Biology subjects

Zhang, L.

Publications and source records attributed to Zhang, L..

At least 829 records · Page 46Linked to original sources

bioRxiv2023

SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection

A better mechanistic understanding of virus-host interactions can help reveal vulnerabilities and identify opportunities for therapeutic interventions. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecycle. Here, we use subcellular proteomics, ribosome profiling analyses and reporter assays to detect changes in polysome composition and protein synthesis during SARS-CoV-2 (CoV2) infection. We identify specific translation factors and molecular chaperones whose inhibition impairs infectious particle production without major toxicity to the host. We find that CoV2 non-structural protein Nsp1 selectively enhances virus translation through functional interactions with initiation factor EIF1A. When EIF1A is depleted, more ribosomes initiate translation from an upstream CUG start codon, inhibiting translation of non-structural genes and reducing viral titers. Together, our work describes multiple dependencies of CoV2 on host biosynthetic networks and identifies druggable targets for potential antiviral development.

microbiology↗

bioRxiv2023

A fungal pathogen manipulates phytocytokine signaling for plant infection

Phytocytokines are hormone-like plant peptides that modulate immune homeostasis and development. Phytosulfokine (PSK) mediates plant growth and attenuates activation of plant pattern-triggered immunity (PTI). We show that the small cysteine-containing effector VdSCP8 from Verticillium dahliae (Vd) is a virulence-promoting protein that suppresses PTI in Arabidopsis thaliana and Nicotiana benthamiana. Apoplastic SCP8 suppresses immune activation through leucine-rich repeat ectodomain pattern recognition receptors. SCP8 virulence and immunosuppressive activities require PHYTOSULFOKINE RECEPTOR 1 (PSKR1), which binds PSK and forms a complex with co-receptor BAK1 for PTI suppression. We find that PSK, like SCP8, suppresses PTI, SCP8 stimulates PSKR1-BAK1 complex formation, and that Vd requires PSK signaling for host infection. SCP8 interacts with an apoplastic subtilase, and co-expression of SCP8 and subtilase inhibitors reduces PTI suppression. Our findings suggest that a multi-host plant pathogen manipulates PTI by enhancing immunosuppressive PSK signaling, likely through plant subtilase activity.

plant biology↗

bioRxiv2023

Variations in Homoeologous Dosage and Epigenomics Mark the Early Evolution of Synthetic Brassica Tetraploids

Polyploidization is important in plant evolution and is becoming increasingly important in crop breeding and material creation. Studies have provided evidence for structural variations and epigenomic repatterning in synthetic polyploidizations, but the relationships between structural and epigenomic variations, as well as their effects on gene expression and phenotypic variations are unknown. Here, we investigated the genome-wide large deletion/duplication regions (DelDups) and genomic methylation dynamics, in the leaf organ as a representative, of progenies from eight generations that derived from the synthetic tetraploidization between Brassica rapa and Brassica oleracea. We found that half or complete deletion/duplication of fragments ranging in size from 400 kb to 65.85 Mb, with a mean size of 5.70 Mb, occurred frequently from the first generation of selfing and thereafter. The genes located in these DelDups expressed at levels expected for a positive dosage effect, as indicated by the positive association between expression and the copy number of these genes. Plants containing these DelDups also showed distinct phenotypic variations. The whole genome methylation level experienced significant fluctuations in different generations and eventually decreased in the latter generations. Moreover, the DelDups did not show methylation changes from other individuals of the same generation, and the local regions with methylation alterations did not affect gene expression. Our findings provide new insights into the early evolution of polyploid genomes and guide the use of synthetic polyploidizations in breeding.

genomics↗

bioRxiv2023

Enzyme-mediated alkynylation enables transcriptome-wide identification of pseudouridine modifications

Pseudouridine ({Psi}) is one of the most abundant chemical modifications that exists in various types of RNA species and is known to play important roles in RNA function. The advances in studies of {Psi} in less abundant messenger RNA species have been hindered by a lack of suitable methods to precisely and sensitively map their distributions. Here we show that a methyltransferase from Methanocaldococcus jannaschii can label RNA {Psi} efficiently and specifically with various functional groups, both in isolated RNA and inside cells. We leveraged this enzymatic labeling strategy to develop ELAP-seq as a facile method to enrich {Psi}-modified transcripts for the detection of {Psi} modifications at single base resolution with high sensitivity and low background. Using this method, we identified over 10, 000 candidate {Psi} sites from human transcripts, which provides new insights into {Psi} biosynthesis and function. Our study provides a chemical biology method that specifically labels {Psi} for its detection and functional alteration.

biochemistry↗

bioRxiv2023

A generalized approach to genetic drift and its applications -- I. An example of the evolution of ribosomal RNA genes

Multi-copy gene systems that evolve within, as well as between, individuals are common. They include viruses, mitochondrial DNAs, multi-gene families etc. The paradox is that neutral evolution in two stages should be slower than single-copy systems but the opposite is often true. We now apply the Haldane model, recently generalized as the GH model (1), to quantify genetic drift in mammalian ribosomal RNA genes (rDNAs). On average, the copy number (C) is 150 - 300 per haploid. A neutral mutation in rDNA should take 4NC* generations to become fixed (N, the population size; C *, the effective copy number within individuals). While C > C* >> 1 is expected, the observed fixation time in mouse is < 4N, leading to the paradox of C* < 1. Genetic drift of rRNA genes thus appears 10-100 times stronger than in single-copy genes. The large increases are driven by a host of molecular mechanisms such as gene conversion and unequal crossover. Although each mechanism of drift is very difficult to quantify, the GH model permits the estimation of their total effects that constitute the aggregate "evolutionary noises". In humans, the fixation rate of rRNA genes is higher than the theoretical maximum of drift, hence, justifying the inference of adaptive evolution. In conclusion, the stochastic evolution in multi-copy gene systems, including viruses and others, can be effectively tracked by GH model.

evolutionary biology↗

bioRxiv2023

HCCDB v2.0: Decompose the Expression Variations by Single-cell RNA-seq and Spatial Transcriptomics in HCC

Large-scale transcriptomic data are crucial for understanding the molecular features of hepatocellular carcinoma (HCC). By integrating 15 transcriptomic datasets of HCC clinical samples, the first version of HCCDB was released in 2018. The meta-analysis of differentially expressed genes and prognosis-related genes across multiple datasets provides a systematic view of the altered biological processes and the inter-patient heterogeneities of HCC with high reproducibility and robustness. After four years, the database needs to integrate recently published datasets. Furthermore, the latest single-cell and spatial transcriptomics provided a great opportunity to decipher the complex gene expression variations at the cellular level with spatial architecture. Here, we present HCCDB v2.0, an updated version that combines bulk, single-cell, and spatial transcriptomic data of HCC clinical samples. It dramatically expands the bulk sample size, adding 1656 new samples of 11 datasets to the existing 3917 samples, thereby enhancing the reliability of transcriptomic meta-analysis. A total of 182,832 cells and 69,352 spatial spots are added to the single-cell and spatial transcriptomics sections, respectively. A novel single-cell level and 2-dimension (sc-2D) metric was proposed to summarize the cell type-specific and dysregulated gene expression patterns. Results are all graphically visualized in our online portal, allowing users to easily retrieve data through a user-friendly interface and navigate between different views. With extensive clinical phenotypes and transcriptomic data in the database, we show two applications for identifying prognosis-associated cells and tumor microenvironment. HCCDB v2.0 is available at http://lifeome.net/database/hccdb2.

cancer biology↗

bioRxiv2023

TRAIL agonists rescue mice from radiation-induced lung injury

Cancer therapy is often limited by toxicity from pneumonitis. This often-lethal side effect is known to be impacted by innate immunity, and in particular the pathways regulated by the TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from the lethal effects of radiation. We found that two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound #10 (TIC10/ONC201), could achieve this goal. Both compounds could completely protect mice from lethality by reducing pneumonitis, alveolar-wall thickness, and oxygen desaturation. At the molecular level, this protection appeared to be due to the inhibition of CCl22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from high doses of radiation exposure has important translational implications. One Sentence SummaryPrevention of lethality, pneumonitis, lung fibrosis and skin dermatitis post-{psi}-irradiation by short- term treatment with innate immune TRAIL pathway agonists

pathology↗

bioRxiv2023

Structural basis for flagellin induced NAIP5 activation.

The NAIP/NLRC4 inflammasome is activated when NAIP binds to a gram-negative bacterial ligand. Initially, NAIP exists in an inactive state with a wide-open conformation. Upon ligand binding, the winged helix domain (WHD) of NAIP is activated and forms steric clash with NLRC4 to open it up. However, how ligand binding induces the conformational change of NAIP is less clear. To understand this process, we investigated the dynamics of the ligand binding region of inactive NAIP5 and solved the cryo-EM structure of NAIP5 in complex with its specific ligand, FliC from flagellin, at 2.93 [A] resolution. The structure revealed a "trap and lock" mechanism in FliC recognition, whereby FliC-D0C is first trapped by the hydrophobic pocket of NAIP5, then locked in the binding site by the insertion domain (ID) and C-terminal tail (CTT) of NAIP5. The FliC-D0N domain further inserts into the loop of ID to stabilize the complex. According to this mechanism, FliC activates NAIP5 by bringing multiple flexible domains together, particularly the ID, HD2, and LRR domains, to form the active conformation and support the WHD loop in triggering NLRC4 activation.

immunology↗

bioRxiv2023

Decoded EEG Neurofeedback-Guided Cognitive Reappraisal Training for Emotion Regulation

Neurofeedback is an innovative self-training that adjusts and enhances brain function. One of the more studied application scenarios with neurofeedback training is emotion regulation. Compared with regional brain activity-informed neurofeedback techniques, neurofeedback protocols using the decoded brain states as feedback signals could make the setting of regulation targets more specific and objective. In the present study, we constructed an EEG neurofeedback-guided cognitive reappraisal training protocol for emotion regulation. Forty-two healthy participants (20 females; 22.4{+/-}2.2 years old) were recruited and were randomly assigned to either the neurofeedback group or the control group. During the training process, we calculate the real-time self-regulation performance on the evoked emotion based on the decoded emotional states and fed it back to the subjects as the feedback signal. According to our results, real-time feedback of the regulation effect helps subjects improve emotion regulation performance for emotional stimuli with low positive valence. Further analysis of selected EEG features for emotion classification revealed the neural correlates with neurofeedback training. This newly proposed neurofeedback training protocol is a promising treatment for emotion-related mental disorders, with the potential to be a low-cost and high-portability brain-based, non-invasive, neural modulation technique.

neuroscience↗

bioRxiv2023

Physicochemical, functional, and evolutionary characteristics of protein loop regions in human and Escherichia coli proteomes

Protein loops often play crucial roles in the formation of binding and enzyme active sites. However, the general structural and biological characteristics of these loops remain unclear. In this study, we investigated protein loop regions on a large scale from structural and evolutionary perspectives. After removing redundancy at the protein chain level, 555,516, 102,901, and 24,818 loops were extracted from the entire PDB, Homo sapiens, and Escherichia coli proteins, respectively. Regardless of whether they were isolated from humans or E. coli, numerous loop sequences tended to be unique among proteins or protein chains. However, loop properties exhibited high similarity or conservation, including length, distance, and stretch. The CATH classification analysis suggested that most loops connected the same superfamily, while the heterogeneity of superfamily context repertoires was not explained at the topology or homologous level. In contrast, the functions of conserved loops between human and E. coli proteins were not consistently conserved, with sequences exhibiting considerable divergence in enrichment. The amino acid composition profiles showed that loops from humans exhibited a preference for serine, whereas E. coli loops had biases for glycine and alanine. Although the amino acid composition was primarily determined by the species, the composition of certain special types of loops clustered separately from other classes, suggesting the existence of conserved loops with complex functions. Collectively, this study provides a detailed overview of protein loops from the structural, functional, and evolutionary perspectives and a vast natural loop repertoire for mining additional information.

bioinformatics↗

bioRxiv2023

Protein Dynamics Govern the Oxyferrous State Lifetime of an Artificial Oxygen Transport Protein

It has long been known that the alteration of protein side chains which occlude or expose the heme cofactor to water can greatly affect the stability of the oxyferrous heme state. Here we demonstrate that the rate of dynamically-driven water penetration into the core of an artificial oxygen transport protein also correlates with oxyferrous state lifetime by reducing global dynamics, without altering the structure of the active site, via the simple linking of the two monomers in a homodimeric artificial oxygen transport protein using a glycine-rich loop. The tethering of these two helices does not significantly affect the active site structure, pentacoordinate heme binding affinity, reduction potential, or gaseous ligand affinity. It does, however, significantly reduce the hydration of the protein core as demonstrated by resonance Raman spectroscopy, backbone amide hydrogen exchange, and pKa shifts in buried histidine side chains. This further destabilizes the charge-buried entatic state and nearly triples the oxyferrous state lifetime. These data are the first direct evidence that dynamically-driven water penetration is a rate-limiting step in the oxidation of these complexes. It furthermore demonstrates that structural rigidity which limits water penetration is a critical design feature in metalloenzyme construction and provides an explanation for both the failures and successes of earlier attempts to create oxygen-binding proteins. SignificanceThis communication sheds light on one of the more controversial areas in protein folding and design: the dynamic nature of the hydrophobic core and its relationship to metalloprotein function, in particular the relationship between dynamic solvent penetration into the protein core and the stability of metalloenzyme intermediates. We demonstrate that the basic tetrameric scaffold that is the classic helical bundle model for cofactor binding and activation can be easily upgraded to a more rigid, less dynamic, single chain helical bundle by merely taking the same helical sequences and converting it to a single chain protein connected by simple, nonoptimized glycine-rich loops. Importantly, our results explain the decades-long history of failure in the design of proteins capable of stably forming an oxyferrous state - the requirement for a protein large enough to protect the heme porphyrin surface with both structural specificity and sufficient structural rigidity to restrict water penetration into the protein core. Finally, we believe this is the first use of Deep UV Resonance Raman spectroscopy to monitor dynamic water penetration in a functional protein. This method may prove useful moving forward to many research groups.

biophysics↗

bioRxiv2023

Zfp318 controls the recallability of memory B cells

Expression of the transcriptional regulator ZFP318 is induced in germinal center (GC)- exiting memory B cell precursors and memory B cells (MBCs). Using a conditional ZFP318 fluorescence reporter that also enables ablation of ZFP318-expressing cells, we found that ZFP318-expressing MBCs were highly enriched with GC-derived cells. Although ZFP318-expressing MBCs constituted only a minority of the antigen-specific MBC compartment, their ablation severely impaired recall responses. Deletion of Zfp318 did not alter the magnitude of primary responses but markedly reduced MBC participation in recall. CD40 ligation promoted Zfp318 expression, whereas B-cell receptor (BCR) signaling was inhibitory. Enforced ZFP318 expression enhanced recall performance of MBCs that otherwise responded poorly. ZFP318-deficient MBCs expressed less mitochondrial genes, had structurally compromised mitochondria, and were susceptible to reactivation-induced cell death. The abundance of ZFP318-expressing MBCs, instead of the number of antigen-specific MBCs, correlated with the potency of prime-boost vaccination. Therefore, ZFP318 controls the MBC recallability and represents a quality checkpoint of humoral immune memory.

immunology↗

bioRxiv2023

Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer

High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a high stromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. Single-cell transcriptomics of the HGSOC TME from public and in-house datasets revealed a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors had a lower fraction of certain T cells, natural killer (NK) cells, and macrophages and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicated that epithelial cancer cells and CA-MSCs secreted CXCL12 that interacted with the CXCR4 receptor, which was overexpressed on NK and CD8+ T cells. CXCL12 and/or CXCR4 antibodies confirmed the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.

cancer biology↗

bioRxiv2023

Histone lactylation antagonizes senescence and skeletal muscle aging via facilitating gene expression reprogramming

One of the prominent drivers of cellular senescence and/or aging is epigenetic alteration, through which orchestrated regulation of gene expression is achieved during the processes. Accumulating endeavors have been devoted to identifying histone modifications-related mechanisms underlying senescence and aging. Here, we show that histone lactylation, a recently identified histone modification bridging metabolism, epigenetic regulation of gene expression and cellular activities in response to internal and external cues, plays a crucial role in counteracting senescence as well as mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, the abundance of histone lactylation is markedly decreased during senescence and aging but restored following manipulation of the metabolic environment. Genome-wide distribution profiling and gene expression network analysis uncover that the maintenance of histone lactylation level is critical for suppressing senescence and aging programs via targeting of proliferation- and homeostasis-related pathways. We also confirmed that the level of histone lactylation is not only controlled by glycolysis but also regulated by NAD+ content in vivo. More intriguingly, running exercise enhances the level of histone lactylation and reconstructs the cell landscape and communications of mouse skeletal muscle, leading to rejuvenation and functional improvement. Our study highlights the role of histone lactylation in regulating senescence as well as aging-related tissue function, implying that this modification could be used as a novel marker of senescence, and provides a potential target for aging intervention via metabolic manipulation.

cell biology↗

bioRxiv2023

TPR domain assigns versatility of BcTir/Tpr system against viral infection

NAD+-derived signal produced by TIR domain triggered the host immune responses. The ubiquitous TPR domain involved in signal recognition and effector activation were found widely assembled with the TIR domain. However, the immune roles of these assemblies remain elusive. Here, a two-gene operon, one containing a TIR domain, designated as BcTir, and the other, BcTpr, from Bacillus cereus, exhibited anti-phage immunity. BcTpr, but not BcTir, exhibited NADase activity to produce the cyclic ADPR (cADPR) isomer and mediate NAD+ depletion. Noticeably, the truncated N terminus of BcTpr only depleted NAD+ unless at the presence of TPR domain to generate cADPR isomer unveiling its role played for glycosite selection. In addition, the BcTir/Tpr system significantly repressed viral proliferation and increased oxidation resistance by scavenging excessive reactive oxygen species (ROS) upon phage infection. These findings unraveled a multifunctional role of the BcTir/Tpr system during immune responses. In BriefThe bacterial BcTir/Tpr system was identified with the ability to protect against phage infection via NAD+ depletion, viral replication repression, and ROS homeostasis, in which BcTpr played a dual role in NAD+-derived signal production and NAD+ depletion. HighlightsO_LIThe BcTir/Tpr system works as a BcTir-BcTpr complex against phage infection. C_LIO_LIBcTpr, instead of BcTir, generates the NAD+-derived cADPR isomer through its glycosidase domain at N terminus. C_LIO_LIThe amount of cADPR isomer production is regulated by the helix numbers of the TPR domain at C terminus of BcTpr. C_LIO_LIThe BcTir/Tpr system can depress phage proliferation and decrease ROS production upon phage infection. C_LI

microbiology↗

bioRxiv2023

Rapid intracellular acidification is a novel plant defense response countered by the brown planthopper

The brown planthopper (BPH) is the most destructive insect pest in rice. Through a stylet, BPH secrets a plethora of salivary proteins into rice phloem cells as a crucial step of infestation. However, how various salivary proteins function in rice cells to promote insect infestation is poorly understood. Among them, one of the salivary proteins is predicted to be a carbonic anhydrase (NlCA). The survival rate of the NlCA-RNA interference (RNAi) BPH insects was extremely low on rice, indicating a vital role of this salivary protein in BPH infestation. We generated NICA transgenic rice plants and found that NlCA expressed in rice plants could restore the ability of NlCA-RNAi BPH to survive on rice. Next, we produced rice plants expressing the ratiometric pH sensor pHusion and found that NlCA-RNAi BPH induced rapid intracellular acidification of rice cells during feeding. Further analysis revealed that both NlCA-RNAi BPH feeding and artificial of lowering intracellular pH activated plant defense responses, and that NICA-mediated intracellular pH stabilization is linked to diminished defense responses, including reduced callose deposition at the phloem sieve plates and suppressed defense gene expression. Given the importance of pH homeostasis across the kingdoms of life, discovery of NICA-mediated intracellular pH modulation uncovered a new dimension in the interaction between plants and piecing/sucking insect pests. The crucial role of NICA for BPH infestation of rice suggests that NICA is a promising target for chemical or trans-kingdom RNAi-based inactivation for BPH control strategies in plants. HighlightsO_LIRapid intracellular acidification is a novel plant defense response. C_LIO_LIBrown planthopper delivers into rice tissues a major virulence protein, carbonic anhydrase (NlCA), critical for survival. C_LIO_LINlCA counters intracellular acidification to suppress plant defense. C_LIO_LIResults implicate existence of pH-responsive regulators of defense responses in the rice-brown planthopper interaction. C_LI In briefThe brown planthopper (BPH) is the most devasting insect pest in rice. Jiang et al. discovered that BPH secretes a salivary carbonic anhydrase (NICA) to regulate the intracellular pH of the rice cell to facilitate its feeding and survival on rice plants and that NICA-counters host intracellular pH acidification to diminished defense responses. These findings uncovered that intracellular pH homeostasis is a previously uncharacterized battleground in plant-insect interactions, but also open a door to future discovery of pH-responsive intracellular regulators of defense responses, which could add a new research dimension in the study of plant-biotic interactions.

plant biology↗

bioRxiv2023

Discovery of new deaminase functions by structure-based protein clustering

The elucidation of protein function and its exploitation in bioengineering have greatly contributed to the development of the life sciences. Existing protein mining efforts generally rely on amino acid sequences rather than protein structures due to technical difficulties in structural elucidation. We describe here for the use of AlphaFold2 to predict and subsequently cluster an entire protein family based on predicted structure similarities. We selected the deaminase family of proteins to analyze and through this approach identified many previously unknown deaminase properties. We applied these new deaminases to the development of new cytosine base editors with distinct features. Although we found many new double-stranded DNA deaminases from the DddA-like protein clade, we were surprised to find that most of the proteins in this family were not actually double-stranded DNA cytidine deaminases. From this protein clade, we engineered the smallest single-strand specific cytidine deaminase, which facilitates the first efficient cytosine base editor to be packaged into a single AAV vector. Importantly, we also profiled a deaminase from this clade that edits robustly in soybean plants, which previously suffered from poor editing by cytosine base editors. These newly discovered deaminases based on AI-assisted structural predictions greatly expand the utility of base editors for therapeutic and agricultural applications.

molecular biology↗

bioRxiv2023

Longevity-associated SMAD3 non-coding centenarian variant impairs a cell-type specific enhancer to reduce inflammation

Given the pro and anti-geronic roles of the TGF-{beta} superfamily in aging, we hypothesized that human longevity involves genetic variation in TGF-{beta} signaling genes. Here we utilized a candidate functional genomic approach to identify and characterize functional variants in TGF- {beta} signaling associated with human longevity. Targeted sequencing of 113 genes involved in aging- associated TGF- {beta} signaling in an Ashkenazi Jewish centenarian cohort identified genetic variants robustly associated with human longevity. In particular, a centenarian-enriched intronic variant residing in a cell-type specific enhancer in SMAD3, a critical receptor-regulated TGF- {beta} signal transducer, was identified. This non-coding SMAD3 variant (rs8040709) altered binding of ELK1, a member of the ETS family of transcription factor important for enhancer activity in certain cell types, resulting in reduced SMAD3 expression. Analysis of the variant in cell types derived from gene edited iPSCs demonstrated the variant reduced SMAD3 expression, senescence and inflammation in endothelial cells. In addition, heterozygosity in SMAD3 improved healthspan and reduced senescence in the Ercc1-/{Delta} progeroid mouse model of accelerated aging. Taken together, these experiments demonstrate that variants in a cell type specific enhancer of SMAD3 resulted in reduced expression, senescence and inflammation and contributes to human longevity. Thus, SMAD3 represents a validated targeted for drug development for extending human healthspan.

genetics↗