cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions.

The use of pharmacological chaperones (PCs) to stabilize specific enzymes and impart a therapeutic benefit is an emerging strategy in drug discovery. However, designing molecules that can bind optimally to their targets at physiological pH remains a major challenge. Our previous study found that dibasic polyhydroxylated pyrrolidine 5 exhibited superior pH-selective inhibitory activity and chaperoning activity for human α-galactosidase A (α-Gal A) compared with its monobasic parent molecule, 4. To further investigate the role of different C-2 moieties on the pH-selectivity and protecting effects of these compounds, we designed and synthesized a library of monobasic and dibasic iminosugars, screened them for α-Gal A-stabilizing activity using thermal shift and heat-induced denaturation assays, and characterized the mechanistic basis for this stabilization using X-ray crystallography and binding assays. We noted that the dibasic iminosugars 5 and 20 protect α-Gal A from denaturation and inactivation at lower concentrations than monobasic or other N-substituted derivatives; a finding attributed to the nitrogen on the C-2 methylene of 5 and 20, which forms the bifurcated salt bridges (BSBs) with two carboxyl residues, E203 and D231. Additionally, the formation of BSBs at pH 7.0 and the electrostatic repulsion between the vicinal ammonium cations of dibasic iminosugars at pH 4.5 are responsible for their pH-selective binding to α-Gal A. Moreover, compounds 5 and 20 demonstrated promising results in improving enzyme replacement therapy and exhibited significant chaperoning effects in Fabry cells. These findings suggest amino-iminosugars 5 and 20 as useful models to demonstrate how an additional exocyclic amino group can improve their pH-selectivity and protecting effects, providing new insights for the design of pH-selective PCs.

Hexanucleotide repeat expansion in C9ORF72 (C9) is the most prevalent mutation among amyotrophic lateral sclerosis (ALS) patients. The patients carry over ~30 to hundreds or thousands of repeats translated to dipeptide repeats (DPRs) where poly-glycine-arginine (GR) and poly-proline-arginine (PR) are most toxic. The structure-function relationship is still unknown. Here, we examined the minimal neurotoxic repeat number of poly-GR and found that extension of the repeat number led to a loose helical structure disrupting plasma and nuclear membrane. Poly-GR/PR bound to nucleotides and interfered with transcription. We screened and identified a sulfated disaccharide that bound to poly-GR/PR and rescued poly-GR/PR-induced toxicity in neuroblastoma and C9-ALS-iPSC-derived motor neurons. The compound rescued the shortened life span and defective locomotion in poly-GR/PR expressing Drosophila model and improved motor behavior in poly-GR-injected mouse model. Overall, our results reveal structural and toxicity mechanisms for poly-GR/PR and facilitate therapeutic development for C9-ALS.

Stem cell niche and root meristem size are maintained by signaling networks of a peptide hormone, Root Meristem Growth Factor 1 (RGF1). How RGF1 regulates root meristem development is an essential question for understanding stem cell function. Recently, we reported that RGF1 controls root development by modulating Reactive Oxygen Species (ROS) distributions along Arabidopsis root developmental zones. RGF1 increased superoxide (O2-) levels in the meristematic zone (youngest stage). In contrast, hydrogen peroxide (H2O2) distributions started to be reduced in the elongation zone (transition stage) and the differentiation zone (mature stage). The root meristem master regulator (PLT2) protein stability is modulated by these two ROS altered by RGF1. However, the mechanism of how ROS modulates the PLT2 protein stability remained obscure. In this work, we discovered the regulation and modification mechanism of the PLT2 protein stability through ROS under the RGF1 signal. 1) We showed that one of the cysteines of the PLT2 played a pivotal role in modulating their stability through ROS. Substitution of the 212th cysteine enhanced the PLT2 protein stability through ROS and generated a larger root meristem compared with the native form PLT2 protein. 2) We detected S-sulfenylation of the PLT2 protein after H2O2 treatment. H2O2 treatment reduced the native form PLT2 protein levels but not the cysteine substitution form of PLT2 suggesting that modification of PLT2 by H2O2 modulate the PLT2 stability. H2O2 oxidizes a free thiol of cysteine and generates sulfenylated cysteine. We detected more S-sulfenylation of PLT2 after the H2O2 treatment compared with the Mock treatment. 3) We found the downstream gene regulation mechanisms of the cysteine substitution form PLT2 protein. The cysteine replacement form-PLT2 line generated a larger root meristem and had broader localization of the protein. The accumulated PLT2 protein with a cysteine substitution upregulated the downstream genes related to cell proliferation and reduced the gene expression of the differentiation genes. The transcriptome analysis showed the downstream gene regulation mechanism of the cysteine substitution line.

Salvia miltiorrhiza is used in Eastern medicine to treat cardiovascular diseases which contains water‐soluble and lipid‐soluble bioactive compounds, including phenolic acids and diterpenoid tanshinones, respectively; the latter gives its root surface a red color. Several studies have sought to inactivate genes related to the bioactive compounds in S. miltiorrhiza by introducing CRISPR/Cas‐based genome editing cassette via Agrobacterium‐mediated hairy root transformation. Nevertheless, chimaeras in transformation and removing transgenes in plants with high‐genetic heterozygosity like S. miltiorrhiza present significant challenges. We established a protoplast regeneration system for S. miltiorrhiza using either sgRNA/Cas9 ribonucleoprotein (RNP) complexes or plasmids carrying CRISPR/Cas9 system genes to target one or multiple sites for editing the genes through a single transfection event. Seven transcription factor genes-MYB28, MYB36, MYB39, MYB100, basic leucine zipper 1 (bZIP1), bZIP2 and MYB98 were selected as targets for mutagenesis. bZIP1 is a negative regulator of tanshinone biosynthesis and a positive regulator of phenolic acid biosynthesis, whereas bZIP2 is a negative regulator of phenolic acid biosynthesis. Protoplast regenerated plants harboring knockout mutations of either gene had deeper red roots, with higher levels of lipid‐soluble compounds. We demonstrated high‐efficiency gene editing in various transcription factor genes in S. miltiorrhiza through a single transfection event using transgene‐free CRISPR/Cas9 reagents in protoplasts, and regeneration of knockout plants through a newly established system, which requires 6 months from transfected protoplasts to whole plants.

This article systematically summarizes the diversity and broad bioactivities of bacterial-derived polyyne compounds, including antibacterial, antifungal, and antiviral properties, while exploring their potential applications in biotechnology and medicine. Additionally, it provides an in-depth analysis of the structures and biosynthetic pathways of bacterial polyyne biosynthetic gene clusters (BGCs), demonstrating how core genes and tailoring enzymes work together to produce and diversify these compounds. The article also addresses the challenges of instability in polyyne production, proposing strategies such as metabolic engineering and protein engineering to optimize their stable production. Furthermore, utilizing genome mining techniques, it identifies new resources of bacterial polyyne BGCs, paving the way for the discovery of novel polyyne compounds. Finally, the article highlights the potential of bacterial polyynes in antifungal treatments, cancer therapy, and other disease management applications, emphasizing the need for further research into their toxicity and application safety, thereby laying a solid foundation for innovative applications in biotechnology and medicine.

As an essential nutrient element, phosphorus (P) is primarily acquired and translocated as inorganic phosphate (Pi) by plant roots. Pi is often sequestered in the soil and becomes limited for plant growth. Plants have developed a sophisticated array of adaptive responses, termed P starvation responses (PSRs), to cope with P deficiency by improving its external acquisition and internal utilization. Over the past two to three decades, remarkable progress has been made toward understanding how plants sense and respond to changing environmental P. This review provides an overview of the molecular mechanisms that regulate or coordinate PSRs, emphasizing P transport, sensing and signaling. We present the major players and regulators responsible for Pi uptake and translocation. We then introduce how P is perceived at the root tip, how systemic P signaling is operated, and the mechanisms by which the intracellular P status is sensed and conveyed. Additionally, the recent exciting findings about the influence of P on plant-microbe interactions are highlighted. Finally, the challenges and prospects concerning the interplay between P and other nutrients and strategies to enhance P utilization efficiency are discussed. Insights obtained from this knowledge may guide future research endeavors in sustainable agriculture.

Epithelial cell adhesion molecule (EpCAM) is known to widely be expressed in varieties of solid tumors and tumor-initiating cells thereby fuelling cancer progression via participating in several critical signaling pathways. Such participation distinctly includes the extracellular (EpEX) as well as the intracellular (EpICD) domains of the EpCAM. A recent study indicated EpICD functions as a transcriptional co-factor for the receptors of Wnt signaling, a key pathway involved in multitudes of cancer-associated functionalities including colorectal cancer (CRC) pathogenesis. In addition, the report showed that a humanized form of EpCAM neutralizing antibody hEpAb2-6 successfully blocks EpICD-mediated Wnt receptor expression establishing a possible therapeutics for the treatment of colorectal cancer. Previous studies show that Wnt signaling is critical in CRC progression wherein higher Wnt receptor expressions have been associated with robust Wnt activity. In this study, use CRC patient derived organoids (PDOs), xenografts (PDX) and various CRC cell line derived xenografts to show EpICD actively interacts with the promoters of Wnt receptors (FZD6 and LRP5/6) upregulating transcription therefore promoting Wnt activity. In addition, activation of Wnt signaling induces cleavage activity of metalloprotease γ-secretase in order to augment further shedding of EpICD, establishing a positive-feedback-loop. In this line, hEpAb2-6 treatment attenuates shedding of EpICD increasing its membrane accumulation therefore blocking corresponding nuclear translocation. As a result, hEpAb2-6 successfully decreases the expressions of the Wnt receptors impeding the signaling processing. Thus, the antibody potentiates therapeutic benefit in various PDX and orthotopic models of human CRC increasing the overall survivals of the animals. Whilst the study highlights the mechanistic insights of EpICD mediated Wnt receptor expression, it establishes the relevant efficacies of hEpAb2-6 as a potential therapeutic antibody for the treatment of CRC.

SARS-CoV-2 has been continuously evolving which hampers the effectiveness of current vaccines against COVID-19. Monoclonal antibodies (mAbs) targeting to the spike protein can be used to treat patients at risk of severe COVID-19. Therefore, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 various (sub)variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes in lung tissues enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.

Chronic hepatitis B (CHB) is a leading cause of hepatocellular carcinoma (HCC) worldwide. In the natural history of CHB, the HBeAg-positive phase is a critical period for the transition from immune tolerance to immune activation. Patients in the immune-tolerant phase typically exhibit high viral loads and normal liver function, they are traditionally considered to have a lower risk of HCC. However, there is a lack of precise non-invasive markers to stratify HCC risk during this phase. HBsAg concentration, an essential marker of HBV infection, has been widely used to assess disease risk in HBeAg-negative patients with low viral loads, but its longitudinal changes and association with HCC risk in HBeAg-positive patients remain unclear. This study analyzed 319 untreated HBeAg-positive CHB patients from the REVEAL-HBV cohort to investigate the impact of longitudinal HBsAg changes on HCC risk. Using trajectory modeling, patients were classified into two groups: the \"persistently high HBsAg group\" (HBsAg levels ≥10⁴ IU/mL) and the \"non-stationary group.\" Results showed that the annual incidence rate of HCC was significantly lower in the persistently high HBsAg group compared to the non-stationary group (0.37% vs. 1.16%), with a similarly lower incidence of liver cirrhosis. Multivariate analysis identified genotype C, age over 40, and non-stationary HBsAg patterns as independent risk factors for HCC. Additionally, in the persistently high HBsAg group, the basal core promoter (BCP) mutation was significantly associated with increased HCC risk. This study highlights the utility of HBsAg trajectory patterns for stratifying HCC risk in HBeAg-positive patients. Persistently high HBsAg levels may indicate immune tolerance and lower HCC risk, providing a practical tool for identifying high-risk patients and guiding clinical management.

A collaborative study led by Dr. Ruey-Bing Yang from Academia Sinica and first author Dr. Yuh-Charn Lin from Taipei Medical University has revealed that the membrane protein SCUBE2 (Signal peptide-CUB-epidermal growth factor-like domain-containing protein 2) plays a critical role in maintaining vascular barrier function during inflammation. Conducted in collaboration with Dr. Ya-Jen Chang from Academia Sinica and Professor Chun-Min Lo from National Yang Ming Chiao Tung University, highlights how SCUBE2 stabilizes endothelial cell adherens junctions to prevent vascular leakage. This research, published on June 13, 2024, in Cardiovascular Research, suggests new therapeutic strategies for inflammation-related diseases. The study demonstrates that SCUBE2 interacts with VE-cadherin and VE-protein tyrosine phosphatase (VE-PTP) in endothelial cells to reduce endothelial barrier dysfunction during inflammation. The research team found that mice with SCUBE2 gene knockout exhibited increased vascular leakage after local injection of histamine or vascular endothelial growth factor and were more susceptible to systemic inflammatory responses induced by acute endotoxin or influenza virus. Conversely, mice overexpressing SCUBE2 showed enhanced protective effects. In summary, the study reveals that SCUBE2 promotes vascular integrity by recruiting VE-PTP to dephosphorylate VE-cadherin and stabilize endothelial cell adherens junctions. Additionally, the data suggest that overexpression or upregulation of SCUBE2 could help prevent vascular leakage in inflammatory diseases. This discovery provides a new potential therapeutic target for a range of inflammation-related human pathologies.

The transition from natal downs for thermoregulation to juvenile feathers for flight is an environmental adaptation in avian evolution. As the regulatory switches for this transition are mostly unknown, we conducted gene regulatory analysis and functional perturbations in developing feathers. We elucidated four switches. First, extracellular matrix reorganization leads to peripheral pulp formation, mediating epithelial-mesenchymal interactions for branching morphogenesis. Second, α-SMA compartmentalizes dermal papilla stem cells for feather renewal cycling. Third, LEF1 works as a key hub of Wnt signaling to build rachis and convert radial downy to bilateral symmetry. Fourth, scale keratins strengthen feather sheath with SOX14 as the epigenetic regulator. These switches are largely conserved in chicken (precocial) and zebra finch (altricial), two distantly related species, suggesting their conservation in all birds.

Fishery overexploitation has been known to profoundly impact the life history traits of marine species. We found compelling evidence of significant changes in the age composition, growth rates, and habitat of the critically endangered large yellow croaker over three distinct geological periods: the Pleistocene, Holocene, and the present day. Through analysis of otoliths, our study reveals that modern large yellow croakers exhibit a younger age structure and faster growth rates compared to their historical counterparts. Notably, the environmental habitat of these croakers has also shifted, with historical populations inhabiting a broader range of environments, including brackish and inshore waters, unlike the strictly marine habitats observed today. Our findings illustrate how historical exploitation and environmental changes have drastically influenced the life history traits of this once-abundant species, providing crucial insights for conservation efforts.

Due to the prevailing conditions of perpetual darkness, low temperatures, and high pressures, the deep sea has long considered a realm devoid of rhythms. However, recent studies have uncover rhythmic activities in deep-sea organisms, challenging the conventional belief in the deep sea's arrhythmic nature. Nevertheless, understanding the environmental cues that drive the rhythmic activities of deep-sea animals remains a paramount question in chronobiology.To explore the dynamics of deep-sea habitats, this study conducted a comprehensive analysis of year-long underwater recordings obtained off Minamitorishima Island in the Pacific Ocean. The results showed that even at a depth of 5552 meters, the hydrophone captured a diverse array of biological sounds. Temporal analysis further revealed evident diurnal and seasonal patterns in the abyssal plain soundscape. In particular, after sunset, biological choruses influenced the soundscape, giving rise to a phenomenon called "acoustic twilight." These choruses are likely associated with mid-water fish performing diel vertical migration. As they traverse the aphotic zone, these signals might function as a natural timekeeper, enabling deep-sea organisms to perceive day-night rhythms. This study also unveiled a diverse array of cetacean sounds during nighttime. These acoustic signals, along with associated vibrations, could offer environmental cues, aiding deep-sea scavengers in locating food resources such as debris and whale falls.This study underscores the ever-changing nature of the abyssal plain soundscape. Underwater sound serves as a vector for connecting the surface water and the aphotic zone, providing deep-sea organisms with temporal cue for behavioral and physiological adaptation. These findings chart a new course for investigating the chronobiology of deep-sea animals, marking a significant milestone in this field.

This study offers valuable insights into the dynamic relationship between shallow earthquakes and hydrothermal vent activity, illustrating how seismic events can trigger significant changes in marine ecosystems. Through an innovative blend of physicochemical measurements and underwater acoustic monitoring, the results reveal distinct active and silent venting phases, each characterized by unique chemical and acoustic patterns. This long-term time series, a departure from traditional short-term observations, highlights how seismic activity drives rapid environmental shifts, influencing both water chemistry and underwater soundscapes. Understanding this connection is crucial for safeguarding fragile hydrothermal vent ecosystems. Moving forward, continuous, multi-variable monitoring systems will be essential for enabling real-time responses to environmental changes and guiding informed, long-term management strategies.

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. A research team led by Dr. Yin-Ru Chiang at the Biodiversity Research Center, Academia Sinica, and Mei-Jou Chen at the College of Medicine, National Taiwan University, have identified 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). The study purified and characterized the corresponding enzyme, namely NADPH-dependent 5β-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 plasma progesterone levels (~35%). Clostridium-specific antibiotics (metronidazole) restored low plasma 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. The research findings suggest C. innocuum as a causal factor of progesterone resistance in women taking progesterone. The research has been published on November 7, 2024 in Gut Microbes.

Mountain ranges contain high concentrations of endemic species and are indispensable refugia for lowland species that are facing anthropogenic climate change. Forecasting biodiversity redistribution hinges on assessing whether species can track shifting isotherms as the climate warms. However, a global analysis of the velocities of isotherm shifts along elevation gradients is hindered by the scarcity of weather stations in mountainous regions5. Here we address this issue by mapping the lapse rate of temperature (LRT) across mountain regions globally, both by using satellite data (SLRT) and by using the laws of thermodynamics to account for water vapour6 (that is, the moist adiabatic lapse rate (MALRT)). By dividing the rate of surface warming from 1971 to 2020 by either the SLRT or the MALRT, we provide maps of vertical isotherm shift velocities. We identify 17 mountain regions with exceptionally high vertical isotherm shift velocities (greater than 11.67 m per year for the SLRT; greater than 8.25 m per year for the MALRT), predominantly in dry areas but also in wet regions with shallow lapse rates; for example, northern Sumatra, the Brazilian highlands and southern Africa. By linking these velocities to the velocities of species range shifts, we report instances of close tracking in mountains with lower climate velocities. However, many species lag behind, suggesting that range shift dynamics would persist even if we managed to curb climate-change trajectories. Our findings are key for devising global conservation strategies, particularly in the 17 high-velocity mountain regions that we have identified.

Biodiversity is threatened by climate and land-use change, but their synergistic effects and underlying mechanisms remain poorly understood. This study tested two competing hypotheses about species' realized thermal niche: the 'Fixed Niche Breadth' and the 'Habitat Loss - Allee Effect' hypotheses. The first hypothesis suggests that the thermal niche of a species remains constant despite fluctuations in population density caused by land-use change, with environmental synergistic effects arising primarily from the reduced availability of climatically suitable habitats. Conversely, the second hypothesis proposes that land-use change narrows a species' realized niche by reducing population density, as the Allee effect reduces individual fitness at unfavorable temperatures. We developed an individual-based theoretical model incorporating the Allee effect and considered the burying beetle (Nicrophorus nepalensis) in Taiwan as our study organism. The study sites included two elevation gradients in Mt. Hehuan: one in an intact forest and one in a human-modified landscape with significant forest loss. The results supported the model predictions: forest loss in the landscape reduced burying beetle population density, leading to smaller cooperative groups and consequently limiting their ability to compete with blowflies in warmer environments, ultimately leading to a contraction of their realized thermal niche. These findings support the 'Habitat Loss Allele Effect' hypothesis and deepen our understanding of species' vulnerability to combined climate and land-use change threats. The study highlights the importance of considering the demographic and behavioral consequences of land use changes when assessing these environmental challenges.

Nest building is a vital behavior exhibited during breeding in birds, and is possibly induced by environmental and social cues. Although such behavioral plasticity has been hypothesized to be controlled by adult neuronal plasticity, empirical evidence, especially at the neurogenomic level, remains limited. Here, we aim to uncover the gene regu- latory networks that govern avian nest construction and examine whether they are associated with circuit rewiring. We designed an experiment to dissect this complex behavior into components in response to pair bonding and nest material acquisition by manipulating the presence of mates and nest materials in 30 pairs of zebra finches. Whole- transcriptome analysis of 300 samples from five brain regions linked to avian nesting behaviors revealed nesting- associated gene expression enriched with neural rewiring functions, including neurogenesis and neuron projection. The enriched expression was observed in the motor/sensorimotor and social behavior networks of female finches, and in the dopaminergic reward system of males. Female birds exhibited predominant neurotranscriptomic changes to initiate the nesting stage, while males showed major changes after entering this stage, underscoring sex-specific roles in nesting behavior. Notably, major neurotranscriptomic changes occurred during pair bonding, with minor changes during nest material acquisition, emphasizing social interactions in nest construction. We also revealed gene expression associated with reproductive behaviors and tactile sensing for nesting behavior. This study presents novel neurogenomic evidence supporting the hypothesis of adult neural plasticity underlying avian nest-construc- tion behavior. By uncovering the genetic toolkits involved, we offer novel insights into the evolution of animals’ in- nate ability to construct nests.

The factors influencing the microbial composition of corals can be divided into host factors and environmental factors. Host-specific physiological, biochemical, and immune conditions selectively favor the growth of certain microbes within the host. Meanwhile, environmental conditions, such as temperature, nutrients, and pH, influence the growth and colonization capacity of microbes within the coral. However, few studies have focused on the self-adaptive capabilities of coral-associated microbial communities, which can also play a role in shaping microbial composition and even affect the host itself. To investigate these factors, we conducted reciprocal transplantation experiments on the coral Stylophora pistillata between Bitou in northern Taiwan and Gongguan on Green Island. Both locations host corals of the same species, but half of each coral colony was relocated to the other site, while the other half remained in its original location. Monthly observations were made to track changes in the microbial community. Bitou and Gongguan are situated in subtropical and tropical regions, respectively, with distinct environmental conditions. We hypothesized that: (1) different environments would lead to distinct bacterial communities, which would gradually localize, with transplanted and native colonies becoming similar over time; (2) if host effects dominate, the microbial communities at different locations would remain similar despite environmental differences. The results showed that both host and environmental factors influence microbial composition, but environmental factors exert a stronger effect. Microbial communities differed significantly across environments. However, we observed certain resilient microbial groups that remained unchanged despite transplantation, suggesting they are unaffected by environmental shifts. Among these, Endozoicomonas bacteria stood out as a compelling example. Some Endozoicomonas bacteria changed following transplantation, indicating environmental influence, while others were present in corals from both locations initially, highlighting host effects. Notably, some Endozoicomonas bacteria exhibited robust resilience, unaffected by geography or time. These resilient microbes not only maintained their populations but also indirectly influenced other microbial groups and the host. In summary, this is the first study to emphasize the impact of the internal adaptive resilience of microbial communities on coral microbiomes, in addition to the well-documented influences of host and environmental factors.

In this study, we sought to understand how temperature affects the size variations among moths. We examined over 5,300 moths, representing 680 species, collected at 13 locations in Taiwan across diverse climate conditions.We found that smaller moths are less common in colder environments. This could be attributed to the incapability of small moths to stay warm or withstand food scarcity in such harsh conditions. More intriguingly, we also found that habitats where temperature fluctuates a lot throughout the year tend to host moths of various sizes, allowing the coexistence of both large and small moths. Plus, moths of the same species tend to maintain consistent sizes in these dynamic environments, indicating a high level of specialization. The diverse microhabitats available at different times and places in these areas might have enabled various species to occupy and specialize in distinct habitats.What does this all mean? Climate change is altering temperatures and seasonal patterns, which could reshape moth—and potentially other insect—communities. Since moths are vital food for many animals and pollinators for many plants, such changes could have a profound impact on the entire ecosystem. Our study uncovers the mechanisms shaping the composition of biological communities, providing valuable insights for conserving biodiversity in the face of climate change.

Have you ever heard of a fungus that helps plants digest insects? Carnivorous sundew plants (Drosera) use the sticky glands on their leaves to trap insects, and surprisingly, a helpful fungus assists in their digestion process! Researchers at the Biodiversity Research Center, led by Dr. Isheng Jason Tsai, discovered that the acidophilic fungus Acrodontium crateriforme is a crucial partner in the digestion of sundew plants. This fungus thrives on the glands of sundew leaves and significantly enhances the plant's ability to break down prey. Astonishingly, both the plant and the fungus adjust their gene expression to collaborate, secreting special enzymes that speed up digestion and aid in nutrient absorption. This extraordinary partnership reveals how plants and microbes can join forces in remarkable ways to survive and thrive. The findings of this research were published on August 1, 2024, in Nature Microbiology. This research was supported by the “Academia Sinica Investigator Award” and the “NSTC 2030 Cross-Generation Young Scholar Program.” The first author is Dr. Pei-Feng Sun from the TIGP Biodiversity Program.

Over the past decade, lowering nest temperatures has been identified as a conservation strategy for mitigating the effects of global warming and for balancing the sex ratios in sea turtle populations. However, the effectiveness of shading sea turtle nests under the current warming climate has not been fully elucidated, especially in tropical habitats. We recorded environmental conditions of nesting beaches and evaluated the effects of natural shading on clutch temperatures and hatchlings of the green sea turtle Chelonia mydas through high-frequency daily field surveys on Taiping Island in the South China Sea. The entire incubation period equally divided into three windows, first, middle and last, and three levels of sun exposure, low, medium and high, were explored. Natural shading was related to an increased proportion of hatched clutches from 42.86 % to 66.67 % under high and low sun exposure, respectively, accompanied by a reduction in clutch temperature from 31.94 ± 2.02 °C to 30.38 ± 1.72 °C. Nevertheless, shading had no effect on increasing hatch and emergence rates, and incubation temperatures still exceeded the usual pivotal value (29 °C) during the middle incubation window as the sex determination period by a mean temperature of 31.53 ± 1.97 °C, which resulted in potential feminization of green sea turtles on the island and in this sea area. The probability of hatchling abnormalities was the lowest (9.68 %) under low sun exposure, and the likelihood of these abnormalities was strongly correlated with clutch temperatures, particularly during the first and middle incubation windows. Severe abnormalities, such as deformities, weakened as self-righting responses. These findings reveal that natural shading alone is insufficient to lower temperatures to mitigate female-biased sex ratios in green sea turtles in tropical habitats under the current climate and indicate that in situ monitoring and investigations of nesting habitats are necessary for establishing more appropriate regional conservation strategies for sea turtles.

Consisting of more than 7,000 islands, the Philippines is home to many rare and endemic species and is an important hotspot for global biodiversity. Begonias are often found in the few remaining natural tropical forests in the Philippines, and this group of plants, known for their rich and variable leaf shapes, is not only of great horticultural value but also an indicator of a healthy forest ecosystem. At the beginning of the last century, Elmer Merrill, an American scientist who pioneered plant research in the Philippines, counted 89 species of Begonia in the Philippines. By 2023, however, this number had risen to 167, and more than 95% of the species are endemic to the Philippines, with new species of Begonia in the Philippines being published almost every month. Most of these new species have been published in the last 15 years, and the resurgence of Philippine Begonia research that we are witnessing is inextricably linked to the contributions of the late Academia Sinica Research Fellow Dr Ching-I Peng. The three editors of this book, Professor Rosario Rubite of the University of the Philippine Manila, Kuo-Fang Chung of Academia Sinica, and Southeast Asia Taxonomy Research Leader Dr Mark Hughes of the Royal Botanic Gardens Edinburgh, were inspired and encouraged by Dr Peng to continue to devote themselves to the classification, evolution and conservation of Begonias. With the help of a large number of local scientists and enthusiasts from the Philippines, "Begonia of the Philippines" illustrates 124 species of begonias in the Philippines and presents to the world not only the richness of plant diversity in the Philippines, but also an assessment of the current conservation status of each species, which is an important and substantial contribution to the conservation of a major global biodiversity hotspot.

Plants of the Ophioglossaceae family (a type of fern) all possess non-green, underground gametophytes, indicating that they likely depend on fungi (such as mycorrhizal fungi) to acquire carbon nutrients by parasitizing other photosynthetic plants. However, previous research has mainly focused on Ophioglossaceae plants that grow aboveground, neglecting species within the family that survive as epiphytes, such as Ophioderma pendulum. Additionally, there is a hypothesis suggesting that epiphytic ferns may have difficulty associating with the widely distributed mycorrhizal fungi in terrestrial environments.Through the study of the fungal communities in the leaves and roots of Ophioderma pendulum, an epiphytic species found in low-altitude forests in Taiwan, we found a significant presence of mycorrhizal fungi in the roots of epiphytic Ophioderma pendulum. This indicates the importance of these fungi for the survival of epiphytic Ophioderma pendulum in their habitat.

The phylogeography of intertidal invertebrates in the northwestern Indian Ocean is poorly known due to difficulties in crossing diverse political regions for sampling. This study, based on mitochondrial cytochrome c oxidase subunit 1 (cox1) and nuclear sodium-potassium ATPase alpha-subunit (NaK) sequences, is the first assessment of the phylogeography of the intertidal barnacle Chthamalus barnesi in the Indian Ocean and includes all peripheral seas of the northwestern region. Our phylogenetic analyses defined 1 monophyletic clade, suggesting that C. barnesi does not comprise any cryptic species. Phylogeographic analyses showed no clear differentiation among populations of C. barnesi, except in the Red Sea. This isolated population apparently did not leave the Red Sea during post-Pleistocene glaciation. High ΦST values between the Red Sea and other populations is further indication of isolation. Low values of ΦST among the Persian Gulf, Gulf of Oman and the northeastern Arabian Sea indicate gene flow among these populations. Analysis of molecular variance revealed no significant genetic differentiation among these 3 areas. Phylogeographic analyses suggested that there may be 2 major populations (Red Sea and northwestern Indian Ocean) of C. barnesi in the Indian Ocean resulting from interactions between the Pleistocene glaciation and present-day ocean currents. Among these populations, the Persian Gulf seems to have a higher probability of being the ancestral population. After the Red Sea, the Persian Gulf has the highest genetic diversity of the cox1 gene. This evidence suggests that the Arabian Sea population may have originated from the expansion of the Persian Gulf population after the Pleistocene glaciation.

Poleward range expansion of marine organisms is commonly attributed to anthropogenic ocean warming. However, the extent to which a single species can migrate poleward remains unclear. Here we used molecular data to examine the current distribution of the Pocillopora damicornis species complex in Taiwan waters and applied niche modeling to predict its potential range through the end of the 21st Century. The P. damicornis species complex is widespread across shallow, tropical and subtropical waters of the Indo-Pacific regions. Our results revealed that populations from subtropical nonreefal coral communities are P. damicornis, whose native geographical ranges are approximately between 23°N and 35°N. In contrast, those from tropical reefs are P. acuta. Our analysis of 50 environmental data layers demonstrated that the concentrations of CaCO3 polymorphs had the greatest contributions to the distributions of the two species. Future projections under intermediate shared socioeconomic pathways (SSP) 2–4.5 and very high (SSP5–8.5) scenarios of greenhouse gas emissions showed that while sea surface temperature (SST) isotherms would shift northwards, saturation isolines of two CaCO3 polymorphs, calcite (Ωcal) and aragonite (Ωarag), would shift southwards by 2100. Subsequent predictions of future suitable habitats under those conditions indicated that distinct delimitation of geographical ranges for the two species would persist, and neither would extend beyond its native geographical zones, indicating that tropical Taiwan waters are the northern limit for P. acuta. In contrast, subtropical waters are the southern limit for P. damicornis. We concluded that the decline in CaCO3 saturation would make high latitudes less inhabitable, which could be one of the boundary elements that limit poleward range expansion driven by rising SSTs and preserve the latitudinal diversity gradient (LDG) on Earth. Consequently, poleward migration of tropical reef corals to cope with warming oceans should be reevaluated.

Some bilateral animals have highly specialized genomes, especially model organisms like fruit flies, nematodes, zebrafish, and planarians. Evolutionary biologists have noted this specialization since their genomes were sequenced. Conversely, marine invertebrates such as sea urchins, amphioxus, scallops, and ribbon worms exhibit conserved genome structures unchanged for over 500 million years. Typically, a phylum's genome structure is either conserved or specialized. Studies on Annelida, however, reveal a rare exception. Most annelids are marine, but some live on land and in freshwater. Assistant Research Fellow Yi-Jyun Luo's team from the Biodiversity Research Center analyzed the chromosomal-level genomes of 23 annelid species. They found that while most annelids have conserved genome structures, Clitellates, including leeches and earthworms, are entirely different. The team developed a rearrangement index, showing that leeches and earthworms possess the most highly rearranged genomes among bilaterians. The research, published in August 2024 in Molecular Biology and Evolution, was funded by the Academia Sinica Career Development Award.

We used genomic data to understand the population genetic structure of a protected flagship beetle species endemic in Taiwan. Our results showed that the current conservation strategy to treat the species as one unit is the best management plan. However, we further argue that additional approaches, such as assisted gene flow, may be applied to this system. More importantly, our study demonstrated how biodiversity conservation practitioners can draw information from genomic data to help with planing future strategies for wildlife managements.

The ability to sense prey-derived cues is essential for predatory lifestyles. Under low-nutrient conditions, Arthrobotrys oligospora and other nematode-trapping fungi develop dedicated structures for nematode capture when exposed to nematode-derived cues, including a conserved family of pheromones, the ascarosides. A. oligospora senses ascarosides via conserved MAPK and cAMP–PKA pathways; however, the upstream receptors remain unknown. Here, using genomic, transcriptomic and functional analyses, we identified two families of G protein-coupled receptors (GPCRs) involved in sensing distinct nematode-derived cues. GPCRs homologous to yeast glucose receptors are required for ascaroside sensing, whereas Pth11-like GPCRs contribute to ascaroside-independent nematode sensing. Both GPCR classes activate conserved cAMP–PKA signalling to trigger trap development. This work demonstrates that predatory fungi use multiple GPCRs to sense several distinct nematode-derived cues for prey recognition and to enable a switch to a predatory lifestyle. Identification of these receptors reveals the molecular mechanisms of cross-kingdom communication via conserved pheromones also sensed by plants and animals.

In this study, we found that ferroptosis, an iron- and lipid-peroxidation-dependent cell death, propagates across human cells over long distances at constant speeds (~5.5 μm/min) via reactive oxygen species (ROS) trigger waves (A). ROS feedback loops control wave progression. Ferroptotic stress activates these loops, creating bistable cellular redox systems that enable ROS propagation. We also, for the first time, demonstrate the role of ferroptosis in embryonic development. Ferroptosis is critical for the muscle remodeling in embryonic avian limb (ferroptosis (4-HNE) in embryonic limb, B & C; muscle development after suppressing ferroptosis using UAMC-3203, D & E), suggesting its function in tissue sculpting during embryogenesis. These findings reveal ferroptosis\'s importance in coordinating large-scale cell death, offering insights into embryonic development and human pathologies.

Developing programmable bacterial cell-cell adhesion is an emerging approach for studying microbial interactions and enabling bioengineering applications. However, identifying functional cell adhesion molecules (CAMs) that target bacterial membrane proteins in their native conformations remains a significant challenge. Here, we present a whole-cell screening platform tailored to discover CAMs within a synthetic nanobody library. By leveraging the bacterial type IV secretion system (T4SS)—a contact-dependent DNA delivery nanomachine—we developed a new platform incorporating a positive feedback mechanism, enabling the selective enrichment of bacteria displaying functional CAMs that mediate interbacterial adhesion. With our newly designed platform, we successfully identified nanobody CAMs targeting three distinct bacterial outer membrane proteins (TraN, OmpA, and OmpC). These CAMs exhibited stable and specific binding to their corresponding antigens, enabling precise interbacterial interactions, including targeted DNA transfer and toxin delivery, thereby highlighting their potential for advanced functionalities. Collectively, our study promises an ease-of-use approach to discover nanobody CAMs for programming bacterial cell-cell adhesion, opening new avenues for studying bacterial interactions, engineering microbial communities, and developing targeted antimicrobial strategies.

UFMylation is an emerging ubiquitin-like post-translational modification that regulates various biological processes. Dysregulation of the UFMylation pathway leads to human diseases including cancers. However, the physiological role of UFMylation in T cells remains unclear. A research team led by Dr. Yu-Ru Lee at the Institute of Biomedical Sciences, Academia Sinica, reported that mice with conditional knockout (cKO) Ufl1, a UFMylation E3 ligase, in T cells exhibit effective tumor control. Single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in Ufl1 cKO mice. Moreover, UFL1 promotes PD-1 UFMylation to antagonize PD-1 ubiquitination and degradation. Furthermore, AMPK phosphorylates UFL1 at Thr536, disrupting PD-1 UFMylation to trigger its degradation. Of note, UFL1 ablation in T cells reduces PD-1 UFMylation, subsequently destabilizing PD-1 and enhancing CD8+ T cell activation. Thus, Ufl1 cKO mice bearing tumors have a better response to anti-CTLA-4 immunotherapy. Collectively, This research findings uncover a crucial role of UFMylation in T cells and highlight UFL1 as a potential target for cancer treatment. This research has been published on February 19, 2024 in Molecular Cell.

A collaborative study led by Dr. Ruey-Bing Yang from Academia Sinica and first author Dr. Yuh-Charn Lin from Taipei Medical University has revealed that the membrane protein SCUBE2 (Signal peptide-CUB-epidermal growth factor-like domain-containing protein 2) plays a critical role in maintaining vascular barrier function during inflammation. Conducted in collaboration with Dr. Ya-Jen Chang from Academia Sinica and Professor Chun-Min Lo from National Yang Ming Chiao Tung University, highlights how SCUBE2 stabilizes endothelial cell adherens junctions to prevent vascular leakage. This research, published on June 13, 2024, in Cardiovascular Research, suggests new therapeutic strategies for inflammation-related diseases. The study demonstrates that SCUBE2 interacts with VE-cadherin and VE-protein tyrosine phosphatase (VE-PTP) in endothelial cells to reduce endothelial barrier dysfunction during inflammation. The research team found that mice with SCUBE2 gene knockout exhibited increased vascular leakage after local injection of histamine or vascular endothelial growth factor and were more susceptible to systemic inflammatory responses induced by acute endotoxin or influenza virus. Conversely, mice overexpressing SCUBE2 showed enhanced protective effects. In summary, the study reveals that SCUBE2 promotes vascular integrity by recruiting VE-PTP to dephosphorylate VE-cadherin and stabilize endothelial cell adherens junctions. Additionally, the data suggest that overexpression or upregulation of SCUBE2 could help prevent vascular leakage in inflammatory diseases. This discovery provides a new potential therapeutic target for a range of inflammation-related human pathologies.

Computational design, directed evolution, and recombinant protein technology have opened up new venues for therapeutic designs for cancer treatment. The latest research from the teams of Dr. Mou Yun and Dr. Jack Hu, Associate Research Fellow at the Institute of Biomedical Sciences, Academia Sinica, showcases a novel therapeutic protein design that can activate both cytotoxic T lymphocytes and natural killer (NK) cells in the tumor microenvironment for synergistic tumor containment. The therapeutic protein, named superantigen-based tri-functional yeast-display-enhanced multivalent immune cell engager (STYMIE), is comprised of three separated components, including a directed-evolution-enhanced superantigen for CD8 T cell and NK cell activation, a computationally designed cytokine for sustained immune cell stimulation, and a tumor-homing antibody for targeted delivery. The study demonstrates effective suppression of immune-suppressive tumor types, including colorectal cancer, breast cancer, and lung cancer, and it further reveals insights into immune cell activation mechanism behind superantigens. This research highlights new design principles in immune cell engagers and has been published in "Advanced Science" on June 28th, 2024. Tumors often leverages multiple immune-suppressive mechanisms to escape from immune attacks, and efforts to recruit immune cells into the tumor microenvironment have inspired development of tumor-targeted immune cell engagers toward bridging T lymphocytes and cancer cells. This study explored a new design strategy that leverages superantigens known to activated multiple immune cell types. To increase the functionality of superantigens, the researchers adopted a yeast-display directed evolution technique to identify mutants with enhanced affinity to immunoreceptors. The researchers further fused the enhanced superantigen to an Fc receptor, immunological cytokine, and a tumor-targeting nanobody. The resulting chimeric protein enables extended systemic circulation, robust tumor accumulation, and CD8 T cell and NK cell recruitment to the tumor microenvironment, thereby promoting the elimination of cancer cells. Dr. Yao-An Yu, the lead researcher in this study, further discovered the underlying molecular mechanism behind superantigen-mediated T cell activation. Through the adoption of CRISPR knock-out technology for immunoreceptor screen, Yao-An identified CD2 and CD58 as primary ligands that engage with superantigens. Preservation of D55G on superantigen mutants was also identified as a critical factor for T cell receptor engagement, as its alteration was observed to abrogate T cell activation. This research opens up new possibilities in cancer treatment as CD8 T cells and NK cells work synergistically to prevent tumor immune escape. While CD8 T cells can recognize mutant neoantigens displayed by the major histocompatibility complex (MHC) on cancer cells, many cancer cells can downregulate MHC expression to minimize CD8 T cell engagement. These low-MHC-expressing tumor cells, however, are particularly susceptible to NK cell attack. The STYMIE developed in the study engages with both CD8 T cells and NK cells to impede tumor progression. The work is the culmination of Dr. Mou's continuing commitment to fusion protein engineering, which has ushered in a variety of protein design and development strategies. This research was published in Advanced Science on June 28th, 2024 (IF: 15.1), under the title "High-Affinity Superantigen-Based Trifunctional Immune Cell Engager Synergizes NK and T Cell Activation for Tumor Suppression." The main authors include graduate student Yao-An Yu and Research Assistant Wen-Ching Lin. Collaborative investigators include Dr. Che-Ming Jack Hu from the Institute of Biomedical Sciences (IBMS) at Academia Sinica and Dr. Chung-Yuan Mou from the Department of Chemistry, National Taiwan University. Dr. Mou Yun was a former Associate Research Fellow at IBMS. Dr. Mou unfortunately passed away on 23rd August 2023. Future correspondence can be addressed to Dr. Hu.

Heart failure remains a significant global contributor to mortality, marked by the adult human heart's incapacity to self-repair or compensate for the loss of cardiac muscle cells. Stem cell therapy has emerged as a promising strategy for replenishing lost cardiac muscle cells and revitalizing heart function. Under the leadership of Professor Patrick CH Hsieh at the Institute of Biomedical Sciences, Academia Sinica in Taiwan, an innovative research team has made remarkable strides in both murine and non-human primate models. Their groundbreaking research successfully regenerated damaged hearts through the simultaneous transplantation of endothelial cells and cardiomyocytes derived from human induced pluripotent stem cells (iPSCs). This pivotal study has paved the way for new possibilities in the realm of cardiac regeneration.

Pain is a common yet complex phenomenon involving both physical sensations and emotional responses. While the basic understanding of pain has advanced, the brain mechanisms driving these responses remain unclear. A team led by Dr. Chien-Chang Chen from the Institute of Biomedical Sciences (IBMS), Academia Sinica, has made a significant breakthrough in understanding the neural basis of chronic pain. The findings were published in Cell Reports on November 26, 2024. The study revealed that chronic pain activates specific neuronal populations in the anterior paraventricular nucleus of the thalamus (PVA). These neurons are responsible for processing either the sensory or emotional aspects of pain, with their activity changing based on the pain type. Stimulating these neurons led to tactile hypersensitivity and avoidance behaviors, while suppressing them alleviated pain. Additionally, these neurons send signals to the bed nucleus of the stria terminalis (BNST) and the nucleus accumbens (NAc), which independently regulate different pain-related behaviors. This discovery provides new insights into pain mechanisms and potential therapeutic strategies. This research not only deepens our understanding of pain mechanisms but also paves the way for innovative chronic pain treatments that could significantly improve patients' quality of life.

Proteins on the surface of cells and viruses are often coated by a dense layer of sugar molecules, participating in host recognition and immune evasion. Despite its significance, this sugar \"cloak\" has remained elusive to structural biologists, akin to the tale of the king\'s new clothes. In the protein structure database, these glycans are generally omitted. To address this challenge, the Hsu laboratory integrated advanced cryo-electron microscopy, mass spectrometry, and small-angle X-ray scattering to quantitatively define the chemical compositions and molecular shapes of the glycans of a series of coronavirus spike proteins that serve as key experimental data as inputs to help develop the computational algorithm, GlycoSHIELD, together with Matteusz Sikora (Max Planck Institute for Biophysics, Germany) Cyril Hanus (Université Paris-Cité, France). GlycoSHIELD provides a library of pre-computed conformational ensembles of glycan structures, which can be selected and grafted onto the atomic structures of the proteins of interest. This tool is computationally efficient, allowing researcher to generate fully glycosylated protein models within minutes using a personal computer. This breakthrough empowers researchers to delve into the spatial arrangement of sugar molecules on protein surfaces, understand their shielding effects, and anticipate their impact on biological functions and protein structure.

Infecting approximately half of the human population, Helicobacter pylori is auxotrophic for cholesterol which it converts to various cholesteryl α-glucoside derivatives, including cholesteryl 6\'-acyl α-glucoside (CAG). Since the related biosynthetic enzymes can be translocated to the host cells, the acyl chain of CAG comes from its precursor phosphatidylethanolamine (PE) in the host membranes. In this work CAG10:0, CAG18:3 and CAG22:6 were found to cause the most adverse effect on the bacterial adhesion. Further LC–MS analysis indicated that the treatment of PE(10:0)2 resulted in dual effects to inhibit the bacterial adhesion, including the generation of CAG10:0 and significant changes in the membrane compositions. In particular, the PE(10:0)2 treatment significantly reduced bacterial adhesion in mouse models. Our approach of membrane remodeling has thus shown great promise as a new anti-H. pylori therapy.

We used cryogenic electron microscopy (cryo-EM) to resolve the structure of hamster sHaPrP(23−144) fibrils prepared at pH 3.7. This 2.88 Å cryo-EM structure has two protofilaments with an amyloid core covering residues 94‒144. Interestingly, this sHaPrP(23−144) fibril structure differs from a recently reported structure formed by the human or mouse counterpart at pH 6.5. Moreover, sHaPrP(23−144) fibrils have many structural features in common with infectious prions. Whether this structure is infectious remains to be determined. More importantly, the sHaPrP(23−144) structure is different from the sHaPrP(108‒144) fibrils prepared in the same fibrillization buffer, indicating that the N terminal disordered region, possibly the positively charged cluster, influences the misfolding pathway of the prion protein.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting over 1% of the global population. Individuals with ASD often exhibit complex behavioral conditions, including significant social difficulties and repetitive behaviors. Moreover, ASD often co-occurs with several other conditions, including intellectual disabilities and anxiety disorders. The etiology of ASD remains largely unknown owing to its complex genetic variations and associated environmental risks. Ultimately, this poses a fundamental challenge for the development of effective ASD treatment strategies. Previously, we demonstrated that daily supplementation with the probiotic Lactiplantibacillus plantarum PS128 (PS128) alleviates ASD symptoms in children. However, the mechanism underlying this improvement in ASD-associated behaviors remains unclear. Here, we used a well-established ASD mouse model, induced by prenatal exposure to valproic acid (VPA), to study the physiological roles of PS128 in vivo. Overall, we showed that PS128 selectively ameliorates behavioral abnormalities in social and spatial memory in VPA-induced ASD mice. Morphological examination of dendritic architecture further revealed that PS128 facilitated the restoration of dendritic arborization and spine density in the hippocampus and prefrontal cortex of ASD mice. Notably, PS128 was crucial for restoring oxytocin levels in the paraventricular nucleus and oxytocin receptor signaling in the hippocampus. Moreover, PS128 alters the gut microbiota composition and increases the abundance of Bifidobacterium spp. and PS128-induced changes in Bifidobacterium abundance positively correlated with PS128-induced behavioral improvements. Together, our results show that PS128 treatment can effectively ameliorate ASD-associated behaviors and reinstate oxytocin levels in VPA-induced mice, thereby providing a promising strategy for the future development of ASD therapeutics.

Humans are classified under the phylum Chordata, which together with phyla Echinodermata and Hemichordata belong to Deuterostomia. To trace our own evolutionary history, biologists have strived to understand the characteristics of the deuterostome ancestor. However, due to the lack of chromosomal-level genome assemblies of hemichordates, a key group in deuterostomes, the ancestral genome composition and chromosomal architecture of the deuterostome ancestor remains a mystery. Research Fellow Yi-Hsien Su and the Marine Research Station Chief Jr-Kai Yu at the Institute of Cellular and Organismic Biology, Academia Sinica led an international research team and successfully generated the chromosomal-level genome assemblies of two hemichordate acorn worms collected from Penghu, Taiwan and California, USA. The research team deduced the chromosomal architecture of the deuterostome common ancestor and the chromosomal rearrangement events specific to chordates, echinoderms, and hemichordates. This research establishes the genomic architecture of the deuterostome ancestor and provides new insights into the evolutionary history of deuterostomes. This study has been published on June 3, 2024 in the journal PLOS Biology. The first-author is Dr. Che-Yi Lin, and other members of the Taiwan research team include Yi-Chih Chen, Cindy Chou, Ching-Yi Lin, Tzu-Pei Fan and Chang-Tai Tsai. This study is supported by funding from Institute of Cellular and Organismic Biology and grants from Academia Sinica (AS-GC-111-L01 to Y.H.S. and J.K.Y.), and National Science and Technology Council, Taiwan (112-2326-B-001-004 to Y.H.S. and 110-2621-B-001-001-MY3 to J.K.Y.).

Humans are chordates, which together with echinoderms and hemichordates belong to deuterostomes. Their embryogenesis are comparable, but develop into distinct body forms. To understand developmental mechanisms of deuterostomes and their evolutionary history, Research Fellow Yi-Hsien Su and the Marine Research Station Chief Jr-Kai Yu at ICOB collaborated with a Spanish team to globally and quantitively analyze hemichordate developmental transcriptomes and open chromatin regions. The research team deciphered a biphasic transcriptional program and proposed that gastrulation is the stage of highest molecular resemblance in deuterostomes. Much of the molecular basis of deuterostome development was probably present in the bilaterian last common ancestor.

Humans are classified under the phylum Chordata, which together with phyla Echinodermata and Hemichordata belong to Deuterostomia. To trace our own evolutionary history, biologists have strived to understand the characteristics of the deuterostome ancestor. However, due to the lack of chromosomal-level genome assemblies of hemichordates, a key group in deuterostomes, the ancestral genome composition and chromosomal architecture of the deuterostome ancestor remains a mystery. Research Fellow Yi-Hsien Su and the Marine Research Station Chief Jr-Kai Yu at the Institute of Cellular and Organismic Biology, Academia Sinica led an international research team and successfully generated the chromosomal-level genome assemblies of two hemichordate acorn worms collected from Penghu, Taiwan and California, USA. The research team deduced the chromosomal architecture of the deuterostome common ancestor and the chromosomal rearrangement events specific to chordates, echinoderms, and hemichordates.

Certain insects, like beetles and butterflies, can undergo massive tissue replacement during their development, a transformation process considered unique to insects. Dr. Chen-Hui Chen and his team at the Institute of Cellular and Organismic Biology (ICOB) created the palmuscle myofiber tagging and tracking system for in toto monitoring of the growth and fates of ~5000 fast myofibers in developing zebrafish larvae. They found that zebrafish, as a vertebrate model, can similarly undergo complete muscle elimination and replacement during post-embryonic development. This unexpected finding was published in June this year in the EMBO J.

Some vertebrate animals, such as zebrafish and salamanders, are able to heal large-sized cutaneous wounds within hours. Investigating this process may reveal new approaches in regenerative medicine. Dr. Chen-Hui Chen at the Institute of Cellular and Organismic Biology (ICOB), along with Dr. Ji-Yen Cheng at the Research Center for Applied Sciences (RCAS), and their teams have developed a macroscopic live imaging platform capable of capturing a total of ~60,000 Superficial Epithelial Cells (SECs) within a single field of view. They found that fin-resident epithelial cells are highly mobile, migrating to cover nearby millimeter-sized body wounds. Thus, they propose that fin tissues or vertebrate appendages may act as a massive reservoir of healing cells, speeding up wound closure and tissue repair. This unexpected finding was published in July this year in the journal Current Biology.

In plants, mobile mRNAs travel between cells through intercellular pores, plasmodesmata, and a long distance via phloem in the vascular tissue, to modulate plant development systemically. However, how mobile mRNAs target plasmodesmata to initiate cell-to-cell movement is unclear. Dr. Tien-Shin Yu’s group in the Institute of Plant and Microbial Biology unveiled the machinery supporting the intracellular transport of mobile mRNAs. They identified endosomal RNA-binding proteins ROCs specifically bridge mobile mRNAs onto the surface of endosomes. The organelle-bound mobile mRNA complex co-transports with endosomes through cytoskeleton networks toward plasmodesmata. This study reveals a hitchhiking strategy is used to direct mobile mRNAs for intercellular delivery. The results have been published in the January issue of Nature Plants in 2024.

Plants use nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) to recognize pathogens. In solanaceous plants, the NRC (NLR required for cell death) family forms a complex network with helper and sensor NLRs to resist pathogens. However, the evolution and function of NRC networks outside solanaceous plants are unclear. Our phylogenomic analysis of NLRs across asterid lineages showed significant expansion of NRC networks in most lamiids, but not in Ericales and campanulids. Transient expression assays in Nicotiana benthamiana validated simple NRC network architectures in Ericales and campanulids, but complex architectures in lamiids. Phylogenetic analysis identified three conserved NRC0 subclades and several lamiid-specific NRC subclades with diversifying selection. Functional analyses showed that members of the NRC0 subclades across plant lineages are partially interchangeable, whereas lamiid-specific NRCs lack interchangeability. Our findings highlight the distinct evolutionary pattern of NRC networks in asterids and provide potential insights into transferring disease resistance across plant lineages.

Histone modifications can regulate transcription epigenetically by marking specific genomic loci, which can be mapped using chromatin immunoprecipitation sequencing (ChIP-seq). Here we present QHistone, a predictive database of 1,534 ChIP-seqs from 27 histone modifications in Arabidopsis, offering three key functionalities. Firstly, QHistone employs machine learning to predict the epigenomic profile of a query protein, characterized by its most associated histone modifications, and uses these modifications to infer the protein's role in transcriptional regulation. Secondly, it predicts synergistic regulatory activities between two proteins by comparing their profiles. Lastly, it detects previously unexplored co-regulating protein pairs by screening all known proteins. QHistone accurately identified histone modifications associated with specific known proteins, and allows users to computationally validate their results using gene expression data from various plant tissues. These functions demonstrate a novel approach to utilizing epigenome data for gene regulation analysis, making QHistone a valuable resource for the scientific community (https://qhistone.paoyang.ipmb.sinica.edu.tw).

Plant productivity is impaired by even small decreases in water availability during drought. While this is of increasing global concern because of climate change, our ability to improve plant stress resistance is limited by a lack of understanding of how plant cells detect and respond to water limitation. The Verslues laboratory found that mutation of the Non-Phototrophic Hypocotyl3 (NPH3)-domain protein NRL5 causes plants to become hypersensitive to drought stress because of mis-regulated proline metabolism. The NPH3-domain is a protein feature that is unique to plants and was of unknown function despite the fact that NPH3-domain proteins have been implicated in important signaling pathways such as phototropism and hormone response. We demonstrated that NRL5, and other NPH3-domain proteins, have GTPase activity despite having no similarity to known GTPases. The NPH3 domain was required for NRL5 to interact with and control the function of proteins involved in vesicle trafficking. Trafficking interactions are in turn important for NRL5 polar localization. These results demonstrate that NPH3 proteins constitute a previously unsuspected layer of regulation controlling intracellular trafficking and cellular polarization in plants. The results also demonstrate that correct regulation of proline metabolism is critically important for drought resistance.