, to diminish the effect of epigenetic drifting. We analyzed DNA methylation from a single genomic region of ELOV2, which was sufficient to construct an age-prediction model comprising 15 CpG sites. This model is further validated by an independent cohort as well as a multi-center test using trace dried bloodstains. The nature of our analytical pipeline, when combined the assessment of a single genomic locus with high-throughput sequencing, can easily be scaled up with low cost. Taken together, we propose a new age-prediction model featuring accuracy, ease of manipulation, high-throughput, and low cost. This model can be readily applied in both classic and newly emergent forensic contexts that require age estimation.

genetics↗

bioRxiv2024

Biallelic pathogenic variants in DNAH3 cause male infertility in humans and mice

Axonemal protein complexes, including the outer and inner dynein arms (ODA/IDA), are highly ordered structures of the sperm flagella that drive sperm motility. Deficiencies in several axonemal proteins have been associated with male infertility, which is characterized by asthenozoospermia or asthenoteratozoospermia. Dynein axonemal heavy chain 3 (DNAH3) resides in the IDA and is highly expressed in the testis. However, the relationship between DNAH3 and male infertility is still unclear. Herein, we identified biallelic variants of DNAH3 in four unrelated Han Chinese infertile men with asthenoteratozoospermia through whole-exome sequencing (WES). These variants contributed to deficient DNAH3 expression in the patients sperm flagella. Importantly, the patients represented the anomalous sperm flagellar morphology, and the flagellar ultrastructure was severely disrupted. Intriguingly, Dnah3 knockout (KO) male mice were also infertile, especially showing the severe reduction in sperm movement with the abnormal IDA and mitochondrion structure. Mechanically, nonfunctional DNAH3 expression resulted in decreased expression of IDA-associated proteins in the spermatozoa flagella of patients and KO mice, including DNAH1, DNAH6, and DNALI1, the deletion of which has been involved in disruption of sperm motility. Moreover, the infertility of patients with DNAH3 variants and Dnah3 KO mice could be rescued by intracytoplasmic sperm injection (ICSI) treatment. Our findings indicated that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and may further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.

genetics↗

bioRxiv2024

Niche partitioning in a cyanobacterium through divergence of its novel chlorophyll d-based light-harvesting system

The evolution of novel traits can have important consequences for biological diversification. New ecological opportunities provided by a novel trait can trigger subsequent trait modification or niche partitioning; however, the underlying mechanisms of novel trait diversification are still poorly understood. Here, we report that the innovation of a new chlorophyll (Chl) pigment, Chl d, by the cyanobacterium Acaryochloris marina was followed by the functional divergence of its light-harvesting complex. We identified three major photosynthetic spectral types based on Chl fluorescence properties for A. marina laboratory strains, with shorter and longer wavelength types more recently derived from an ancestral intermediate phenotype. Members of the different spectral types exhibited extensive variation in the Chl-binding proteins as well as the Chl energy levels of their photosynthetic complexes. This spectral type divergence is associated with differences in the wavelength dependence of both growth rate and photosynthetic oxygen evolution. We conclude that the divergence of the light-harvesting apparatus has consequently impacted A. marina ecological diversification through specialization on different far-red photons for photosynthesis.

evolutionary biology↗

bioRxiv2024

SnapFISH-IMPUTE: an imputation method for multiplexed DNA FISH data

Chromatin spatial organization plays a crucial role in gene regulation. Recently developed and prospering multiplexed DNA FISH technologies enable direct visualization of chromatin conformation in nucleus. However, incomplete data caused by limited detection efficiency can substantially complicate and impair downstream analysis. Here, we present SnapFISH-IMPUTE that imputes missing values in multiplexed DNA FISH data. Analysis on multiple published datasets shows that the proposed method preserves the distribution of pairwise distances between imaging loci, and the imputed chromatin conformations are indistinguishable from the observed conformations. Additionally, imputation greatly improves downstream analyses such as identifying enhancer-promoter loops and clustering cells into distinct cell types. SnapFISH-IMPUTE is freely available at https://github.com/hyuyu104/SnapFISH-IMPUTE.

bioinformatics↗

bioRxiv2023

Prokaryotic microbial diversity analysis and metabolic function prediction of salt lakes on the Qinghai-Tibet Plateau

The Dong Taijinar Salt Lake (DT) and Xi Taijinar Salt Lake (XT) have been widely studied as mineral-rich areas. However, little is known about the composition and distribution of the microbial communities in these two lakes. In this study, metagenomics sequencing was used to analyze the diversity and potential functions of the microbial communities in DT and XT. According to our report, the salinity of DT (332.18-358.30 g/L) was 10 times higher than that of XT (20.09-36.83 g/L). Interestingly, the dominant domain in DT was Archaea (96.16%), while that in XT was Bacteria (93.09%). The distribution of Bacteria in the DT revealed 33 phyla and 1717 genera. The dominant genus in DT was Marinobacillus, which was positively correlated with total phosphorus content. There were four main phyla and 153 genera identified in the Archaea of DT. The most abundant Archaea genera in DT were Natronomonas (24.61%) and Halorubrum (23.69%), which were mainly positively correlated with the Na+, Ca2+, and Cl- contents. Similarly, there were 33 phyla and 1906 genera of Bacteria in XT, and Loktanella was the dominant genus. The archaeal taxonomy in XT mainly included four phyla and 149 genera. Proteobacteria and Euryarchaeota were the most abundant bacterial and archaeal phyla in the two salt lakes. Analysis of the halophilic mechanisms of the microorganisms identified in these two salt lakes revealed that the Bacteria in XT preferred to synthesize compatible solutes, whereas the Archaea in DT preferred a "salt-in" adaptation strategy in salt-stressed environments. IMPORTANCEThe Qinghai-Tibet Plateau is the origin of many lakes and mountains in China. Among them, the Dong Taijinar and Xi Taijinar salt lakes are important biological resources with unknown microbial community compositions and functional potentials. The results of this study revealed significant differences in the distribution of Bacteria and Archaea between the two salt lakes. Salinity mainly drives lower biodiversity and restricted bacterial growth and metabolism in the high-salinity and near-saturated Dong Taijinar Salt Lake. This study not only identifies the key microorganisms in two penetrating salt lakes, but also provides insights into the mechanisms of salinity tolerance and the unknown ecological functions of microorganisms in extreme environments.

microbiology↗

bioRxiv2023

IQCH regulates spermatogenesis by interacting with CaM to promote RNA-binding proteins' expression

IQ motif-containing proteins can be recognized by calmodulin (CaM) and are essential for many biological processes. However, the role of IQ motif-containing proteins in spermatogenesis is largely unknown. In this study, we identified a loss-of-function mutation in the novel gene IQ motif-containing H (IQCH) in a Chinese family with male infertility characterized by a cracked flagellar axoneme and abnormal mitochondrial structure. To verify the function of IQCH, Iqch knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the Iqch KO male mice exhibited impaired fertility, which was related to deficient acrosome activity and abnormal structures of the axoneme and mitochondria, mirroring the patient phenotypes. Mechanistically, IQCH can bind to CaM and subsequently regulate the expression of RNA-binding proteins (especially HNRPAB), which are indispensable for spermatogenesis. Overall, this study revealed the function of IQCH, expanded the role of IQ motif-containing proteins in reproductive processes, and provided important guidance for genetic counseling and genetic diagnosis of male infertility.

genetics↗

bioRxiv2023

Latitudinal scaling of aggregation with abundance and its consequences for coexistence in species rich forests

The search for simple principles underlying the complex spatial structure and dynamics of plant communities is a long-standing challenge in ecology1-6. In particular, the relationship between the spatial distribution of plants and species coexistence is challenging to resolve in species-rich communities7-9. Analysing the spatial patterns of tree species in 21 large forest plots, we find that rare species tend to be more spatially aggregated than common species, and a latitudinal gradient in the strength of this negative correlations that increases from tropical to temperate forests. Our analysis suggests that latitudinal gradients in animal seed dispersal10 and mycorrhizal associations11,12,13 may jointly generate this intriguing pattern. To assess the consequences of negative aggregation-abundance correlations for species coexistence, we present here a framework to incorporate the observed spatial patterns into population models8 along with an analytical solution for the local extinction risk14 of species invading from low abundances in dependence of spatial structure, demographic parameters, and immigration. For example, the stabilizing effect of the observed spatial patterns reduced the local extinction risk of species when rare almost by a factor of two. Our approach opens up new avenues for integrating observed spatial patterns into mathematical theory, and our findings demonstrate that spatial patterns, such as species aggregation and segregation, can contribute substantially to coexistence in species-rich communities. This underscores the need to understand the interactions between multiple ecological processes and spatial patterns in greater detail.

ecology↗

bioRxiv2022

Nr4a1 regulates inhibitory circuit structure and function in the mouse brain.

Central neurons express unique repertoires of secreted and transmembrane proteins that define their synaptic connectivity. However, how these molecular programs are regulated remains poorly understood. Our study shows that, in inhibitory GABAergic interneurons in the mouse forebrain, transcription of synaptic organizer molecules is controlled by Nr4a1, a nuclear receptor whose expression is transiently induced by sensory experience and required for normal learning. Nr4a1 exserts opposite effects on local axonal wiring of Parvalbumin- and Somatostatin-positive interneurons that innervate different subcellular domains of their postsynaptic partners. Loss of Nr4a1 activity in these interneurons leads to cell-type-specific transcriptional switches in multiple gene families, including those involved in surface adhesion and repulsion. Our findings reveal a mechanism by which inducible transcription factors dynamically alter the combinatorial synaptic organizing codes for structural plasticity.

neuroscience↗

bioRxiv2022

Adaptation of cyanobacteria to the endolithic light spectrum in hyper-arid deserts

In hyper-arid deserts, endolithic microbial communities survive in the pore spaces and cracks of rocks, an environment that enhances water retention and filters UV radiation. The rock colonization zone is enriched in far-red light (FRL) and depleted in visible light. This poses a challenge to cyanobacteria, which are the primary producers of endolithic communities. Many species of cyanobacteria are capable of Far-Red Light Photoacclimation (FaRLiP), a process in which FRL induces the synthesis of specialized chlorophylls and remodeling of the photosynthetic apparatus, providing the ability to grow in FRL. While FaRLiP has been reported in cyanobacteria from various low-light environments, our understanding of light adaptations for endolithic cyanobacteria remains limited. Here, we demonstrated that endolithic Chroococidiopsis isolates from deserts around the world synthesize chlorophyll f, an FRL-specialized chlorophyll when FRL is the sole light source. The metagenome-assembled genomes of these isolates encoded chlorophyll f synthase and all the genes required to implement the FaRLiP response. We also present evidence of FRL-induced changes to the major light-harvesting complexes of a Chroococidiopsis isolate. These findings indicate that endolithic cyanobacteria from hyper-arid deserts use FRL photo-acclimation as an adaptation to the unique light transmission spectrum of their rocky habitat.

microbiology↗

bioRxiv2022

Comparative genomics in Orobanchaceae provides insight into the origin and evolution of plant parasitism

Orobanchaceae is the largest family of parasitic plants, containing autotrophic and parasitic plants with all degrees of parasitism. This makes it by far the best family for studying the origin and evolution of plant parasitism. Here we provide three high-quality genomes of orobanchaceous plants, the autotrophic Lindenbergia luchunensis and the holoparasitic plants Phelipanche aegyptiaca and Orobanche cumana. Phylogenomic analysis of these three genomes together with those previously published and the transcriptomes of other orobanchaceous species, created a robust phylogenetic framework for Orobanchaceae. We found that an ancient whole-genome duplication (WGD; about 73.48 Mya), which occurred earlier than the origin of Orobanchaceae, might have contributed to the emergence of parasitism. However, no WGD events occurred in any lineage of orobanchaceous parasites except for Striga after divergence from their autotrophic common ancestor, suggesting that, in contrast to previous speculations, WGD is not associated with the emergence of holoparasitism. We detected evident convergent gene loss in all parasites within Orobanchaceae and between Orobanchaceae and dodder Cuscuta australis. The gene families in the orobanchaceous parasites showed a clear pattern of recent gains and expansions. The expanded gene families are enriched in functions related to the development of the haustorium, suggesting that recent gene family expansions may have facilitated the adaptation of orobanchaceous parasites to different hosts. This study illustrates a stepwise pattern in the evolution of parasitism in the orobanchaceous parasites, and will facilitate future studies on parasitism and the control of parasitic plants in agriculture.

plant biology↗

bioRxiv2021

Potential Pharmacodynamic Mechanism of the Main ingredients in Licorice for Chronic Obstructive Pulmonary Disease

PurposeThis study aimed to investigate the effect of essential ingredients of licorice on the chronic obstructive pulmonary disease (COPD). MethodThe ingredients information were obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov/), related genes about COPD was collected from geneCards (http://www.genecards.org/). Network pharmacology was utilized in this study. ResultThe intersection data set contains 20 molecular targets between COPD and liquorice. Protein-protein interaction network showed that there are a total of 58 nodes and 137 edges involved. The link number of AKT1 in PPI network was 39, which is the highest level of interaction. MAPK1 is an important target of Licorice on COPD. ConclusionMAPK signaling pathway could be the important key target of main ingredients of licorice on COPD.

bioinformatics↗

bioRxiv2020

Interaction network of SARS-CoV-2 with host receptome through spike protein

Host cellular receptors are key determinants of virus tropism and pathogenesis. Virus utilizes multiple receptors for attachment, entry, or specific host responses. However, other than ACE2, little is known about SARS-CoV-2 receptors. Furthermore, ACE2 cannot easily interpret the multi-organ tropisms of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV. To identify host cell receptors involved in SARS-CoV-2 interactions, we performed genomic receptor profiling to screen almost all human membrane proteins, with SARS-CoV-2 capsid spike (S) protein as the target. Twelve receptors were identified, including ACE2. Most receptors bind at least two domains on S protein, the receptor-binding-domain (RBD) and the N-terminal-domain (NTD), suggesting both are critical for virus-host interaction. Ectopic expression of ASGR1 or KREMEN1 is sufficient to enable entry of SARS-CoV-2, but not SARS-CoV and MERS-CoV. Analyzing single-cell transcriptome profiles from COVID-19 patients revealed that virus susceptibility in airway epithelial ciliated and secretory cells and immune macrophages highly correlates with expression of ACE2, KREMEN1 and ASGR1 respectively, and ACE2/ASGR1/KREMEN1 (ASK) together displayed a much better correlation than any individual receptor. Based on modeling of systemic SARS-CoV-2 host interactions through S receptors, we revealed ASK correlation with SARS-CoV-2 multi-organ tropism and provided potential explanations for various COVID-19 symptoms. Our study identified a panel of SARS-CoV-2 receptors with diverse binding properties, biological functions, and clinical correlations or implications, including ASGR1 and KREMEN1 as the alternative entry receptors, providing insights into critical interactions of SARS-CoV-2 with host, as well as a useful resource and potential drug targets for COVID-19 investigation.

microbiology↗

bioRxiv2020

Species packing and the latitudinal gradient in local beta-diversity

The decline in species richness at higher latitudes is among the most fundamental patterns in ecology. Whether changes in species composition across space (beta-diversity) contribute to this gradient of overall species richness (gamma-diversity) remains hotly debated. Previous studies that failed to resolve the issue suffered from a well-known tendency for small samples in areas with high gamma-diversity to have inflated measures of beta-diversity. Here, we provide here a novel analytical test, using beta-diversity metrics that correct the gamma-diversity and sampling biases, to compare beta-diversity and species packing across a latitudinal gradient in tree species richness of 21 large forest plots along a large environmental gradient in East Asia. We demonstrate that after accounting for topography and correcting the gamma-diversity bias, tropical forests still have higher beta-diversity than temperate analogs. This suggests that beta-diversity contributes to the latitudinal species richness gradient as a component of gamma-diversity. Moreover, both niche specialization and niche marginality (a measure of niche spacing along an environmental gradient) also increase towards the equator, after controlling for the effect of topographic heterogeneity. This supports the joint importance of tighter species packing and larger niche space in tropical forests while also demonstrating the importance of local processes in controlling beta-diversity.

ecology↗

bioRxiv2020

Optimized culture of retinal ganglion cells and amacrine cells from adult mice

Cell culture is widely utilized to study the cellular and molecular biology of different neuronal cell populations. Current techniques to study enriched neurons in vitro are primarily limited to embryonic/neonatal animals and induced pluripotent stem cells (iPSC). Although the use of these cultures is valuable, the accessibility of purified primary adult neuronal cultures would allow for improved assessment of certain neurological diseases and pathways at the cellular level. Using a modified 7-step immunopanning technique to isolate for retinal ganglion cells (RGCs) and amacrine cells (ACs) from adult mouse retinas, we have successfully developed a model of neuronal culture that maintains for at least one week. Isolations of Thy1.2+ cells are enriched for RGCs, with the isolation cell yield being congruent to the theoretical yield of RGCs in a mouse retina. ACs of two different populations (CD15+ and CD57+) can also be isolated. The populations of these three adult neurons in culture are healthy, with neurite outgrowths in some cases greater than 500{micro}m in length. Optimization of culture conditions for RGCs and CD15+ cells revealed that neuronal survival and the likelihood of neurite outgrowth respond inversely to different culture media. Serially diluted concentrations of puromycin decreased cultured adult RGCs in a dose-dependent manner, demonstrating the potential usefulness of these adult neuronal cultures in screening assays. This novel culture system can be used to model adult neurons in vivo. Studies can now be expanded in conjunction with other methodologies to study the neurobiology of function, aging, and diseases.

neuroscience↗

bioRxiv2020

Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

Monitoring the mutation dynamics of SARS-CoV-2 is critical for the development of effective approaches to contain the pathogen. By analyzing 106 SARS-CoV-2 and 39 SARS genome sequences, we provided direct genetic evidence that SARS-CoV-2 has a much lower mutation rate than SARS. Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. The discrepant phylogenies for the spike protein and its receptor binding domain proved a previously reported structural rearrangement prior to the emergence of SARS-CoV-2. Despite that we found the spike glycoprotein of SARS-CoV-2 is particularly more conserved, we identified a receptor binding domain mutation that leads to weaker ACE2 binding capability based on in silico simulation, which concerns a SARS-CoV-2 sample collected on 27th January 2020 from India. This represents the first report of a significant SARS-CoV-2 mutant, and requires attention from researchers working on vaccine development around the world. HighlightsO_LIBased on the currently available genome sequence data, we provided direct genetic evidence that the SARS-COV-2 genome has a much lower mutation rate and genetic diversity than SARS during the 2002-2003 outbreak. C_LIO_LIThe spike (S) protein encoding gene of SARS-COV-2 is found relatively more conserved than other protein-encoding genes, which is a good indication for the ongoing antiviral drug and vaccine development. C_LIO_LIMinimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. C_LIO_LIWe confirmed a previously reported rearrangement in the S protein arrangement of SARS-COV-2, and propose that this rearrangement should have occurred between human SARS-CoV and a bat SARS-CoV, at a time point much earlier before SARS-COV-2 transmission to human. C_LIO_LIWe provided first evidence that a mutated SARS-COV-2 with reduced human ACE2 receptor binding affinity have emerged in India based on a sample collected on 27th January 2020. C_LI

evolutionary biology↗