Search bioRxiv⌕ Search

Biology subjects

Li, C.-Y.

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

At least 19 recordsLinked to original sources

Hologenomics of xylotrophic bivalves reveals a minimalist, remote-acting evolutionary strategy of wood digestion

Wood constitutes the largest reservoir of biogenic carbon on Earth, yet remarkably few animals can exploit it. While terrestrial wood-feeders like termites rely on highly diverse gut microbiomes, xylotrophic marine bivalves have evolved a fundamentally different approach: a spatially segregated system where intracellular gill symbionts produce enzymes that act remotely within a nearly sterile cecum. However, the genetic and evolutionary basis of this unique symbiosis remains largely elusive. Here, we integrate hologenomics, transcriptomics, and biochemistry of a shallow-water shipworm (Teredo navalis) and a deep-sea borer (Xyloredo sp.). We find that despite diverging approximately 147 million years ago and occupying drastically different habitats, these bivalves maintain a strictly conserved ancestral karyotype and a shared genomic architecture for wood digestion. Our models reveal a clear host-symbiont division of labor. The host genome is specialized for lignin modification and targeted enzyme transport, whereas a highly streamlined symbiont community is responsible for core polysaccharide degradation. Central to this minimalist strategy is a lineage-specific GH5-GH6 dual-catalytic enzyme. By sharing amino acids across proximal binding pockets, this fusion protein unites endo- and exo-cellulase activities, enabling highly synergistic cellulose cleavage without the need for complex microbial communities. Ultimately, our comparative analysis with terrestrial models demonstrates that these marine invertebrates achieve efficient biomass degradation not through microbial expansion, but through extreme functional streamlining and molecular innovation, offering a distinct evolutionary paradigm for marine carbon cycling.

evolutionary biology↗

Internal mechanosensory feedback modulates central pattern generation to coordinate ovulation in Drosophila

Ovulation is a prerequisite for successful reproduction and requires precise coordination of muscle contractions, especially to propel eggs from the paired lateral oviducts into the common oviduct. Although internal mechanosensation is expected to provide critical feedback for this process, the sensorimotor circuitry and mechanisms by which sensory feedback shapes motoneuron activity and coordinates oviduct contractions are still poorly known. Here, in Drosophila, we identify a novel pair of multidendritic mechanosensory neurons (mdn-LO) in the lateral oviducts that express the mechanosensitive channels TMC (transmembrane channel-like protein), PPK (pickpocket), and Piezo. We show that TMC is essential for coordinated ovulation; tmc mutation or neuron-specific knockdown increases egg-jamming at the junction between the lateral and the common oviduct. In contrast, ppk or Piezo mutants display reduced egg-laying but no jamming. Calcium imaging reveals that the mdn-LO neurons are rhythmically activated by oviduct contractions, and chemogenetic stimulation of these neurons triggers muscle contractions. Genetic manipulations of the mdn-LO neurons disrupt egg passage and induce egg-jamming. The axons of the mdn-LO neurons form functional contacts with female-specific oviduct motoneurons in the abdominal neuromeres that express insulin-like peptide 7 (ILP7) and glutamate. Activation of mdn-LO neurons triggers Ca{superscript 2} activity in ILP7 motoneurons and elicits rhythmic oviduct contractions. Importantly, the ILP7 motoneurons exhibit spontaneous rhythmic Ca{superscript 2} activity that is modulated by oviduct contractions and egg movement. Furthermore, triggering activity in the ILP7 neurons induces egg-jamming. Finally, knockdown of ILP7 peptide affects the rate of ovulation, but plays no role in egg jamming, which instead is likely induced by colocalized glutamate. In summary, our study identifies a novel circuit, including the TMC-expressing mdn-LO neurons and a small set of ILP7 motoneurons, that organizes an innate behavior by coupling strategic sensory information and rhythmical motor output to ensure bilateral coordination of oviduct contractions to prevent egg jamming during oviposition. SignificanceOvulation requires precisely coordinated contractions of the lateral oviducts to propel eggs into the common oviduct without jamming. Yet the sensory cells and mechanotransduction channels that coordinate movement through the paired lateral oviducts remain unclear. Here, we identify a novel pair of lateral-oviduct multidendritic neurons (mdn-LO) that express the conserved mechanosensory channels TMC (transmembrane channel-like protein), PPK (pickpocket), and Piezo, and show that TMC is uniquely required to prevent egg jamming at the junction between the lateral and common oviducts. The mdn-LO neurons are activated by oviduct contractions and relay signals to female-specific glutamatergic motoneurons in the abdominal neuromere. These paired oviduct motoneurons are rhythmically active and regulate contractions of the lateral oviducts. Together, our findings demonstrate that TMC-mediated mechanosensory feedback fine-tunes motor output to ensure coordinated ovulation and successful reproduction.

neuroscience↗

Toward Precision Detection of Pyrazinamide Resistance: Critical Concentration Assessment and Rapid Molecular Method Validation

This study aimed to evaluate the diagnostic performance of broth microdilution (BMD) and fluorescence PCR melting curve analysis (MeltPro MTB/PZA assay) for detecting pyrazinamide (PZA) resistance in rifampicin-resistant tuberculosis (RR-TB).RR-TB strains isolated from patients in TB prevention and control in stitutions and designated hospitals in Beijing from January to December 2009 were analyzed. PZA susceptibility was assessed using BMD, MeltPro MTB/PZ A assay (targeting pncA mutations), and whole-genome sequencing (WGS). The sensitivity, specificity, agreement rate, and Kappa value of BMD (at critical c oncentrations (CCs) of 100 g/mL and 200 g/mL)and MeltPro MTB/PZA assa y were evaluated using WGS as the reference standard. At CCs of 100 g/mL and 200 g/mL, BMD showed resistance rates of 63.6% (70/110) and 45.5% (50/110), respectively. Compared to WGS, BMD demonstrated sensitivities of 96 .1% and 92.2%, specificities of 64.4% and 94.9%, with {kappa} values of 0.590 and 0.872, respectively. The MeltPro assay detected resistance in 44.5% (53/119) of strains, with 89.7% sensitivity, 98.4% specificity, and {kappa} value of 0.882. The MeltPro MTB/PZA assay demonstrates high diagnostic accuracy for PZA resista nce screening in RR-TB patients, supporting its utility as a frontline detection t ool. BMD at 200 g/mL showed better concordance with WGS. Additionally, f ive novel pncA mutations (Ile5Thr, Leu27Gln, Ser67stop, Pro69Arg, Trp119Ser) identified in this study expand the catalog of known resistance-associated vari ants and offer new targets for mechanistic investigations. IMPORTANCEThis study evaluates the diagnostic performance of broth micr odilution and a rapid molecular assay in detecting pyrazinamide resistance in R R-TB, providing insight into reliable testing approaches and resistance profiles.

microbiology↗

Multi-Omics Mapping of Gut Microbiota's Role in Progesterone Metabolism

5-neurosteroids such as allopregnanolone and isopregnanolone play critical roles in neurological health and mood regulation, yet current therapeutic production faces significant limitations. We demonstrate that specific gut microbes represent a previously unrecognized source of bioavailable 5-neurosteroids that reach the central nervous system via the gut-brain axis. Through integrated metabolomic and genomic analyses of progesterone-amended fecal cultures, we identified Holdemania as a major producer of isopregnanolone via microbial steroid 5-reductase (BaiJ type 2) and 3{beta}-hydroxysteroid dehydrogenase/reductase. Phylogenetic analysis revealed that BaiJ-like sequences cluster predominantly within Firmicutes, with Holdemania species forming a distinct clade. In female C57BL/6 mice administered progesterone and H. filiformis, 5-neurosteroids including isopregnanolone predominated in gut tissues while allopregnanolone was the major hepatic neurosteroid. Critically, using stable isotope tracing with [3,4-{superscript 1}3C2]progesterone, we detected {superscript 1}3C-labeled isopregnanolone in brain tissue, providing direct evidence for gut-to-brain transport of microbiota-derived neurosteroids. High-fat diet significantly enhanced brain 5-neurosteroid accumulation. Global meta-analysis reveals reduced Holdemania abundance in PCOS patients (n = 346) compared to healthy women (n = 321). These findings identify gut microbiota as pharmacologically relevant neurosteroid producers and position H. filiformis as a promising probiotic candidate for enhancing endogenous neurosteroid production to treat mood disorders and other neuropsychiatric conditions. HighlightsO_LIHoldemania was identified as a major producer of 5-neurosteroids, particularly isopregnanolone, in the intestinal tract C_LIO_LIHoldemania 5-reductase (BaiJ type 2) belongs to a distinct phylogenetic clade compared to characterized Clostridium BaiJ (type 1) C_LIO_LI5-neurosteroids occurred predominantly in the cecum of female mice administered H. filiformis, progesterone, and high-fat diet C_LIO_LI{superscript 1}3C-labeled 5-neurosteroids were detected in brain tissue of female mice orally administered [3,4-{superscript 1}3C2]progesterone and H. filiformis, demonstrating gut-to-brain transport C_LIO_LIGut microbes such as H. filiformis represent promising probiotic candidates for enhancing 5-neurosteroid production and circulation via the gut-brain axis C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/628284v3_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1b85caaorg.highwire.dtl.DTLVardef@cbb352org.highwire.dtl.DTLVardef@169f7fcorg.highwire.dtl.DTLVardef@17c638_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

Clostridium innocuum, an opportunistic gut pathogen, inactivates host gut progesterone and arrests ovarian follicular development

HighlightsO_LIWe identified Clostridium innocuum as a key player in gut progesterone metabolism. C_LIO_LIProgesterone is converted into epipregnanolone with negligible progestogenic activity. C_LIO_LIWe identified the enzyme and mechanisms of microbial epipregnanolone production. C_LIO_LIC. innocuum caused decreased serum progesterone and follicular arrest in female mice. C_LIO_LIC. innocuum is a causal factor of progesterone resistance in women taking progesterone. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/585140v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@14cceaborg.highwire.dtl.DTLVardef@1946432org.highwire.dtl.DTLVardef@13e46d2org.highwire.dtl.DTLVardef@19b9a25_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG In briefChen et al. identified Clostridium innocuum as a major species involved in gut progesterone metabolism, with epipregnanolone as the main product, and elucidated the molecular mechanisms. C. innocuum inactivates gut progesterone in female mice, leading to decreased circulating progesterone levels. C. innocuum is also a causal factor of follicular arrest. Levels of progesterone, an endogenous female hormone, increase after ovulation; progesterone is crucial in the luteal phase to maintain successful pregnancy and prevent early miscarriage. Both endogenous and exogenous progesterone are recycled between the liver and gut; thus, the gut microbiota regulate host progesterone levels by inhibiting enterohepatic progesterone circulation. Our data indicated Clostridium innocuum as a major species involved in gut progesterone metabolism in women with infertility. C. innocuum converts progesterone into the neurosteroid epipregnanolone (with negligible progestogenic activity). We purified and characterized the corresponding enzyme, namely NADPH-dependent 5{beta}-dihydroprogesterone reductase, which is highly oxygen sensitive and whose corresponding genes are prevalent in C. innocuum. Moreover, C. innocuum-administered female C57BL/6 mice (aged 7 weeks) exhibited decreased serum progesterone levels ([~]35%). Clostridium-specific antibiotics (metronidazole) restored low serum progesterone levels in these mice. Furthermore, prolonged C. innocuum administration (12 weeks) arrested ovarian follicular development in female mice. Cytological and histological analyses indicated that C. innocuum may cause luteal phase insufficiency and affect menstrual regularity. Our findings suggest C. innocuum as a causal factor of progesterone resistance in women taking progesterone.

microbiology↗

VHL loss enables immune checkpoint blockade therapy by boosting type I interferon response.

Despite a moderate mutation burden, clear cell renal cell carcinoma (ccRCC) responds well to immune checkpoint blockade (ICB) therapy. Here we report that loss-of-function mutations in the von Hippel-Lindau (VHL) gene, the most frequent in ccRCC, underlies its responsiveness to ICB therapy. We demonstrate that genetic knockout of the VHL gene enhanced the efficacy of anti-PD-1 therapy in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1 and HIF2 induced by VHL gene loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA (mtDNA), which triggered cGAS-STING activation and induced type I interferons. Our study thus provided novel mechanistic insights into the role of VHL gene loss in potentiating ccRCC immunotherapy.

cancer biology↗

A molecularly distinct cell type in the dmPAG regulates intermale aggression behaviors in mice

BackgroundThe periaqueductal gray (PAG) is a central hub for regulation of aggression, while little is known on the circuitry and molecular mechanisms that govern this regulation. We investigate the role of a distinct cell type, Tachykinin 2-expressing (Tac2+) neurons, located in the dorsomedial PAG (dmPAG), in modulating aggression in mice. MethodsWe combined activity mapping, in vivo Ca2+ recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. ResultsWe reveal that the dmPAGTac2 neurons were selectively activated during fighting behaviors. Activation of the dmPAGTac2 neurons evoked, while inhibition or genetic ablation of the dmPAGTac2 neurons suppressed fighting behaviors. TRAP profiling of dmPAGTac2 neurons revealed that fighting behaviors specifically induced enrichment of serotonin-associated transcripts to the dmPAGTac2 neurons. Last, we validated these findings by selectively delivering pharmacological agent into the dmPAG and reversed the behavioral outcomes induced by chemogenetic manipulation. ConclusionsWe identify that the dmPAGTac2 neuron can regulate mouse aggressive behavior and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/562724v3_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@afc876org.highwire.dtl.DTLVardef@91e355org.highwire.dtl.DTLVardef@1e41e43org.highwire.dtl.DTLVardef@17ef3f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Adaptive Functions of Structural Variants in Human Brain Development

Quantifying the structural variants (SVs) in nonhuman primates could provide a niche to clarify the genetic backgrounds underlying human-specific traits, but such resource is largely lacking. Here, we report an accurate SV atlas in a population of 562 rhesus macaques, verified by two public SV benchmarks, an inhouse benchmark of eight macaque genomes with long-read sequencing and another inhouse benchmark of one macaque genome with whole-genome assembly. This accurate, quantitative SV map indicates stronger purifying selection on inversions, one type of poorly-clarified SVs to date, especially for those located on regulatory regions, suggesting a strategy for prioritizing inversions with the most important functions. Based on the distribution and the evolutionary features of these inversions in macaque population, we then identified 75 human-specific inversions, clarified their functional effects and prioritized them. Notably, the top-ranked inversions have substantially shaped the human transcriptome, through their dual-effects of reconfiguring the ancestral genomic architecture and introducing regional mutation hotspots at the inverted regions. As a proof-of-concept, we linked APCDD1, located on one of these inversions with the highest rank score and downregulated in human brains, to neuronal maturation. The accumulation of human-specific mutations on its promoter region, accelerated by the formation of the inversion, contributed to the decreased expression in humans. Notably, the overexpression of APCDD1 could accelerate the neuronal maturation, while its depletion in mice delays the neuronal maturation. This study thus highlights the contribution of SVs, especially the inversions, to the distinct features in human brain development.

evolutionary biology↗

Genetic tools for the study of the mangrove killifish, Kryptolebias marmoratus, an emerging vertebrate model for phenotypic plasticity

Kryptolebias marmoratus (Kmar), a teleost fish of the order Cyprinodontiformes, has a suite of unique phenotypes and behaviors not observed in other fishes. Many of these phenotypes are discrete and highly plastic -varying over time within an individual, and in some cases reversible. Kmar and its interfertile sister species, K. hermaphroditus, are the only known self-fertile vertebrates. This unusual sexual mode has the potential to provide unique insights into the regulation of vertebrate sexual development, and also lends itself to genetics. Kmar is easily adapted to the lab and requires little maintenance. However, its internal fertilization and small clutch size limits its experimental use. To support Kmar as a genetic model, we compared alternative husbandry techniques to maximize recovery of early cleavage-stage embryos. We find that frequent egg collection enhances yield, and that protease treatment promotes the greatest hatching successes from diapause. We completed a forward mutagenesis screen and recovered several mutant lines that serve as important tools for genetics in this model. Several will serve as useful viable recessive markers for marking crosses. Importantly, the mutant kissylips lays embryos at twice the rate of wild-type. Combining frequent egg collection with the kissylips mutant background allows for a substantial enhancement of early embryo yield. These improvements were sufficient to allow experimental analysis of early development and the successful mono- and bi-allelic targeted knockout of an endogenous tyrosinase gene with CRISPR/Cas9 nucleases. Collectively, these tools will facilitate modern developmental genetics in this fascinating fish, leading to future insights into the regulation of plasticity.

developmental biology↗

6mA-Sniper: Quantifying 6mA Sites in Eukaryotes at Single-Nucleotide Resolution

While N6-methyldeoxyadenine (6mA) modification has been linked to fundamental regulatory processes in prokaryotes, its prevalence and functional implications in eukaryotes are controversial. Here, we report 6mA-Sniper to quantify 6mA sites in eukaryotes at single-nucleotide resolution. With 6mA-Sniper, we delineated an accurate 6mA profile in C. elegans with 2,034 sites, significantly enriched on sequences of [GC]GAG motif. Twenty-six of 39 6mA events with MnlI restriction endonuclease sites were experimentally verified, demonstrating the feasibility of this method. Notably, the enrichment of these 6mA sites on a specific sequence motif, their within-population conservation and the combinatorial patterns, and the selective constrains on them jointly support an active model for the shaping of the profile by some undiscovered methyltransferases. In a joint study (Cell Research, in revision), Ma et al. reported METL-9 as a new methyltransferase in shaping the basal and stress-dependent 6mA profile in C. elegans. Notably, with the 6mA profile identified by 6mA-Sniper at single-nucleotide resolution, we found that the levels of 6mAs are significantly decreased in strains with the removal of METL-9 (METL-9 KO-OP50), while generally increased after P. aeruginosa infection, further verified the efficiency of 6mA-Sniper in accurately pinpointing 6mA sites. Moreover, for the regions marked by 998 6mA sites emerged specifically after the infection, we identified an enrichment of the upregulated genes after the infection. The gene upregulations are likely mediated through a mutual exclusive crosstalk between 6mA and H3K27me3 modification, as supported by their co-occurrence, and the signal of increased H3K27me3 at regions marked by 6mAs depleted in METL-9 KO-OP50 strains. Notably, in different C. elegans strains, the cross-strain genetic variants removing 6mA sites are associated with the decreased expression of their host genes, and the removal of two randomly-selected 6mA events with genome editing directly decreased the expression of their host genes. We thus highlight 6mA regulation as a previously-neglected regulator of transcriptome in eukaryotes.

genomics↗

Effects of substrate on shrimp growth, water quality and bacterial community in the biofloc system nursing Penaeus vannamei postlarvae at a salinity of 5{per thousand}

This study aimed to investigate the effects of substrate on water quality, shrimp growth and bacterial community in the biofloc system with a salinity of 5{per thousand}. Two treatments, biofloc system with (sB) or without (nB) addition of elastic solid packing filler (nylon) as substrate, were set up. Penaeus vannamei postlarvae (PL, ~ stage 15) were stocked at a density of 4000 PL m-3 in each treatment with triplicates for a 28-days culture experiment, taking glucose as carbon source (C:N 15:1). Results showed that the survival rate (96.3{+/-}3.6%), FCR (0.76{+/-}0.06) and productivity (1.54{+/-}0.12 kg m-3) in sB treatment were significantly better than those in nB treatment (81.0{+/-}7.1%, 0.98{+/-}0.08 and 1.14{+/-}0.09 kg m-3, P<0.05). All water parameters were in the recommended ranges. Substrate showed significant effect on TAN, TSS, turbidity, biofloc volume, pH and carbonate alkalinity (P < 0.05). Actinobacteria (4.0-22.7%), Bacteroidetes (10.4-33.5%), Firmicutes (0.2-11.2%), Planctomycetes (4.0-14.9%) and Proteobacteria (29.4-59.0%) were the most dominant phyla for both treatments. However, the bacterial community in sB treatment showed to be significantly different from that in nB treatment (Jaccard distance 0.94{+/-}0.01, P=0.001). Substrate showed significant effects on Shannon, Heip, Pielou and Simpson index, as well as relative abundances of Actinobacteria, Bacteroidetes and Planctomycetes (P < 0.05). The results suggested that addition of substrate affected the shrimp growth, water quality and bacterial community in the biofloc system nursing P. vannamei PL with a 5{per thousand} salinity.

zoology↗

CHDbase: A Comprehensive Knowledgebase for Congenital Heart Disease-related Genes and Clinical Manifestations

Congenital heart disease (CHD) is the most common cause of major birth defects, with a prevalence of 1%. Although an increasing number of studies reporting the etiology of CHD, the findings scattered throughout the literature are difficult to retrieve and utilize in research and clinical practice. We therefore developed CHDbase, an evidence-based knowledgebase with CHD-related genes and clinical manifestations manually curated from 1114 publications, linking 1124 susceptibility genes and 3591 variations to more than 300 CHD types and related syndromes. Metadata such as the information of each publication and the selected population and samples, the strategy of studies, and the major findings of study were integrated with each item of research record. We also integrated functional annotations through parsing ~50 databases/tools to facilitate the interpretation of these genes and variations in disease pathogenicity. We further prioritized the significance of these CHD-related genes with a gene interaction network approach, and extracted a core CHD sub-network with 163 genes. The clear genetic landscape of CHD enables the phenotype classification based on the shared genetic origin. Overall, CHDbase provides a comprehensive and freely available resource to study CHD susceptibility, supporting a wide range of users in the scientific and medical communities. CHDbase is accessible at http://chddb.fwgenetics.org/.

genetics↗

Bacterial composition and inferring function profiles in the biofloc system rearing Litopenaeus vannamei postlarvae at a low salinity

This study aimed to investigate the bacterial composition and inferring function profiles in the biofloc system rearing Litopenaeus vannamei postlarvae (PL) at a low salinity condition. PL (~ stage 15) were stocked in four parallel tanks filled in water with a salinity of 5.0{per thousand} at a density of 4000 individuals per m3 for a 28-days culture experiment, during which glucose was added as carbon source with a C:N of 20:1. At the end of experiment, water was sampled from each tank and pooled to extract microbial DNA for high-throughput sequencing of V3-V4 region of 16S rRNA gene. Results showed that the bacterial community at 28 d was dominated by phyla of Proteobacteria (45.8%), Bacteroidetes (21.1%), Planctomycetes (13.5%), Chlamydiae (10.3%) and Firmicutes (6.8%). A proportion of 81% inferring KEGG functions of this bacterial community associated with metabolism. Among functions relating to nitrogen metabolism, 48.5% were involved in the conversion of ammonia to glutamate, but the proportion of those involved in transformation among ammonia, nitrite and nitrate was 18.0% in total, inferring higher protein-synthesis but lower inorganic nitrogen-transformation capacities of the bacterial community. At the same time (28 d), high levels of total nitrogen (231.3{+/-}6.0 mg L-1) and biofloc (127.0{+/-}63.0 mL L-1), but low concentrations of ammonia (0.04{+/-}0.01 mg L-1), nitrite (0.2{+/-}0.1 mg L-1) and nitrate (12.9{+/-}2.5 mg L-1) were observed. The results supply a novel insight for understanding the function of bacterial community in the biofloc system nursing L. vannamei PL at a low salinity.

systems biology↗

Social experience alters different types of learning abilities controlled by distinct brain nuclei in Kryptolebias marmoratus

Fighting experiences strongly influence aggressive behavior and physiology (winner-loser effects). These effects are conserved from invertebrates to vertebrates, but the underlying mechanisms remain unclear. Recent studies indicate that the brain social decision-making network (SDN) plays a key role in guiding experience-induced behavioral change. Also, while most studies have focused on how winning and losing experiences alter aggression, growing evidence points to these experiences driving multiple behavioral effects, including changes in the ability to learn. In mangrove rivulus fish (Kryptolebias marmoratus), we discovered that single winning experiences significantly improved spatial learning but not risk-avoidance learning, whereas single losing experiences drove the exact opposite to occur. These results provide strong evidence that winning and losing modulate diverse behaviors served by key nodes within the SDN, specifically the dorsolateral pallium (Dl; fish homolog to mammalian hippocampus, which serves spatial learning) and dorsomedial pallium (Dm; fish homolog to mammalian basolateral amygdala, which responds to fear). We therefore quantified whole-proteome expression within the forebrain (where Dm and Dl are located) of adult rivulus with divergent social experiences. We discovered 23 proteins were significantly differentially expressed in the forebrains of winners and losers. Differentially expressed proteins in losers related to modulation of cellular processes, apoptosis and learning while those in winners related to neuronal plasticity, neuroendocrine homeostasis, energy utilization, and learning. These results imply that winner-loser effects might be governed by very different patterns of protein expression, which could explain why winners and losers show such pronounced differences in behavioral performance. Significance StatementSocial interactions permeate the daily lives of most animals and often result in changes in behavior for all parties. This implies that social experiences reorganize the brain in ways that promote the expression of alternative behaviors, or that help individuals cope with the outcome of such interactions. But how do aggressive interactions sculpt the brain at the molecular level? We used an emerging model organism, Kryptolebias marmoratus, to examine whether experiences modulate learning ability and then probe the potential neural mechanisms underlying these behavioral changes. We discovered that single winning and losing experiences dramatically altered spatial learning and risk-avoidance learning, respectively, indicating that winning and losing experiences have markedly different effects on the brain and cognitive processes. ClassificationBiological Sciences, Ecology

animal behavior and cognition↗

Cholecystokinin-like Peptide Mediates Satiety by Inhibiting Sugar Attraction

Feeding is essential for animal survival and reproduction and is regulated by both internal states and external stimuli. However, little is known about how internal states influence the perception of external sensory cues that regulate feeding behavior. Here, we investigated the neuronal and molecular mechanisms behind nutritional state-mediated regulation of gustatory perception in control of feeding behavior in the brown planthopper and Drosophila. We found that feeding increases the expression of the cholecystokinin-like peptide, sulfakinin (SK), and the activity of a set of SK-expressing neurons. Starvation elevates the transcription of the sugar receptor Gr64f and SK negatively regulates the expression of Gr64f in both insects. This Gr64f regulation is by direct action of SK neurons on Gr64f-expressing neurons of the proboscis and proleg tarsi that co-express the SK receptor CCKLR-17D3. Our findings thus demonstrate how nutritional state induces peptide signaling to modulate sweet perception and thereby feeding behavior.

neuroscience↗

Novel enzyme for dimethyl sulfide-releasing in bacteria reveals a missing route in the marine sulfur cycle

Dimethylsulfoniopropionate (DMSP) is an abundant and ubiquitous organosulfur molecule and plays important roles in the global sulfur cycle. Cleavage of DMSP produces volatile dimethyl sulfide (DMS), which has impacts on the global climate. Multiple pathways for DMSP catabolism have been identified. Here we identified yet another novel pathway, the ATP DMSP lysis pathway. The key enzyme, AcoD, is an ATP-dependent DMSP lyase. AcoD belongs to the acyl-CoA synthetase superfamily, which is totally different from other DMSP lyases, showing a new evolution route. AcoD catalyses the conversion of DMSP to DMS by a two-step reaction: the ligation of DMSP with CoA to form the intermediate DMSP-CoA, which is then cleaved to DMS and acryloyl-CoA. The novel catalytic mechanism was elucidated by structural and biochemical analyses. AcoD is widely distributed in many bacterial lineages including Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria and Firmicutes, revealing this new pathway plays important roles in global DMSP/DMS cycles.

ecology↗

Diversity Across the Pancreatic Ductal Adenocarcinoma Disease Spectrum Revealed by Network-Anchored Functional Genomics

Cancers are highly complex ecosystems composed of molecularly distinct sub-populations of tumor cells, each exhibiting a unique spectrum of genetic features and phenotypes, and embedded within a complex organ context. To substantially improve clinical outcomes, there is a need to comprehensively define inter- and intra-tumor phenotypic diversity, as well as to understand the genetic dependencies that underlie discrete molecular subpopulations. To this end, we integrated CRISPR-based co-dependency annotations with a tissue-specific co-expression network developed from patient-derived models to establish CoDEX, a framework to quantitatively associate gene-cluster patterns with genetic vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). Using CoDEX, we defined multiple prominent anticorrelated gene-cluster signatures and specific pathway dependencies, both across genetically distinct PDAC models and intratumorally at the single-cell level. Of these, one differential signature recapitulated the characteristics of classical and basal-like PDAC molecular subtypes on a continuous scale. Anchoring genetic dependencies identified through functional genomics within the gene-cluster signature defined fundamental vulnerabilities associated with transcriptomic signatures of PDAC subtypes. Subtype-associated dependencies were validated by feature-barcoded CRISPR knockout of prioritized basal-like-associated genetic vulnerabilities (SMAD4, ILK, and ZEB1) followed by scRNAseq in multiple PDAC models. Silencing of these genes resulted in a significant and directional clonal shift toward the classical-like signature of more indolent tumors. These results validate CoDEX as a novel, quantitative approach to identify specific genetic dependencies within defined molecular contexts that may guide clinical positioning of targeted therapeutics.

cancer biology↗

Single cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

Germ cells are vital for reproduction and heredity. However, the mechanisms underlying female germ cell development in primates, especially in late embryonic stages, remain elusive. Here, we performed single-cell RNA sequencing of 12471 cells from whole fetal ovaries, and explored the communications between germ cells and niche cells. We depicted the two waves of oogenesis at single cell resolution and demonstrated that progenitor theca cells exhibit similar characteristics to Leydig cells in fetal monkey ovaries. Notably, we found that ZGLP1 displays differentially expressed patterns between mouse and monkey, which is not overlapped with NANOG in monkey germ cells, suggesting its role in meiosis entry but not in activating oogenic program in primates. Furthermore, the majority of germ cell clusters that highly expressed PRDM9 and SPO11 might undergo apoptosis after cyst breakdown, leading to germ cell attrition. Overall, our work provides new insights into the molecular and cellular basis of primate fetal ovary development at single-cell resolution.

developmental biology↗