Highlights
Inst. of Biomedical Sciences（5）
張雅貞 CHANG, YA-JEN
Science Translational Medicine
07 June 2023
Asthma is a common chronic airway disease. Inhaled corticosteroids (ICS) are the mainstay asthma therapy. However, there is inter-individual variability in the response to ICS, and a few patients have limited disease control and experience persistent symptoms, despite use of ICS. Neutrophil extracellular traps (NETs) have been shown to increase in the lungs and sputum of patients with severe asthma. However, the association between NETs and response to ICS in asthma is unclear. In our study, we investigate the association between gene, NETs and asthma by the transcriptomic profile from asthma patients, and experimental results from in vitro and asthma murine model. The study unravels that neutrophil-related pathways and a unique neutrophil gene module related to uncontrolled asthma. NETs from peripheral neutrophils were found to be a predictor for ICS non-response. It was confirmed that corticosteroids could not suppress neutrophilic genes or inflammation in both clinical and in vivo settings. Airway hyperreactivity and inflammation were inhibited after disrupting NETs by DNase I treatment in vivo. Finally, from neutrophil RNA sequencing, the gene expression of CCL4L2 was identified to be higher in ICS non-response. CCL4L2 expression showed a significant positive correlation with NET production. These results highlight CCL4L2 and NETs as potential therapeutic targets for individuals with asthma refractory to ICS.
Conspectus
李永凌 LEE, YUNGLING
Science Translational Medicine
7 June 2023
Asthma is a common chronic airway disease. Inhaled corticosteroids (ICS) are the mainstay asthma therapy. However, there is inter-individual variability in the response to ICS, and a few patients have limited disease control and experience persistent symptoms, despite use of ICS. Neutrophil extracellular traps (NETs) have been shown to increase in the lungs and sputum of patients with severe asthma. However, the association between NETs and response to ICS in asthma is unclear. The research groups led by Dr. Yungling Lee and Dr. Ya-Jen Chang investigate the association between gene, NETs and asthma by the transcriptomic profile from asthma patients, and experimental results from in vitro and asthma murine model. The study unravels that neutrophil-related pathways and a unique neutrophil gene module related to uncontrolled asthma. NETs from peripheral neutrophils were found to be a predictor for ICS non-response. It was confirmed that corticosteroids could not suppress neutrophilic genes or inflammation in both clinical and in vivo settings. Airway hyperreactivity and inflammation were inhibited after disrupting NETs by DNase I treatment in vivo. Finally, from neutrophil RNA sequencing, the gene expression of CCL4L2 was identified to be higher in ICS non-response. CCL4L2 expression showed a significant positive correlation with NET production. These results highlight CCL4L2 and NETs as potential therapeutic targets for individuals with asthma refractory to ICS.
Conspectus
王宜萱 WANG, I-HSUAN
Molecular Therapy
08 September 2023
Developing Broad-Spectrum Antibody Drugs to Combat Variants of COVID-19
In the post-COVID-19 era, developing enduring and broad-spectrum antiviral drugs is paramount to preventing widespread outbreaks from variants of the virus and potential emerging coronaviruses. Driven by the viruses' reliance on hACE2 as the primary cellular receptor, we collaborated with Dr. Mi-Hua Tao's research groups in our institute to discover a monoclonal antibody ch2H2, which exhibited a high affinity to the viral Spike protein binding site on hACE2. This antibody, without affecting the biological function of hACE2, demonstrated robust inhibitory effects against various COVID-19 viral variants in in vivo neutralization studies. Utilizing adeno-associated virus (AAV) delivery in animal experiments, a single injection resulted in sustained and high levels of ch2H2 antibodies in mice. In prophylactic administration against the Omicron variant BA.5, which led to declined vaccine effectiveness, AAV/ch2H2 significantly reduced viral loads and mitigated pulmonary pathological changes. These findings underscore the potential of AAV-delivered hACE2-blocking antibodies as a promising avenue for broad-spectrum antiviral drug development in the future.
Conspectus
謝清河 HSIEH, PATRICK C.H.
Circulation
21 Sep 2023
Human Heart Tissue Regeneration in Non-human Primates: A Breakthrough
The research team led by Dr. Patrick C.H. Hsieh, a distinguished research fellow at the Institute of Biomedical Sciences, Academia Sinica, has published an important study in \"Circulation,\" confirming that the co-transplantation of endothelial cells and cardiomyocytes derived from human induced Pluripotent Stem Cells (hiPSC-ECs and hiPSC-CMs) can successfully regenerate damaged heart tissues and restore heart function in non-human primates. Heart failure remains a major global cause of death, as the adult heart struggles to self-repair or compensate for lost cardiac muscle cells. The study conducted by Dr. Hsieh\'s lab demonstrates significant therapeutic effects by simultaneously transplanting differentiated hiPSC-ECs and hiPSC-CMs into the damaged areas of the heart. The co-transplanted animals showed a notable improvement in the graft size and maturity of hiPSC-CMs, while hiPSC-ECs treatment significantly promoted angiogenesis, accompanied by significant recovery in cardiac function. This groundbreaking research not only achieved success in mouse models but also yielded exciting results in non-human primate models. The title of the study, \"Combined Therapy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells for Regenerating Mouse and Non-Human Primate Damaged Hearts,\" was published in \"Circulation\" on October 31, 2023, with a high journal impact factor of 39.9, highlighting the exceptional importance of the research. The collaborative effort of the research team extended across international boundaries, including Dr. Tim Kamp and Dr. Tim Hacker from the University of Wisconsin-Madison in the United States. This groundbreaking study not only represents a significant breakthrough in academia but also opens a door for the treatment of heart diseases, bringing valuable hope for health and life.
Conspectus
陶秘華 TAO, MI-HUA
Molecular Therapy
08 September 2023
Developing Broad-Spectrum Antibody Drugs to Combat Variants of COVID-19
In the post-COVID-19 era, developing enduring and broad-spectrum antiviral drugs is paramount to preventing widespread outbreaks from variants of the virus and potential emerging coronaviruses. Driven by the viruses' reliance on hACE2 as the primary cellular receptor, we collaborate with Dr. I-Hsuan Wang (Institute of Biomedical Sciences at Academia Sinica) to discover a monoclonal antibody ch2H2, which exhibited a high affinity to the viral Spike protein binding site on hACE2. This antibody, without affecting the biological function of hACE2, demonstrated robust inhibitory effects against various COVID-19 viral variants in in vivo neutralization studies. Utilizing adeno-associated virus (AAV) delivery in animal experiments, a single injection resulted in sustained and high levels of ch2H2 antibodies in mice. In prophylactic administration against the Omicron variant BA.5, which led to declined vaccine effectiveness, AAV/ch2H2 significantly reduced viral loads and mitigated pulmonary pathological changes. These findings underscore the potential of AAV-delivered hACE2-blocking antibodies as a promising avenue for broad-spectrum antiviral drug development in the future.
ConspectusInst. of Biological Chemistry （3）
吳昆峯 WU, KUEN-PHON
ACS Synthetic Biology
09 August 2023
AI Accelerates Protein Design and Enhances Enzyme Activity
Unlocking the potential of protein activation has historically posed challenges, necessitating extensive screening and biochemical assays. Kuen-Phon Wu has led a team to demonstrate a paradigm shift. By integrating the advanced deep learning tool, ProteinMPNN, they have engineered ubiquitin into a potent allosteric activator tailored for Rsp5 E3 ligase. The entire process was fully automated from protein designs to sample preparation to functional assays took only three months. This milestone heralds a new era, where AI-driven protein design obviates the need for exhaustive experimental screening and validation. This work underscores the pivotal role of AI tools in revolutionizing biological and biomedical research.
Conspectus
陳佩燁 CHEN, RITA PEI-YEH
Nature Communications
06 September 2023
Abuse of antibiotics has led to the emergence of multidrug-resistant microbial pathogens, presenting a pressing challenge in global healthcare. Membrane-disrupting antimicrobial peptides (AMPs) combat so-called “superbugs” via mechanisms different than conventional antibiotics and have good application prospects in medicine, agriculture, and the food industry. However, the mechanism of AMPs has not been fully characterized at the cellular level due to a lack of high-resolution imaging technologies that can reveal cellular membrane disruption events in the hydrated state. Previously, Dr. Rita Chen has de novo designed a series of peptides with a unique sequence pattern showing excellent antimicrobial activity. In this study, we used cryo-electron tomography (cryo-ET) to directly visualize the pepD2M-induced disruption of the outer and inner membranes of the Gram-negative bacterium Escherichia coli, and compared it with a well-known honeybee venom peptide, melittin. This study demonstrates the peptide-induced morphological changes of bacterial membranes in a native-like state at nanometer resolution. AMPs could be our new hope in the war combating multidrug-resistant pathogens.
Conspectus
陳瑞華 CHEN, RUEY-HWA
Molecular Cell
16 October 2023
PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly
Purinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. In this study, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies.
ConspectusAgricultural Biotechnology Research Center（7）
何承訓 HO, CHENG-HSUN
Heliyon
CIPK15-mediated inhibition of NH4+ transport protects Arabidopsis from submergence
Ammonium (NH4+) serves as a vital nitrogen source for plants, but it can turn toxic when it accumulates in excessive amounts. Toxicity is aggravated under hypoxic/anaerobic conditions, e.g., during flooding or submergence, due to a lower assimilation capacity. AMT1; 1 mediates NH4+ uptake into roots. Under conditions of oxygen-deficiency, i.e., submergence, the CBL-interacting protein kinase OsCIPK15 has been shown to trigger SnRK1A signaling, promoting starch mobilization, thereby the increasing availability of ATP, reduction equivalents and acceptors for NH4+ assimilation in rice. Our previous study in Arabidopsis demonstrates that AtCIPK15 phosphorylates AMT1; 1 whose activity is under allosteric feedback control by phosphorylation of T460 in the cytosolic C-terminus. Here we show that submergence cause higher NH4+ accumulation in wild-type, plant but not of nitrate, nor in a quadruple amt knock-out mutant. In addition, submergence triggers rapid accumulation of AtAMT1;1 and AtCIPK15 transcripts as well as AMT1 phosphorylation. Significantly, cipk15 knock-out mutants do not exhibit an increase in AMT1 phosphorylation; however, they do display heightened sensitivity to submergence. These findings suggest that CIPK15 suppresses AMT activity, resulting in decreased NH4+ accumulation during submergence, a period when NH4+ assimilation capacity may be impaired.
Conspectus
何承訓 HO, CHENG-HSUN
Bio-protocol
20 August 2023
Fluorescent Biosensor Imaging of Nitrate in Arabidopsis thaliana
Nitrate (NO3–) is an essential element and nutrient for plants and animals. Despite extensive studies on the regulation of nitrate uptake and downstream responses in various cells, our knowledge of the distribution of nitrogen forms in different root cell types and their cellular compartments is still limited. Previous physiological models have relied on in vitro biochemistry and metabolite level analysis, which limits the ability to differentiate between cell types and compartments. Here, to address this, we report a nuclear-localized, genetically encoded fluorescent biosensor, which we named nlsNitraMeter3.0, for the quantitative visualization of nitrate concentration and distribution at the cellular level in Arabidopsis thaliana. This biosensor was specifically designed for nitrate measurements, not nitrite. Through genetic engineering to create and select sensors using yeast, Xenopus oocyte, and Arabidopsis expression systems, we developed a reversible and highly specific nitrate sensor. This method, combined with fluorescence imaging systems such as confocal microscopy, allows for the understanding and monitoring of nitrate transporter activity in plant root cells in a minimally invasive manner. Furthermore, this approach enables the functional analysis of nitrate transporters and the measurement of nitrate distribution in plants, providing a valuable tool for plant biology research. In summary, we provide a protocol for sensor development and a biosensor that can be used to monitor nitrate levels in plants.
Conspectus
常怡雍 CHARNG, YEE-YUNG
Plant Cell
22 October 2022
Maintenance of abiotic stress memory in plants: Lessons learned from heat acclimation
The dynamic behavior of humans and even other animals highlights the existence and importance of memory. However, the static lifestyle of plants does not make it easy for people to realize that plants have memories, let alone their importance. Scientists have long observed that plants can preserve, to varying degrees, their experiences of environmental change, which alters their behaviors. These phenomena, such as vernalization (the plant's memory of winter), were considered exceptional cases. However, due to conceptual breakthroughs and experimental evidence, the more general phenomenon of priming/acclimation has come to be understood as a phenomenon that plants can remember. Priming/acclimation in plants refers to the alteration of subsequent behavior by previous experience, while memory refers to the retention of that capacity to alter. Memory should be closely related to the adaptation of plants to environmental changes. Understanding how plants maintain memory for adversity will help produce more adaptable crops to climate change. There are still many misunderstandings and problems in the literature on plant memory, especially the conceptual ambiguities and lack of easy-to-follow specifications. In addition to reviewing the critical advances in this field, this article contributes to the clarification of the concept of plant memory, clearly proposes the criteria for evaluating the abiotic memory of plants, analyzes the molecular mechanisms that maintain memory, and summarizes the currently known regulatory pathways and components involved in the maintenance of memory, using heat acclimation as an example.
Conspectus
林于鈴 LIN, YU-LING
Journal of Experimental & Clinical Cancer Research
21 April 2023
Phytogalactolipids activate antitumor humoral immunity for the treatment of colorectal cancer
We demonstrated a new pharmacological function of phytogalatolipids isolated from plant medicine Crassocephalum rabens on dominant anti-tumor humoral responses. Phytogalatolipids effectively inhibit tumor growth in colorectal tumor allograft mice and attract massive B cells into the tumor. Phytogalatolipids induce B cell differentiation in spleens and tumors, resulting in high titers of antitumor antibodies in serum. Galactolipids-induced antitumor antibodies specifically recognize surface antigens on the plasma membrane of cancer cells and trigger stronger antibody-dependent cytotoxicity, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). We discovered that these galactolipids can interact with IL-6 receptors on T cells, activate STAT3 and cMaf, and cause T cells to secrete IL-21, which in turn induces B cell differentiation through the IL-21R/STAT3/Blimp-1 pathway. Therefore, galactolipids induce B cell activation in a T cell-dependent manner and trigger antitumor antibodies, thereby preventing the progression of colorectal cancer. This research suggests that galactolipid-induced humoral immunity may be a new and effective immunotherapy for colorectal cancer.
Conspectus
邱子珍 CHIOU, TZYY-JEN
Dose-dependent long-distance movement of microRNA399 duplex regulates phosphate homeostasis in Arabidopsis
MicroRNA399 (miR399), a phosphate (Pi) starvation-induced long-distance signal, is first produced in shoots and moves to roots to suppress PHO2 encoding a ubiquitin conjugase, leading to enhanced Pi uptake and root-to-shoot translocation. However, the molecular mechanism underlying miR399 long-distance movement remains elusive. In this study, hypocotyl grafting with various Arabidopsis mutants or transgenic lines expressing artificial miR399f was employed. The movement of miR399 across graft junction and the rootstock PHO2 transcript and scion Pi levels were analyzed to elucidate the potential factors involved. Our results showed that miR399f precursors are cell-autonomous and mature miR399f movement is independent of its biogenesis, sequence context, and length (21 or 22 nucleotides). Expressing viral silencing suppressor P19 in the root stele or blocking unloading in the root phloem pore pericycle (PPP) antagonized its silencing effect, suggesting that the miR399f/miR399f* duplex is a mobile entity unloaded through PPP. Notably, the scion miR399f level positively correlates with its amount translocated to rootstocks, implying dose-dependent movement. This study uncovers the molecular basis underlying the miR399-mediated long-distance silencing in coordinating shoot Pi demand with Pi acquisition and translocation activities in the roots.
Conspectus
邱子珍 CHIOU, TZYY-JEN
TWAS coupled with eQTL analysis reveals the genetic connection between gene expression and flowering time in Arabidopsis
Genome-wide association study (GWAS) has improved our understanding of complex traits, but challenges exist in distinguishing causation versus association caused by linkage disequilibrium. Instead, transcriptome-wide association studies (TWAS) detect direct associations between expression levels and phenotypic variations, providing an opportunity to better prioritize candidate genes. To assess the feasibility of TWAS, we investigated the association between transcriptomes, genomes, and various traits in Arabidopsis, including flowering time. The associated genes formerly known to regulate growth allometry or metabolite production were first identified by TWAS. Next, for flowering time, six TWAS-newly identified genes were functionally validated. Analysis of the expression quantitative trait locus (eQTL) further revealed a trans-regulatory hotspot affecting the expression of several TWAS-identified genes. The hotspot covers the FRIGIDA (FRI) gene body, which possesses multiple haplotypes differentially affecting the expression of downstream genes, such as FLOWERING LOCUS C (FLC) and SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1). We also revealed multiple independent paths towards the loss of function of FRI in natural accessions. Altogether, this study demonstrates the potential of combining TWAS with eQTL analysis to identify important regulatory modules of FRI-FLC-SOC1 for quantitative traits in natural populations.
Conspectus
陳逸然 CHEN, YET-RAN
Nature Communications
04 August 2023
XCP1 cleaves Pathogenesis-related protein 1 into CAPE9 for systemic immunity in Arabidopsis
The significant breakthrough of this research is the successful determination of the physiological function and activity of PR1, confirming PR1 as the precursor protein of a highly active immune cytokine CAPE. In response to bacterial infections, plants must utilize a specific protease conducting caspase-like activity to release CAPE from PR1 to initiate systemic defense responses. We proposed the functional name of this enzyme as Enzyme Specific for CAPE Production (ESCAPE). This study further identifies XCP1 as the protein possessing ESCAPE function, with its enzymatic activity for CAPE production being highly temperature-sensitive. Importantly, plants lacking XCP1 cannot effectively activate systemic defense responses upon sensing a conserved molecular pattern from bacteria. Moreover, even when plants cannot synthesize or perceive salicylic acid, direct application of trace amounts of CAPE can still activate systemic defense responses in plants. As salicylic acid serves as a central signaling role for plants to counteract pathogen attacks, many pathogens inhibit its mechanism in various ways to enhance their virulence. Recent reports also indicate that a warming climate directly affects the broad-spectrum defense response mediated by salicylic acid. Combining these findings with the present study, this phenomenon might be related to the thermo-sensitive activity of plant ESCAPE (XCP1). Therefore, the direct application of CAPE peptides or the optimization of mechanisms for CAPE production within plants could contribute to broadly enhancing defense capabilities against diseases. This research outcome holds vital implications for bolstering crop disease resistance and offers a new perspective for addressing the impact of global warming on plant immunity.
ConspectusInst. of Molecular Biology （3）
夏國強 HSIA, KUO-CHIANG
Nature Communications
08 September 2023
The transcription factor TATA-box binding protein (TBP) modulates gene expression in nuclei. This process requires the involvement of nuclear transport receptors, collectively termed karyopherin-β (Kap-β) in yeast, and various regulatory factors. In previous studies we showed that Kap114p, a Kap-β that mediates nuclear import of yeast TBP (yTBP), modulates yTBP-dependent transcription. However, how Kap114p associates with yTBP to exert its multifaceted functions has remained elusive. Here, we employ single-particle cryo-electron microscopy to determine the structure of Kap114p in complex with the core domain of yTBP (yTBPC). Remarkably, Kap114p wraps around the yTBPC N-terminal lobe, revealing a structure resembling transcriptional regulators in complex with TBP, suggesting convergent evolution of the two protein groups for a common function. We further demonstrate that Kap114p sequesters yTBP away from promoters, preventing a collapse of yTBP dynamics required for yeast responses to environmental stress. Hence, we demonstrate that nuclear transport receptors represent critical elements of the transcriptional regulatory network.
Conspectus
蔡宜芳 TSAY, YI-FANG
Nature Plants
13 April 2023
Study of vacuole glycerate transporter NPF8.4 reveals a new role of photorespiration in C/N balance
Photorespiration is a complex process that recovers a two-carbon compound glycerate generated by RuBisCO oxygenation back into the Calvin–Benson–Bassham cycle. Our recent evidence shows that photorespiration is not just a futile cycle; instead, it plays a role in nitrogen flux. The localization of NPF8.4 in the tonoplast, along with the reduced vacuolar glycerate content observed in an npf8.4 mutant and the glycerate efflux activity detected in an oocyte expression system, reveals that NPF8.4 acts as a tonoplast glycerate influx transporter. It sequesters the photorespiratory carbon intermediate, glycerate, into vacuoles during nitrogen depletion, thereby reducing carbon assimilation and helping to maintain a balanced carbon–nitrogen ratio. Our study demonstrates that the expression of NPF8.4 and most photorespiration-associated genes, as well as the rate of photorespiration, is upregulated in response to short-term nitrogen (N) depletion, providing a temporary nitrogen source for amino acid remodeling. Additionally, our findings highlight the intriguing involvement of vacuoles, along with the well-known organelles chloroplasts, peroxisomes, and mitochondria, in the photorespiration pathway. This regulation is particularly crucial in alleviating growth retardation and early senescence under nitrogen-deficient conditions. Thus, our study of NPF8.4 reveals a novel aspect of photorespiration, shedding light on its contribution to nitrogen flux.
Conspectus
薛雁冰 HSUEH, YEN-PING
Science Advances
18 Jan 2023
A carnivorous mushroom paralyzes and kills nematodes via a volatile ketone
Fungal predatory behavior on nematodes has evolved independently in all major fungal lineages. The basidiomycete oyster mushroom, Pleurotus ostreatus, is a carnivorous fungus that preys on nematodes to supplement its nitrogen intake under nutrient-limiting conditions. However, the chemical identity of the nematocidal toxin remains unclear. To further investigate the mechanism of P. ostreatus’s potent nematocidal activity, we conducted forward genetic screens and isolated mutants that cannot paralyze nematodes. We found that paralysis deficient mutants fail to form lollipop-like structures, called toxocysts, on the fungal hyphae, suggesting a correlation between the structure and toxin production. By GC-MS analysis, we identified a volatile ketone, 3-octanone, in toxocysts which when exposed to C. elegans, triggered rapid paralysis, calcium influx, and neuronal cell death. We demonstrated that 3-octanone disrupts membrane integrity, causing extracellular calcium influx into the cytosol and mitochondria, which presents a novel mechanism of nematode killing by a predatory fungus. We believe that these results will pave way for parasitic nematode control in the future.
ConspectusInst. of Cellular and Organismic Biology （3）
許惠真 HSU, HWEI-JAN
Excess dietary sugar impairs Drosophila adult stem cells via elevated reactive oxygen species-induced JNK signaling
High-sugar diets (HSDs) often lead to obesity and type 2 diabetes, both metabolic syndromes associated with stem cell dysfunction. However, it is unclear whether excess dietary sugar affects stem cells. Here, we report that HSD impairs stem cell function in the intestine and ovaries of female Drosophila prior to the onset of insulin resistance, a hallmark of type 2 diabetes. Although 1 week of HSD leads to obesity, impaired oogenesis and altered lipid metabolism, insulin resistance does not occur. HSD increases glucose uptake by germline stem cells (GSCs) and triggers reactive oxygen species-induced JNK signaling, which reduces GSC proliferation. Removal of excess sugar from the diet reverses these HSD-induced phenomena. A similar phenomenon is found in intestinal stem cells (ISCs), except that HSD disrupts ISC maintenance and differentiation. Interestingly, tumor-like GSCs and ISCs are less responsive to HSD, which may be because of their dependence on glycolytic metabolism and high energy demand, respectively. This study suggests that excess dietary sugar induces oxidative stress and damages stem cells before insulin resistance develops, a mechanism that may also occur in higher organisms.
Conspectus
陳振輝 CHEN, CHEN-HUI
Nature Physics
19 June 2023
Interdisciplinary collaboration reveals 'mechanical waves' in zebrafish tailfin
For over 250 years, biologists have been puzzled by why highly regenerative animals regrow lost appendages at the rate that is proportional to the amount of appendage loss. A team led by Dr. Chen-Hui Chen at the Institute of Cellular and Organismic Biology (ICOB) and Dr. Keng-Hui Lin at the institute of physics (IOP) discovered a ‘mechanical wave’ that governs positional sensing during wound healing and regeneration. This unexpected finding has been published in the journal Nature Physics in June 2023.
Conspectus
高承福 KAO, CHENG-FU
Cell Reports
28 November 2023
Imagine our heart as a home under construction, with cardiomyocytes as the diligent builders. Scientists have long pondered the blueprint guiding these builders. A collaborative effort has shed light on a key figure in this process: a protein called RNF20. This research was conducted by Dr. Cheng-Fu Kao's team from the Institute of Cellular and Organismic Biology at Academia Sinica, in collaboration with Drs. Yao-Ming Chang, Chien-Chang Chen, and Yu-Ting Yen from the Institute of Biomedical Sciences at Academia Sinica.RNF20 isn't just any foreman on the construction site; it's more akin to an architect holding the master plan of epigenetic regulation. This involves the subtle art of switching genes on and off without altering the DNA itself. The heart's critical construction phase spans the first three weeks of a mouse's life. This period is vital for proper heart development. Without the epigenetic architect RNF20, the heart cannot be built correctly, putting the mice's survival beyond four weeks at risk. Utilizing advanced genomic analysis tools, the researchers meticulously tracked RNF20's orchestration of heart muscle maturation. They discovered that RNF20's primary directive is to ensure a robust heart structure, much like laying a solid foundation for a house. It then manages the cell growth cycle, scheduling work to ensure that each heartbeat is strong and precise. Furthermore, RNF20 oversees the metabolic pathways, crucial for the smooth operation of the heart's functions.Moreover, RNF20 intriguingly serves as an epigenetic regulator. It adjusts the heart's internal space by tightly winding or unwinding DNA around histones, ensuring optimal cardiomyocyte function. This meticulous organization is key to maintaining a stable heartbeat. RNF20 also reinforces connections between heart muscle cells (ID proteins), crucial for preserving the heart's rhythmic harmony. This landmark study not only establishes RNF20 as an indispensable epigenetic regulator in heart development but also opens new avenues for treating heart conditions. The findings, offering fresh perspectives, provide hope for advancements in cardiac health and treatment.
ConspectusInst. of Plant and Microbial Biology （5）
謝明勳 HSIEH, MING-HSIUN
The Plant Journal
23 November 2023
Dr. Ming-Hsiun Hsieh’s laboratory has created transgenic rice with enhanced vitamin B1 in the seed. The research group introduced a bacterial gene encoding thiamin monophosphate kinase into Arabidopsis and rice, creating an additional route for thiamin diphosphate biosynthesis and increasing total vitamin B1.
Conspectus
賴爾珉 LAI, ERH MIN
mBio
6 March 2023
Agrobacterial T6SS influences disease occurrence and microbiota of crown galls
The type VI secretion system (T6SS) is a widespread antibacterial weapon used by many pathogenic bacteria for interbacterial competition. However, knowledge regarding the effects of the T6SS antagonism in pathogenesis and shaping microbiota in complex microbial community is limited. By establishing a soil inoculation method mimicking natural infection of phytopathogenic agrobacteria coupled with optimized bacterial 16S rRNA gene amplicon sequencing, the research team provided evidence that the T6SS promotes disease occurrence and influences crown gall microbiota composition.
Conspectus
賴爾珉 LAI, ERH MIN
EMBO Reports
17 April 2023
Glycine zipper-mediated effector translocation into target cells
Type VI secretion systems (T6SSs) are contractile nanomachines used by bacteria to deliver effectors into target cells, enabling antagonism, virulence or nutrient acquisition. Antibacterial T6SS effectors exert their activity either in the periplasm, cytoplasm or on the membrane of target cells. While numerous antibacterial T6SS effectors have been identified, the underlying molecular mechanism by which T6SS and its associated effectors breach target cell membranes for translocation into cytoplasm still remains unknown. Understanding this mechanism provides implications over effector delivery and holds great importance for unravelling microbial interactions. By studying the T6SS DNase effector 1 (Tde1) of a soil-borne phytopathogen Agrobacterium strain C58, the research team uncovered that the effector itself plays an active role for entry into target prey cells for toxicity. The authors found that the N-terminus of Tde1 containing a single transmembrane domain overlapping with repeated glycine zipper motifs can cause membrane permeabilization in a G39xxxG43-dependent manner. Through co-immunoprecipitation, secretion, and DNase activity assays, the authors found that the N-terminus of Tde1 is necessary and sufficient for interaction with the adaptor protein Tap1 for secretion and the amino acid substitution of G39xxxG43 motif retains the Tde1 DNase activity and its interaction with Tap1 for secretion. Further, superfolder GFP fusion for translocation and interbacterial competition experiments showed that the G39xxxG43 motif of Tde1 is critical for target cell delivery and bacterial killing in DNase-dependent manner. Collectively, the authors discover that Tde1 DNase effector employs glycine zipper for translocation into target cells, representing a novel role of glycine zipper in effector delivery instead of toxicity.Considering the widespread presence of glycine zipper motifs in bacterial effectors besides pore-forming toxins, the authors proposed that this glycine zipper-mediated delivery could be a common strategy deployed by many bacterial toxins for translocation across target cell membranes. This finding provides a theoretical basis of using the non-toxic effector module for the delivery of proteins of interests such as genetic modifiers into target cells. This strategy also offers an advantage over transforming foreign DNA for expressing a protein of interest from creating undesired genome manipulation.
Conspectus
顧銓 KU, CHUAN
Genome Biology
09 January 2023
Development and evolution of xylem — the most abundant tissue on Earth
Xylem is the most abundant biological tissue on Earth. It provides mechanical support for trees, transports water to various parts of the plant body, and forms wood, an essential natural resource in our daily life. Therefore, how plants regulate the formation of xylem and how it has evolved over time are two important questions in biology. A research team led by Dr. Chuan Ku (Institute of Plant and Microbial Biology, Academia Sinica) and Ying-Chung Jimmy Lin (National Taiwan University) sampled stem xylem tissue from four tree species and collected transcriptomic data (gene expression profiles) from tens of thousands individual xylem cell protoplasts. Combining single-cell and laser capture microdissection sequencing methods, they were able to map transcriptomes to cells with specific morphology and to reconstruct an atlas of developing xylem cells through clustering and trajectory analyses of single cells. The four species represent different lineages of flowering plant (angiosperm) evolution, including a more basal angiosperm Liriodendron chinense, two core eudicots Populus trichocarpa and Eucalyptus grandis, and a basal eudicot Trochodendron aralioides. The vast majority of angiosperms have libriform fibers for mechanical support, vessel elements for conducting water, and ray parenchyma cells for lateral transport of nutrients. However, T. aralioides, which is native to Taiwan and endemic to East Asia, has undergone an \"evolutionary reversal\" and does not have libriform fibers and vessel elements, which are replaced by tracheids similar to those seen in gymnosperms. This work shows that the developmental trajectories of ray cells are highly conserved across the four woody plants. Although the libriform fibers and vessel elements of L. chinense are morphologically similar to those in eudicots, they have their distinct developmental lineages. It was also found that the tracheids of T. aralioides exhibit strong transcriptomic similarity to vessel elements rather than libriform fibers of other eudicots. Through cross-species comparisons, this work not only provides important information on xylem formation, but also opens up new perspectives for research on plant tissue evo-devo.
Conspectus
馬麗珊 MA, LAY-SUN
Nature Communications
16 September 2023
Ustilago maydis PR-1-like protein has evolved two distinct domains for dual virulence activities
A new finding has elucidated the co-evolutionary arms race between fungal pathogens and their host plants. Dr. Lay-Sun Ma and her collaborators, Drs. Yin-Ru Chiang and Chuan-Chih Hsu, disclosed how the corn smut pathogen Ustilago maydis thrives on infecting its host. The process involves a sophisticated counter-defense between two structurally conserved proteins, plant pathogenesis-related PR-1 for plant defense and fungal PR-1-like (PR-1L) proteins for fungal virulence, respectively. By producing PR-1L proteins, U. maydis confers resistance to toxic plant phenolics. U. maydis also hijacks the corn protease CatB3 to release a mimetic peptide from PR-1L to counteract the immunity-triggering peptide derived from the plant PR-1. This process suppresses plant immunity, enabling successful colonization of the fungus. These findings fill the knowledge gap of fungal parasitism in crops and the co-evolutionary dynamics of PR-1L and PR-1 protein in pathogens and their hosts, enabling the strategic improvement of crops to combat fungal pathogens.
ConspectusGenomics Research Center （4）
林國儀 LIN, KUO-I
Journal of the American Chemical Society
23 April 2023
Polysaccharides have been used as immunogens for the development of vaccines against bacterial infection. However, application of oligosaccharides to vaccine development is limited thus far. In this study, we aimed to understand how an oligosaccharide-based vaccine is processed by dendritic cells (DCs), a type of professional antigen presenting cells. By studying the mechanism of immunogenicity of a Globo-H (GH) (a glycosphingolipid, GSL) glycan-conjugate vaccine, we elucidated the intracellular enzymatic processing and presentation of an oligosaccharide-conjugate cancer vaccine by DCs. This oligosaccharide-conjugate vaccine was known to elicit antibodies against the glycan moieties of GH and the other two globo-series GSLs, Gb5 and SSEA4. Globo-series GSLs are expressed on several types of cancer and their stem cells, but how GH glycan-conjugate vaccine elicited the cross-globo series GSL anti-cancer immunity was not known. We found that the GH glycan of the vaccine can be processed by fucosidase 1 in the early endosome of DCs, yielding the Gb5 glycan (a common glycan antigen of the globo-series GSLs) along with the GH glycan to be presented by MHC class II to trigger the subsequent cross-reactive antibody responses. Thus, these findings provide insights into our understanding of the specificity and origin of cross-reactivity of antibodies elicited by the oligosaccharide-conjugate vaccine and demonstrate, for the first time, the mechanism of processing and presentation of an oligosaccharide vaccine by DCs. This discovery is expected to facilitate the design and development of glycoconjugate vaccines based on oligosaccharide antigens.
Conspectus
莊樹諄 CHUANG, TREES-JUEN
Nucleic Acids Research
27 July 2023
Trans-spliced RNAs (ts-RNAs) are a type of non-co-linear (NCL) transcripts that consist of exons in an order topologically inconsistent with the corresponding DNA template. Detecting ts-RNAs is often interfered by experimental artifacts, circular RNAs (circRNAs) and genetic rearrangements. Particularly, intragenic ts-RNAs, which are derived from separate precursor mRNA molecules of the same gene, are often mistaken for circRNAs through analyses of RNA-seq data. Here we developed a bioinformatics pipeline (NCLscan-hybrid), which integrated short and long RNA-seq reads to minimize false positives and proposed out-of-circle and rolling-circle long reads to distinguish between intragenic ts-RNAs and circRNAs. Combining NCLscan-hybrid screening and multiple experimental validation steps successfully confirmed that four NCL events, which were previously regarded as circRNAs in databases, originated from trans-splicing. CRISPR-based endogenous genome modification experiments further showed that flanking intronic complementary sequences can significantly contribute to ts-RNA formation, providing an efficient/specific method to deplete ts-RNAs. We also experimentally validated that one ts-RNA (ts-ARFGEF1) played an important role for p53-mediated apoptosis through affecting the PERK/eIF2a/ATF4/CHOP signaling pathway in breast cancer cells. This study thus described both bioinformatics procedures and experimental validation steps for rigorous characterization of ts-RNAs, expanding future studies for identification, biogenesis, and function of these important but understudied transcripts.
Conspectus
謝世良 HSIEH, SHIE-LIANG
EMBO Molecular Medicine
22 May 2023
Inhibition of SARS-CoV-2-mediated thromboinflammation by CLEC2.Fc
With the rampant spread of the novel coronavirus (SARS-CoV-2) worldwide, it has caused severe inflammation and even death in COVID-19 patients. Even after recovery, there is still a possibility of contracting long COVID, which has long-lasting and serious impacts on the lives of diagnosed individuals. Thromboinflammation refers to the combination of blood clotting and inflammation, and it is the primary cause of disease progression and mortality in COVID-19 patients. Autopsies have shown the presence of platelet-rich clots and microangiopathy (abnormalities in small blood vessels) in various organs. Furthermore, studies have found persistent microclots in the plasma of both acute COVID-19 and long COVID patients. However, the exact molecular mechanism of SARS-CoV-2-induced thromboinflammation remains unclear.Dr. Shie-Liang Edmond Hsieh and his research team have discovered a direct interaction between spleen tyrosine kinase (Syk)-coupled receptor CLEC2, which is highly expressed in platelets and alveolar macrophages, and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. They have observed that SARS-CoV-2 induces a different type of neutrophil extracellular trap (NET) formation, known as aggregated NETs, in the presence of platelets. Moreover, by stimulating platelets and neutrophils with lentivirus expressing the RBD of the SARS-CoV-2 spike protein, they have confirmed that SARS-CoV-2 activates platelets through the binding of RBD and CLEC2, leading to increased NET formation and thromboinflammation.To evaluate the potential therapeutic implications of these findings, the research team administered recombinant CLEC2 protein (CLEC2.Fc) to mice infected with SARS-CoV-2 (AAV-hACE2-infected mice). They found that recombinant CLEC2.Fc effectively inhibited the formation of NETs in the lungs and hearts induced by SARS-CoV-2 infection, and reduced thromboinflammation in the mice.This suggests that CLEC2 serves as a novel pattern recognition receptor for SARS-CoV-2, and CLEC2.Fc is a promising therapeutic agent to counteract SARS-CoV-2-induced thromboinflammation and potentially reduce the risk of post-acute sequelae of COVID-19 (PASC).
Conspectus
黃雯華 HWANG-VERSLUES, WENDY-WENHUA
Cancer Research
18 January 2023
MEX3A mediates p53 degradation to suppress ferroptosis and facilitate ovarian cancer tumorigenesis
Ovarian cancer (OC) is one of the leading causes of cancer death in women. The overall 5-year survival rate for OC is lower than 50%. Due to a lack of specific symptoms and early detection methods, most OC patients are diagnosed after the cancer has spread. OC is highly heterogeneous. Mutations in p53 are prevalent in the major OC subtype, high-grade serous ovarian carcinoma (HGSOC), while p53 mutations are much less frequent in other OC subtypes, particularly in ovarian clear cell carcinoma (OCCC). Advanced stage OCCC with wild-type (WT) p53 has a worse prognosis and increased drug resistance, metastasis, and recurrence than HGSOC. The mechanisms responsible for driving the aggressiveness of WT p53-expressing OC remain poorly understood. Here, we found that upregulation of MEX3A, a dual-function protein containing a RING finger domain and an RNA-binding domain, was critical for tumorigenesis in WT p53-expressing OC. MEX3A overexpression enhanced the growth and clonogenicity of OCCC cell lines. In contrast, depletion of MEX3A in OCCC cells, as well as ovarian teratocarcinoma cells, reduced cell survival and proliferative ability. MEX3A depletion also inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase p53 protein stability. MEX3A-mediated p53 protein degradation was crucial to suppress ferroptosis and enhance tumorigenesis. Consistently, p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in ovarian cancer cells expressing WT p53.
ConspectusResearch Center for Biodiversity （19）
何旻杰 HO, MING-JAY
Marine Biodiversity
09 September 2023
Sepioteuthis lessoniana (d'Orbigny, 1826), commonly known as oval squid, is one of the most widely distributed loliginid squids in the Indo-West Pacific. In addition, S. lessoniana in the northwestern Pacific Ocean is considered to represent a complex of three cryptic species (Imai and Aoki 2012). The oval squid lives in various habitats from just below the seawater surface to approximately 100-m depth in warm coastal areas. The preferred spawning grounds of S. lessoniana are shallow, calm inshore waters, with egg capsules observed in the spaces between branches of living stony corals, Sargassum, Gorgonacea, and manufactured bamboo structures. Deeper areas, such as mesophotic coral ecosystems (MCEs) from 50 to approximately 100-m depth, are suggested as potential oval squid spawning grounds based on numeric simulations. However, no capsules have been observed in natural MCE habitats to date except for capsules attached to anchor ropes that were recovered from 100-m depth.On March 1, 2022, we observed over 20 egg capsules of S. lessoniana at 62-m depth, at Gueiwan, Green Island (Lyudao), Taiwan. Each capsule contained around nine eggs, indicating that they could be produced by the deep-water species Aka-ika Sepioteuthis sp. 1. The capsules were attached to the upper section of a colony of Cirrhipathes sp. (Antipathidae), which were overgrown by crinoids or feather stars such as Oligometra spp. and octocorals Carijoa spp.. This colony, along with other individuals without egg capsules attached, is part of a small population attached to several scattered reefs on sandy bottoms. Our finding suggests that the complex structure formed by symbiotic animals overgrowing antipathid corals might create a microhabitat similar to counterparts on shallow-water reefs where egg capsules are commonly found. In addition, our results provide firsthand empirical evidence that MCEs can be hatching grounds. This might be because the ecological functions of MCE patch reefs have been underestimated in previous studies. Micro-ecosystems formed by creatures on patch reefs might act as oases in these deep-water deserts, providing suitable environments that have food and protection for planktonic paralarvae. Our findings call for further research into the role of MCEs in the biology
Conspectus
李文雄 LI, WEN-HSIUNG
Plant biotechnology journal
23 September 2022
Simultaneous detection of miRNA and mRNA at the single-cell level in plant tissues
Detecting the simultaneous presence of a microRNA (miRNA) and a mRNA in a specific tissue can provide support for the prediction that the miRNA regulates the mRNA. Although two such methods have been developed for mammalian tissues, they have a low signal-noise ratio and/or poor resolution at the single-cell level. To overcome these drawbacks, we develop a method that uses sequence-specific miRNA-locked nucleic acid (LNA) and mRNA-LNA probes. Moreover, it augments the detection signal by rolling circle amplification, achieving a high signal-noise ratio at the single-cell level. Dot signals are counted for determining the expression levels of mRNA and miRNA molecules in specific cells. We show a high sequence specificity of our miRNA-LNA probe, revealing that it can discriminate single-base mismatches. Numerical quantification by our method is tested in transgenic rice lines with different gene expression levels. We conduct several applications. First, the spatial expression profiling of osa-miR156 and OsSPL12 in rice leaves reveals their specific expression in mesophyll cells. Second, studying rice and its mutant lines with our method reveals opposite expression patterns of miRNA and its target mRNA in tissues. Third, the dynamic expression profiles of ZmGRF8 and zma-miR396 during maize leaf development provide evidence that zma-miR396 regulates the preferential spatial expression of ZmGRF8 in bundle sheath cells. Finally, our method can be scaled up to simultaneously detect multiple miRNAs and mRNAs in a tissue. Thus, it is a sensitive and versatile technique for studying miRNA regulation of plant tissue development.
Conspectus
林千翔 LIN, CHIEN-HSIANG
Science Advances
7 July 2023
In a groundbreaking interdisciplinary research effort spanning over three years, a team of talented scientists has unveiled a significant breakthrough. Assistant Research Fellow Dr. Chien-Hsiang Lin from the Biodiversity Research Center at Academia Sinica, along with Assistant Professor Dr. Li Lo from the Department of Geological Sciences at National Taiwan University, and Associate Professor Dr. Chih-Lin Wei and Assistant Professor Dr. Sze Ling Ho from the Institute of Oceanography at National Taiwan University, have made a remarkable discovery. Their findings shed light on the intricate relationship between the structure of tropical deep-sea fish communities and fluctuations in seawater temperature.Utilizing exceptionally well-preserved fossil fish otoliths (Fig. 1) extracted from a deep-sea core obtained from the Solomon Sea in the southwest edge of equatorial Pacific Ocean, the research team meticulously reconstructed the composition of deep-sea fish communities throughout the past 460,000 years. By conducting comprehensive analyses that combined ancient seawater temperature records with fish diversity and abundance, the team uncovered intriguing insights.The study primarily revealed a strong correlation between various fish species in the mid-ocean zone and seawater temperature. During the cooler ice ages, fish diversity soared while their overall abundance decreased. Conversely, during the warmer interglacial periods, fish diversity declined while their abundance increased. Remarkably, the team observed that only a select few heat-tolerant fish species, such as Myctophidae and Bregmacerotidae (Fig. 1), managed to thrive in larger numbers. However, the most significant finding emerged when the researchers discovered a substantial decrease in both fish diversity and abundance in the Super interglacial environment, where seawater temperatures surpassed present-day levels. Intriguingly, the study revealed distinct temperature adjustment gradients for fish diversity and abundance, with a notable difference of approximately 2 degrees in the threshold value (Fig. 2).This groundbreaking research represents the first fossil record of fish on such a long timescale and with such high time resolution. Furthermore, it establishes the crucial link between deep-sea fish community and seawater temperatures in the tropics on glacial and interglacial timescales. These findings emphasize the profound sensitivity of deep-sea fish in both oceanic and mesopelagic regions to warming seawater, underscoring the ecological challenges they may face. By enhancing our understanding of the ecosystem impacts resulting from ocean warming, this study serves as an essential and pressing warning for assessing potential repercussions on fish in the future.The complete paper has been published in the esteemed open-access journal, Science Advances. To access the full study, visit: https://www.science.org/doi/10.1126/sciadv.adf0656.
Conspectus
林子皓 LIN, TZU-HAO
Limnology And Oceanography Letters
17 October 2023
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.
Conspectus
江殷儒 CHIANG, YIN-RU
Gut Microbes
26 Feb 2023
Vertebrates, including humans, can synthesize a variety of sex hormones; however, animals cannot completely degrade these steroids. Sex hormones are recycled between the liver and the gut through enterohepatic circulation; the reabsorption of these steroids occurs mainly in human small intestine as well as rodent caecum. Gut microbes may modify and degrade gut steroids and thus regulate host sex hormone levels and profiles. Abnormally high circulating androgen levels have been considered a causative factor for benign prostatic hypertrophy and prostate cancer in men. Recent animal studies on gut microbiome suggested that gut bacteria are involved in sex steroid metabolism; however, the underlying mechanisms and bacterial taxa remain elusive. Denitrifying betaproteobacteria Thauera spp. are metabolically versatile and often distributed in the animal gut. Thauera sp. strain GDN1 is an unusual betaproteobacterium capable of catabolizing androgen under both aerobic and anaerobic conditions. We administered C57BL/6 mice (aged 7 weeks) with strain GDN1 through oral gavage. The strain GDN1 administration caused a minor increase in the relative abundance of Thauera (≤ 0.1%); however, it has profound effects on the host physiology and gut bacterial community. The results of our ELISA assay and metabolite profile analysis indicated an approximately 50% reduction in serum androgen levels in the strain GDN1-administered male mice. Moreover, androgenic ring-cleaved metabolites were detected in the fecal extracts of the strain GDN1-administered mice. Furthermore, our RT–qPCR results revealed the expression of the androgen catabolism genes in the gut of the strain GDN1-administered mice. We found that the administered strain GDN1 regulated mouse serum androgen levels, possibly because it blocked androgen recycling through enterohepatic circulation. This study discovered that sex steroids serve as a carbon source of gut bacteria; moreover, host circulating androgen levels may be regulated by androgen-metabolizing gut bacteria. Similar functional genes and corresponding androgen-transforming enzymes have been identified in our lactic acid bacteria. Among them, some probiotics can be used directly as food additives in Taiwan. We confirmed their androgen-metabolizing capability through physiological tests. Moreover, administration of these bacterial strains (BRCAS-C1~BRCAS-C3) could apparently alleviate the hair loss caused by dihydrotestosterone, the most potent androgen. Our data thus indicate the possible applicability of androgen-metabolizing gut bacteria as potent probiotics in alternative therapy of hyperandrogenism.
Conspectus
洪志銘 HUNG, CHIH-MING
BMC Biology
20 March 2023
Weak gene–gene interaction facilitates the evolution of gene expression plasticity
In 2015, NASA conducted a study by sending one of a pair of identical twins to a space station for 340 days and having the other stay on the Earth as a control. They found that the one in the space environment showed plastic changes in many phenotypic traits, including artery morphology, immune response, telomere length, etc., compared against his twin brother on Earth. This is a good demonstration of phenotypic plasticity, which means that organisms with the same genetic blueprint may exhibit plastic phenotypes in response to changing environments.Phenotypic plasticity, including gene expression (a molecular phenotype) plasticity, has strong impact on organisms’ adaptive evolution because natural selection acts directly on phenotypes instead of genotypes. Interestingly, phenotypic plasticity itself can also evolve during adaptation. However, what determines the evolution of phenotypic plasticity remains unclear. To examine this topic, we are probably the first team around the world to reciprocally transplant wild birds to common gardens with environments close to their natural habitats in montane and lowland areas to study their gene expression plasticity. We used an elevationally widespread songbird—the rufous-capped babbler—as the study system. In this work, we based on brain and liver transcriptome data from transplanted rufous-capped babblers to reveal that genes with stronger plastic expression more likely have the plasticity altered during altitudinal adaptation. We further showed that functional interdependence among genes determined both magnitude and degree of evolution in gene-expression plasticity, leading to a positive relationship between the latter two characters. These findings suggest that the evolutionary potential of phenotypic plasticity is predictable. Our study also indicates that genes with weak pleiotropic constraints and thus strong plasticity help organisms adapt to frequently changed environments.
Conspectus
町田龍二 MACHIDA, RYUJI
Molecular Ecology Resources
23 September 2021
Metatranscriptomics allows profiling of community mRNA and rRNA transcript abundance under certain environmental conditions. However, variations in the proportion of RNA transcripts across different community size structures remain less explained, thus limiting the possible applications of metatranscriptomics in community studies. Here, we extended the assumptions of the growth-rate hypothesis (GRH) and the metabolic theory of ecology (MTE) to validate the allometric scaling of interspecific RNA transcript (mRNA and rRNA) abundance through metatranscriptomic analysis of mock communities consisting of model organisms. The results suggest that body size imposes significant constraints on RNA transcript abundance. Interestingly, the relationship between the total mitochondrial transcript abundance (mRNA and rRNA slopes were −0.30 and −0.28, respectively) and body size aligned with the MTE assumptions with slopes close to −¼, while the nuclear transcripts displayed much steeper slopes (mRNA and rRNA slopes were −0.33 and −0.40, respectively). The assumed temperature dependence was not observed in this study. At the gene level, the allometric slopes range from 0 to −1. Overall, the above results showed that larger individuals have lesser RNA transcript abundance per tissue mass than smaller ones regardless of temperature. Analyses of field-collected microcrustacean zooplankton samples demonstrated that the correction of size effect, using the allometric exponents derived from the model organism mock community, explains better the patterns of interspecific RNA transcripts abundance within the metatranscriptome. Integrating allometry with metatranscriptomics can extend the use of RNA transcript reads in estimating ecological processes within complex communities.
Conspectus
端木茂甯 TUAN MU, MAO-NING
Scientific Data
21 December 2023
A global database of bird nest traits
The reproductive success of birds is closely tied to the characteristics of their nests. It is crucial to understand the distribution of nest traits across phylogenetic and geographic dimensions to gain insight into bird evolution and adaptation. Despite the extensive historical documentation on breeding behavior, a structured dataset describing bird nest characteristics has been lacking. To address this gap, we have compiled a comprehensive dataset that characterizes three ecologically and evolutionarily significant nest traits—site, structure, and attachment—for 9,248 bird species, representing all 36 orders and 241 out of the 244 families. By defining seven sites, seven structures, and four attachment types, we have systematically classified the nests of each species using information from text descriptions, photos, and videos sourced from online databases and literature. This nest traits dataset serves as a valuable addition to the existing body of morphological and ecological trait data for bird species, providing a useful resource for a wide range of avian macroecological and macroevolutionary research.
Conspectus
端木茂甯 TUAN MU, MAO-NING
Functional Ecology
14 November 2023
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.
Conspectus
蔡怡陞 TSAI, ISHENG-JASON
Nucleic Acids Research
25 August 2023
Single-worm long-read sequencing reveals genome diversity in free-living nematodes
Obtaining sufficient genetic material from a limited biological source is currently the primary operational bottleneck in studies investigating biodiversity and genome evolution. In this study, we employed multiple displacement amplification (MDA) and Smartseq2 to amplify nanograms of genomic DNA and mRNA, respectively, from individual Caenorhabditis elegans. Although reduced genome coverage was observed in repetitive regions, we produced assemblies covering 98% of the reference genome using long-read sequences generated with Oxford Nanopore Technologies (ONT). Annotation with the sequenced transcriptome coupled with the available assembly revealed that gene predictions were more accurate, complete and contained far fewer false positives than de novo transcriptome assembly approaches. We sampled and sequenced the genomes and transcriptomes of 13 nematodes from early-branching species in Chromadoria, Dorylaimia and Enoplia. The basal Chromadoria and Enoplia species had larger genome sizes, ranging from 136.6 to 738.8 Mb, compared with those in the other clades. Nine mitogenomes were fully assembled, and displayed a complete lack of synteny to other species. Phylogenomic analyses based on the new annotations revealed strong support for Enoplia as sister to the rest of Nematoda. Our result demonstrates the robustness of MDA in combination with ONT, paving the way for the study of genome diversity in the phylum Nematoda and beyond.
Conspectus
趙淑妙 CHAW, SHU-MIAW
Parentage identification of tetraploid bananas using genomics and phylogenetic tree approaches
Triploid bananas are almost sterile. However, in this study, we unexpectedly harvested a few seeds from two edible triploid banana individuals (Genotype: ABB) in our conservation repository where various wild diploid bananas were also grown nearby. Although low germination rates, these harvested seeds could generate into seedlings and their DNA content was determined to be tetraploid. Since bananas contain maternal-inherited plastids and paternal-inherited mitochondria, we sequenced and assembled plastomes and mitogenomes of these seedlings to trace their hybridization history. The coding sequences of both organellar genomic scaffolds were then extracted, aligned, and concatenated for constructing phylogenetic trees. Our results suggest that these tetraploid seedlings are derived from hybridization between edible triploid bananas and wild diploid Musa balbisiana (BB). As a result, we propose a mechanism of creating female triploid gametes via apomeiosis to interpret the germinable seeds produced by triploid bananas. Our study will have implications in not only expanding genetic recombination of bananas but also increasing genetic materials for banana-breeding programs. Further studies on the fusion and developmental processes of the hybrid em-bryos are needed to deepen our knowledge on banana reproduction, polyploidization, and evolution.
Conspectus
趙淑妙 CHAW, SHU-MIAW
Integration of large and diverse angiosperm DNA fragments into Asian Gnetum mitogenomes
Horizontal gene transfer (HGT) events have rarely been reported in gymnosperms. Gnetum is a gymnosperm genus comprising about 50 species sympatric with angiosperms in West African, South American, and Southeast Asian rainforests. Only a single acquisition of an angiosperm mitochondrial intron has been documented to date in Asian Gnetum mitogenomes. We wanted to develop a more comprehensive understanding of frequency and fragment length distribution of such events in this genus.We sequenced and assembled mitogenomes from five Asian Gnetum taxa. These genomes vary remarkably in size and foreign DNA content. We identified 15 mitochondrion-derived and five plastid-derived (MTPT) foreign genes. Our phylogenetic analyses strongly indicate that these foreign genes were transferred from diverse eudicots—mostly from the Rubiaceous genus Coptosapelta and ten genera of Malpighiales. This indicates that Asian Gnetum has experienced multiple independent HGT events. Patterns of sequence evolution strongly indicate DNA-mediated transfer between mitochondria as the primary mechanism giving rise to these HGT events. Most Asian Gnetum taxa are lianas and are often entwined with sympatric angiosperms. We therefore propose that close apposition of Gnetum and angiosperm stems presents opportunities for interspecific cell-to-cell contact through friction and wounding, leading to HGT. This study reveals that multiple HGT events have resulted in massive amounts of angiosperm mitochondrial DNA integrated into Asian Gnetum mitogenomes. Gnetum and its neighboring angiosperms are often entwined with each other, possibly accounting for frequent HGT between these two phylogenetically remote lineages
Conspectus
鍾國芳 CHUNG, KUO-FANG
Cladistics
20 April 2023
Systematics and biogeography of the Old World fern genus Antrophyum
Antrophyum is one of the largest genera of vittarioid ferns (Pteridaceae) and is most diverse in tropical Asia and the Pacific Islands, but also occurs in temperate Asia, Australia, tropical Africa and the Malagasy region. The only monographic study of Antrophyumwas published more than a century ago and a modern assessment of its diversity is lacking. Here, we reconstructed a comprehensivelysampled and robustly supported phylogeny for the genus based on four chloroplast markers using Bayesian inference, maximum likelihoodand maximum parsimony analyses. We then explored the evolution of the genus from the perspectives of morphology, systematicsand historical biogeography. We investigated nine critical morphological characters using a morphometric approach andreconstructed their evolution on the phylogeny. We describe four new species and provide new insight into species delimitation. Wecurrently recognize 34 species for the genus and provide a key to identify them. The results of biogeographical analysis suggest that thedistribution of extant species is largely shaped by both ancient and recent dispersal events.
Conspectus
鍾國芳 CHUNG, KUO-FANG
PLOS One
17 May 2023
This study extensively sampled plants of the Gesneriaceae for molecular phylogenetic analysis and introduced a new genus of Vietnamese Gesneriaceae, Langbiangia. This newly discovered plant genus is currently known to be distributed only in Langbiang Plateau of southern Vietnam, renowned for its exceptionally high biodiversity and indigenous culture. The area has been designated as the Langbiang Biosphere Reserve by the United Nations Educational, Scientific and Cultural Organization (UNESCO). By publishing Langbiangia, this study aims to highlight the unique biodiversity of the Langbiang Plateau, contributing towards the achievement of the 2030 target outlined in the United Nations Convention on Biological Diversity's 'Post-2020 Global Biodiversity Framework,' which aims to protect 30% of terrestrial ecosystems.
Conspectus
陳可萱 CHEN, KO-HSUAN
帶狀瓶爾小草真菌相研究揭露顯著根部叢枝菌根菌
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.
Conspectus
陳可萱 CHEN, KO-HSUAN
The trophic mode and competition of Bryophyte-associated macrofungi
Despite the significant attention given to the interaction between fungi and plants, a group of fungi that coexists with small moss plants has consistently been overlooked. We have limited understanding of the impact of these fungi on plant hosts, whether there is nutrient exchange between them, and even if there is any competition among fungi growing in the same environment. This study focuses on two fungi found on the margins of the walking lamp moss: Rickenella fibula and Galerina cf. minima, aiming to explore the nutrient utilization of moss-associated fungi, their effects on the host, and their influence on the overall fungal community.We found that both types of fungi can acquire carbon from plants and grow inside plant tissues without affecting the photosynthetic performance of the plants, categorizing them as weakly parasitic fungi. The colonization of these two large fungi affects the overall fungal community of the plants, and the presence of these two fungi shows a significant negative correlation. Our research unveils the feeding habits of these understudied fungi and their interactions with plants, highlighting the competitive relationships among such fungi in their habitat.
Conspectus
陳國勤 CHAN, KWOK-KAN
Molecular Ecology
16 August 2023
Acquisition of new genes often results in the emergence of novel functions and is a key step in lineage-specific adaptation. As a group of sessile crustaceans, barnacles establish permanent attachment through initial cement secretion at the larval phase followed by continuous cement secretion in juveniles and adults. However, the origins and evolution of barnacle larval and adult cement proteins remain poorly understood. The research team of Benny K.K. Chan, Research Fellow of Biodiversity Research Center performed microdissection of larval cement glands, transcriptome and shotgun proteomics and immunohistochemistry validation, successfully identified 30 larval and 27 adult cement proteins of the epibiotic turtle barnacle Chelonibia testudinaria, of which the majority are stage-and barnacle-specific. While only two proteins, SIPC and CP100K, were expressed in both larvae and adults, detection of protease inhibitors and the cross-linking enzyme lysyl oxidase paralogs in larvae and adult cement. Different CP52k cement protein paralogues could be detected in larval and adult cement, suggesting stage-specific cement proteins may arise from duplication followed by changes in expression timing of the duplicates. Interestingly, the biochemical properties of larval-and adult-specific CP52k paralogues exhibited remarkable differences. We conclude that barnacle larval and adult cement systems evolved independently, and both emerged from co-option of existing genes and de novo formation, duplication and functional divergence of lineage-specific cement protein genes.
Conspectus
陳昭倫 CHEN, CHAOLUM ALLEN
Coral Reefs
23 August 2023
Jeju Island: a sentinel for tracking ocean warming impacts on high‐latitude benthic communities
As climate changes and anthropogenic pressures increase, marine ecosystem assembly and functioning are altered. High-latitude areas may provide opportunities for some tropical and subtropical organisms to survive. Yet, it is difficult to assess ongoing changes as ecological baselines are often missing. Here, we focus on the rapidly warming region of Jeju Island (South Korea), where thermal changes may have already triggered a poleward expansion of tropical and subtropical taxa and changes in community assembly. In 2012–2014, an island-wide quantitative description of its benthic communities (5 m and 15 m depths) was made, whereas patterns in seawater temperatures were examined from 1981 to 2020. Jeju Island algal assemblage was dominated by the regionally endemic kelp, Ecklonia cava. Turf, encrusting coralline algae, alongside tropical, subtropical, and cosmopolitan macro-algae were also major components of the benthic community. Hermatypic coral cover was higher at the 15 m depth than 5 m depth. Increases in sea water temperatures were highly significant, with differences between the average annual SST [1980–2020] and annual SST reaching up to + 1.61 °C in only 40 yr. The thermal rise was more pronounced in winter than summer, and warming was further accompanied by a major decline in the number of days below 14 °C and 18 °C, which are considered critical thermal thresholds for hermatypic coral survival and reef development, respectively. Warming winter seawater temperatures could ultimately lead to a loss of seasonality and profound modifications of benthic assemblages. This study provides the necessary assessment of benthic community conditions at Jeju Island upon which the ongoing changes in the area can be explicitly demonstrated.
Conspectus黃仁磐 HUANG, JEN-PAN
Molecular Ecology Resources
08 December 2023
The genomic basis of taxonomic and morphological diversity in beetles
Beetles, despite their remarkable biodiversity and a long history of research, remain lacking in reference genomes annotated with structural variations in loci of adaptive significance. We sequenced and assembled high-quality chromosome-level genomes of four Hercules beetles which exhibit divergence in male horn size and shape and body colouration. The four Hercules beetle genomes were assembled to 11 pseudo-chromosomes, where the three genomes assembled using Nanopore data (Dynastes grantii, D. hyllus and D. tityus) were mapped to the genome assembled using PacBio + Hi-C data (D. maya). We demonstrated a striking similarity in genome structure among the four species. This conservative genome structure may be attributed to our use of the D. maya assembly as the reference; however, it is worth noting that such a conservative genome structure is a recurring phenomenon among scarab beetles. We further identified homologues of nine and three candidate-gene families that may be associated with the evolution of horn structure and body colouration respectively. Structural variations in Scr and Ebony2 were detected and discussed for their putative impacts on generating morphological diversity in beetles. We also reconstructed the demographic histories of the four Hercules beetles using heterozygosity information from the diploid genomes. We found that the demographic histories of the beetles closely recapitulated historical changes in suitable forest habitats driven by climate shifts.
ConspectusBiomedical Translation Research Center（5）
李永凌 LEE, YUNGLING
Science Translational Medicine
7 June 2023
Asthma is a common chronic airway disease. Inhaled corticosteroids (ICS) are the mainstay asthma therapy. However, there is inter-individual variability in the response to ICS, and a few patients have limited disease control and experience persistent symptoms, despite use of ICS. Neutrophil extracellular traps (NETs) have been shown to increase in the lungs and sputum of patients with severe asthma. However, the association between NETs and response to ICS in asthma is unclear. The research groups led by Dr. Yungling Lee and Dr. Ya-Jen Chang investigate the association between gene, NETs and asthma by the transcriptomic profile from asthma patients, and experimental results from in vitro and asthma murine model. The study unravels that neutrophil-related pathways and a unique neutrophil gene module related to uncontrolled asthma. NETs from peripheral neutrophils were found to be a predictor for ICS non-response. It was confirmed that corticosteroids could not suppress neutrophilic genes or inflammation in both clinical and in vivo settings. Airway hyperreactivity and inflammation were inhibited after disrupting NETs by DNase I treatment in vivo. Finally, from neutrophil RNA sequencing, the gene expression of CCL4L2 was identified to be higher in ICS non-response. CCL4L2 expression showed a significant positive correlation with NET production. These results highlight CCL4L2 and NETs as potential therapeutic targets for individuals with asthma refractory to ICS.
Conspectus
林宜玲 LIN, YI-LING
Emerging microbes & infections
24 Dec 2022
Numerous vaccines have been developed to address the current COVID-19 pandemic, but safety, cross-neutralizing efficacy, and long-term protectivity of currently approved vaccines are still important issues. In this study, we developed a subunit vaccine, ASD254, by using a nanoparticle vaccine platform to encapsulate the SARS-CoV-2 spike receptor-binding domain (RBD) protein. As compared with the aluminum-adjuvant RBD vaccine, ASD254 induced higher titers of RBD-specific antibodies and generated 10- to 30-fold more neutralizing antibodies. Mice vaccinated with ASD254 showed protective immune responses against SARS-CoV-2 challenge, with undetectable infectious viral loads and reduced typical lesions in lung. Besides, neutralizing antibodies in vaccinated mice lasted for at least one year and were effective against various SARS-CoV-2 variants of concern, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, particle size, polydispersity index, and zeta-potential of ASD254 remained stable after 8-month storage at 4°C. Thus, ASD254 is a promising nanoparticle vaccine with good immunogenicity and stability to be developed as an effective vaccine option in controlling upcoming waves of COVID-19.
Conspectus
胡哲銘 HU, CHE-MING
Advanced Science
24 April 2023
The association between neutrophil extracellular traps (NETs) and response to inhaled corticosteroids (ICS) in asthma is unclear. To better understand this relationship, we analyzed the blood transcriptomes from children with controlled and uncontrolled asthma in the Taiwanese Consortium of Childhood Asthma Study using weighted gene coexpression network analysis and pathway enrichment methods. We identified 298 uncontrolled asthma-specific differentially expressed genes and one gene module associated with neutrophil-mediated immunity, highlighting a potential role for neutrophils in uncontrolled asthma. We also found that NET abundance was associated with nonresponse to ICS in patients. In a neutrophilic airway inflammation murine model, steroid treatment could not suppress neutrophilic inflammation and airway hyperreactivity. However, NET disruption with deoxyribonuclease I (DNase I) efficiently inhibited airway hyperreactivity and inflammation. Using neutrophil-specific transcriptomic profiles, we found that CCL4L2 was associated with ICS nonresponse in asthma, which was validated in human and murine lung tissue. CCL4L2 expression was also negatively correlated with pulmonary function change after ICS treatment. In summary, steroids fail to suppress neutrophilic airway inflammation, highlighting the potential need to use alternative therapies such as leukotriene receptor antagonists or DNase I that target the neutrophil-associated phenotype. Furthermore, these results highlight CCL4L2 as a potential therapeutic target for individuals with asthma refractory to ICS.
Conspectus謝世良 HSIEH, SHIE-LIANG
EMBO Molecular Medicine
22 May 2023
Inhibition of SARS-CoV-2-mediated thromboinflammation by CLEC2.Fc
With the rampant spread of the novel coronavirus (SARS-CoV-2) worldwide, it has caused severe inflammation and even death in COVID-19 patients. Even after recovery, there is still a possibility of contracting long COVID, which has long-lasting and serious impacts on the lives of diagnosed individuals. Thromboinflammation refers to the combination of blood clotting and inflammation, and it is the primary cause of disease progression and mortality in COVID-19 patients. Autopsies have shown the presence of platelet-rich clots and microangiopathy (abnormalities in small blood vessels) in various organs. Furthermore, studies have found persistent microclots in the plasma of both acute COVID-19 and long COVID patients. However, the exact molecular mechanism of SARS-CoV-2-induced thromboinflammation remains unclear.Dr. Shie-Liang Edmond Hsieh and his research team have discovered a direct interaction between spleen tyrosine kinase (Syk)-coupled receptor CLEC2, which is highly expressed in platelets and alveolar macrophages, and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. They have observed that SARS-CoV-2 induces a different type of neutrophil extracellular trap (NET) formation, known as aggregated NETs, in the presence of platelets. Moreover, by stimulating platelets and neutrophils with lentivirus expressing the RBD of the SARS-CoV-2 spike protein, they have confirmed that SARS-CoV-2 activates platelets through the binding of RBD and CLEC2, leading to increased NET formation and thromboinflammation.To evaluate the potential therapeutic implications of these findings, the research team administered recombinant CLEC2 protein (CLEC2.Fc) to mice infected with SARS-CoV-2 (AAV-hACE2-infected mice). They found that recombinant CLEC2.Fc effectively inhibited the formation of NETs in the lungs and hearts induced by SARS-CoV-2 infection, and reduced thromboinflammation in the mice.This suggests that CLEC2 serves as a novel pattern recognition receptor for SARS-CoV-2, and CLEC2.Fc is a promising therapeutic agent to counteract SARS-CoV-2-induced thromboinflammation and potentially reduce the risk of post-acute sequelae of COVID-19 (PASC).
Conspectus陶秘華 TAO, MI-HUA
Molecular Therapy
08 September 2023
Developing Broad-Spectrum Antibody Drugs to Combat Variants of COVID-19
In the post-COVID-19 era, developing enduring and broad-spectrum antiviral drugs is paramount to preventing widespread outbreaks from variants of the virus and potential emerging coronaviruses. Driven by the viruses' reliance on hACE2 as the primary cellular receptor, we collaborate with Dr. I-Hsuan Wang (Institute of Biomedical Sciences at Academia Sinica) to discover a monoclonal antibody ch2H2, which exhibited a high affinity to the viral Spike protein binding site on hACE2. This antibody, without affecting the biological function of hACE2, demonstrated robust inhibitory effects against various COVID-19 viral variants in in vivo neutralization studies. Utilizing adeno-associated virus (AAV) delivery in animal experiments, a single injection resulted in sustained and high levels of ch2H2 antibodies in mice. In prophylactic administration against the Omicron variant BA.5, which led to declined vaccine effectiveness, AAV/ch2H2 significantly reduced viral loads and mitigated pulmonary pathological changes. These findings underscore the potential of AAV-delivered hACE2-blocking antibodies as a promising avenue for broad-spectrum antiviral drug development in the future.
Conspectus