N-acetyltransferase 10 promotes cutaneous wound repair via the NF-κB-IL-6 axis.

Cutaneous wound healing, an integral part for protection of skin barrier, is a complex biological process and intimately associated with keratinocyte migration. However, mechanisms regulating keratinocyte migration in the process of cutaneous wound repair remain largely unknown. Here, we found that N-acetyltransferase 10 (NAT10) is essential for cutaneous wound repair in an in vivo skin wound healing model-a significant delay of wound repair in Nat10 haploinsufficient mice and a remarkable inhibition of keratinocyte migration by NAT10 knockdown in an in vitro keratinocyte migration model. We further demonstrate that loss of NAT10 expression attenuates the wound-induced IL-6/IL-8 expression through inhibiting NF-κB/p65 activity in keratinocytes. By deeply digging, silencing NAT10 compromises the level of nuclear p65 by facilitating its poly-ubiquitination, thus accelerates its degradation in the nucleus. Notably, we detected a strong positive correlation between the expression of NAT10 and relevant NF-kB/p65-IL6 signaling activity in mouse wound skin tissues. Overall, our study reveals an important role of NAT10 on cutaneous wound repair by potentiating NF-κB/p65-IL-6/8-STAT3 signaling. Targeting NAT10 might be a potential strategy for the treatment of skin wound dysfunctions and related diseases.

Comparative transcriptome analysis of sensory genes from the antenna and abdomen of Quadrastichus mendeli Kim.

Quadrastichus mendeli Kim is one of the most important parasitoids of Leptocybe invasa Fisher et La Salle, which is an invasive gall-making pest in eucalyptus plantations in the world. Gall-inducing insects live within plant tissues and induce tumor-like growths that provide the insects with food, shelter, and protection from natural enemies. Empirical evidences showed that sensory genes play a key role in the host location of parasitoids. So far, what kind of sensory genes regulate parasitoids to locate gall-inducing insects has not been uncovered. In this study, sensory genes in the antenna and abdomen of Q. mendeli were studied using high-throughput sequencing. In total, 181,543 contigs was obtained from the antenna and abdomen transcriptome of Q. mendeli. The major sensory genes (chemosensory proteins, CSPs; gustatory receptors, GRs; ionotropic receptors, IRs; odorant binding proteins, OBPs; odorant receptors, ORs; and sensory neuron membrane proteins, SNMPs) were identified, and phylogenetic analyses were performed with these genes from Q. mendeli and other model insect species. The gene co-expression network constructed by WGCNA method is robust and reliable. There were 10,314 differentially expressed genes (DEGs), and among them, 99 genes were DEGs. A comprehensive sequence resource with desirable quality was built by comparative transcriptome of the antenna and abdomen of Q. mendeli, enriching the genomic platform of Q. mendeli.

Biomarkers of aging.

Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.

A Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice.

The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as senolytics, have proven beneficial for health; however, the biomarkers that label in vivo senescence at systemic levels are lacking, thus hindering anti-aging applications. In this study, we generate a Glb1+/m‒Glb1-2A-mCherry (GAC) reporter allele at the Glb1 gene locus, which encodes lysosomal ß-galactosidase-an enzyme elevated in tissues of old mice. A linear correlation between GAC signal and chronological age is established in a cohort of middle-aged (9 to 13 months) Glb1+/m mice. The high GAC signal is closely associated with cardiac hypertrophy and a shortened lifespan. Moreover, the GAC signal is exponentially increased in pathological senescence induced by bleomycin in the lung. Senolytic dasatinib and quercetin (D + Q) reduce GAC signal in bleomycin treated mice. Thus, the Glb1-2A-mCherry reporter mice monitors systemic aging and function decline, predicts lifespan, and may facilitate the understanding of aging mechanisms and help in the development of anti-aging interventions.

Phosphorylation of 17ß-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice.

17ß-hydroxysteroid dehydrogenase-13 is a hepatocyte-specific, lipid droplet-associated protein. A common loss-of-function variant of HSD17B13 (rs72613567: TA) protects patients against non-alcoholic fatty liver disease with underlying mechanism incompletely understood. In the present study, we identify the serine 33 of 17ß-HSD13 as an evolutionally conserved PKA target site and its phosphorylation facilitates lipolysis by promoting its interaction with ATGL on lipid droplets. Targeted mutation of Ser33 to Ala (S33A) decreases ATGL-dependent lipolysis in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Importantly, a transgenic knock-in mouse strain carrying the HSD17B13 S33A mutation (HSD17B1333A/A) spontaneously develops hepatic steatosis with reduced lipolysis and increased inflammation. Moreover, Hsd17B1333A/A mice are more susceptible to high-fat diet-induced nonalcoholic steatohepatitis. Finally, we find reproterol, a potential 17ß-HSD13 modulator and FDA-approved drug, confers a protection against nonalcoholic steatohepatitis via PKA-mediated Ser33 phosphorylation of 17ß-HSD13. Therefore, targeting the Ser33 phosphorylation site could represent a potential approach to treat NASH.

Prophylactic Effect of Simultaneous Placement of Mesh on Incidence of Parastomal Hernia After Miles' Surgical Resection of Colorectal Cancer: A Prospective Study.

INTRODUCTION: To assess the prophylactic effect of simultaneous placement of mesh and the incidence of parastomal hernia (PSH) after abdominoperineal resection of rectal cancer. METHODS: This study included real-world data of 56 surgically resected patients with colorectal cancer who were consecutively assigned to two groups: control (no mesh, n = 32) and experimental (received mesh, n = 24). An artificial patch was placed under the tunica vaginalis of rectus abdominis for patients in the experimental group, whereas those in the control group received routine sigmoidostomy. The median follow-up time was >20 mo. The difference in hazards function was analyzed by cox regression analysis. The Kaplan-Meir analysis was used to determine the survival curves. A P value of <0.05 was considered as significant. RESULTS: The postoperative incidence rate of PSH was lower in the experimental (41.7%) group than in the control group (71.9%; P = 0.045). The PSH postoperative time in the experimental group was significantly delayed compared to the control group (48 mo versus 10 mo; P < 0.001). The risk of progression from H1 to H2 was less in the experimental group compared to the control group (49.28% versus 60.86%; P = 0.14). CONCLUSIONS: Prophylactic mesh placement significantly prolonged postoperative time for the recurrence of PSH. The incidence of recurrence of H2 (severe PSH) requiring secondary surgical repair was also reduced.

Electroantennographic and olfactory responses of Quadrastichus mendeli to eucalyptus volatiles induced by the gall-forming insect Leptocybe invasa.

BACKGROUND: Although parasitoids can precisely locate hidden gall-inducing insects, the host location mechanism is unknown. In this study, our aim was to clarify the olfactory responses of the parasitoid Quadrastichus mendeli to eucalyptus volatiles induced by the gall wasp Leptocybe invasa. RESULTS: Q. mendeli preferred volatiles from gall-damaged plants compared with those produced by mechanically damaged and undamaged plants. Coupled gas chromatographic-electroantennographic detection results demonstrated that 3-carene, decanal, d-limonene, ethanone,1-(4-ethylphenyl)-, p-cymene and benzene,1-methyl-4-(1-methylpropyl)- from DH 201-2 (Eucalyptus grandis × Eucalyptus tereticornis) elicited significant antennal responses in Q. mendeli in all treatments. Q. mendeli was repelled by decanal and d-limonene and was attracted to 3-carene, benzene,1-methyl-4-(1-methylpropyl)-, ethanone,1-(4-ethylphenyl) and p-cymene. Quaternary blends containing 3-carene, p-cymene, benzene,1-methyl-4-(1-methylpropyl)- and ethanone,1-(4-ethylphenyl)- at a ratio of 1:1:1:1 were attractive to Q. mendeli. However, quaternary blends with added decanal and d-limonene alone or both together induced significant repellence in Q. mendeli. CONCLUSION: Our report is the first to demonstrate that volatiles produced by galls induced by L. invasa are attractive to Q. mendeli, which suggests that this parasitoid could utilize herbivore-induced plant volatiles to locate its host. The results are beneficial for understanding the function of plant volatiles in host searching by parasitoids of gall-forming insect pests. © 2022 Society of Chemical Industry.

[A pace recognition method for exoskeleton wearers based on support vector machine-hidden Markov model].

In order to improve the motion fluency and coordination of lower extremity exoskeleton robots and wearers, a pace recognition method of exoskeleton wearer is proposed base on inertial sensors. Firstly, the triaxial acceleration and triaxial angular velocity signals at the thigh and calf were collected by inertial sensors. Then the signal segment of 0.5 seconds before the current time was extracted by the time window method. And the Fourier transform coefficients in the frequency domain signal were used as eigenvalues. Then the support vector machine (SVM) and hidden Markov model (HMM) were combined as a classification model, which was trained and tested for pace recognition. Finally, the pace change rule and the human-machine interaction force were combined in this model and the current pace was predicted by the model. The experimental results showed that the pace intention of the lower extremity exoskeleton wearer could be effectively identified by the method proposed in this article. And the recognition rate of the seven pace patterns could reach 92.14%. It provides a new way for the smooth control of the exoskeleton.

A small-molecule compound D6 overcomes EGFR-T790M-mediated resistance in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a deadly and highly prevalent malignancy. Targeting activated-EGFR mutations in NSCLC via EGFR tyrosine kinase inhibitor (EGFR-TKI) initially achieves a profound therapeutic response, but resistance frequently evolves, reducing treatment options. Here, we present a small-molecule compound D6 which selectively inhibits tumor cell growth and migration in NSCLC cells with EGFR-TKI-resistant T790M-EGFR-activated mutations (T790M-EGFR-AM), e.g., L858R/T790M, 19Del/T790M and L858R/T790M/C797S. D6 mimics a natural product isolated from the roots of Codonopsis pilosula and selectively competes with T790M-EGFR-AM to bind to HSP90, thus facilitating the ubiquitination dependent proteasomal degradation of T790M-EGFR-AM. By contrast, D6 has little impact on typical HSP90 chaperone activity, suggesting low systemic toxicity. Promisingly, D6 combined with erlotinib or osimertinib shows efficacy in overcoming the EGFR-TKIs-resistance in NSCLCs. Our study raises an alternative strategy to overcome T790M-mediated EGFR-TKI resistance in NSCLC via targeting the protein-protein interaction of HSP90 and T790M-EGFR by intervention with D6.

Combined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3ß-SIRT7 axis.

Dietary interventions such as intermittent fasting (IF) have emerged as an attractive strategy for cancer therapies; therefore, understanding the underlying molecular mechanisms is pivotal. Here, we find SIRT7 decline markedly attenuates the anti-tumor effect of IF. Mechanistically, AMP-activated protein kinase (AMPK) phosphorylating SIRT7 at T263 triggers further phosphorylation at T255/S259 by glycogen synthase kinase 3ß (GSK3ß), which stabilizes SIRT7 by decoupling E3 ligase UBR5. SIRT7 hyperphosphorylation achieves anti-tumor activity by disrupting the SKP2-SCF E3 ligase, thus preventing SKP2-mediated K63-linked AKT polyubiquitination and subsequent activation. In contrast, GSK3ß-SIRT7 axis is inhibited by EGF/ERK2 signaling, with ERK2 inactivating GSK3ß, thus accelerating SIRT7 degradation. Unfavorably, glucose deprivation or chemotherapy hijacks the GSK3ß-SIRT7 axis via ERK2, thus activating AKT and ensuring survival. Notably, Trametinib, an FDA-approved MEK inhibitor, enhances the efficacy of combination therapy with doxorubicin and IF. Overall, we have revealed the GSK3ß-SIRT7 axis that must be fine-tuned in the face of the energetic and oncogenic stresses in malignancy.

Selection of EMG Sensors Based on Motion Coordinated Analysis.

The intelligent prosthesis driven by electromyography (EMG) signal provides a solution for the movement of the disabled. The proper position of EMG sensors can improve the prosthesis's motion recognition ability. To exert the amputee's action-oriented ability and the prosthesis' control ability, the EMG spatial distribution and internal connection of the prosthetic wearer is analyzed in three kinds of movement conditions: appropriate angle, excessive angle, and angle too small. Firstly, the correlation characteristics between the EMG channels are analyzed by mutual information to construct a muscle functional network. Secondly, the network's features of different movement conditions are analyzed by calculating the characteristic of nodes and evaluating the importance of nodes. Finally, the convergent cross-mapping method is applied to construct a directed network, and the critical muscle groups which can reflect the user's movement intention are determined. Experiment shows that this method can accurately determine the EMG location and simplify the distribution of EMG sensors inside the prosthetic socket. The network characteristics of key muscle groups can distinguish different movements effectively and provide a new strategy for decoding the relationship between limb nerve control and body movement.

Bicycling Phase Recognition for Lower Limb Amputees Using Support Vector Machine Optimized by Particle Swarm Optimization.

A novel method for recognizing the phases in bicycling of lower limb amputees using support vector machine (SVM) optimized by particle swarm optimization (PSO) is proposed in this paper. The method is essential for enhanced prosthetic knee joint control for lower limb amputees in carrying out bicycling activity. Some wireless wearable accelerometers and a knee joint angle sensor are installed in the prosthesis to obtain data on the knee joint and ankle joint horizontal, vertical acceleration signal and knee joint angle. In order to overcome the problem of high noise content in the collected data, a soft-hard threshold filter was used to remove the noise caused by the vibration. The filtered information is then used to extract the multi-dimensional feature vector for the training of SVM for performing bicycling phase recognition. The SVM is optimized by PSO to enhance its classification accuracy. The recognition accuracy of the PSO-SVM classification model on testing data is 93%, which is much higher than those of BP, SVM and PSO-BP classification models.

SIRT7 activates quiescent hair follicle stem cells to ensure hair growth in mice.

Hair follicle stem cells (HFSCs) are maintained in a quiescent state until activated to grow, but the mechanisms that reactivate the quiescent HFSC reservoir are unclear. Here, we find that loss of Sirt7 in mice impedes hair follicle life-cycle transition from telogen to anagen phase, resulting in delay of hair growth. Conversely, Sirt7 overexpression during telogen phase facilitated HSFC anagen entry and accelerated hair growth. Mechanistically, Sirt7 is upregulated in HFSCs during the telogen-to-anagen transition, and HFSC-specific Sirt7 knockout mice (Sirt7f/f ;K15-Cre) exhibit a similar hair growth delay. At the molecular level, Sirt7 interacts with and deacetylates the transcriptional regulator Nfatc1 at K612, causing PA28γ-dependent proteasomal degradation to terminate Nfatc1-mediated telogen quiescence and boost anagen entry. Cyclosporin A, a potent calcineurin inhibitor, suppresses nuclear retention of Nfatc1, abrogates hair follicle cycle delay, and promotes hair growth in Sirt7-/- mice. Furthermore, Sirt7 is downregulated in aged HFSCs, and exogenous Sirt7 overexpression promotes hair growth in aged animals. These data reveal that Sirt7 activates HFSCs by destabilizing Nfatc1 to ensure hair follicle cycle initiation.

Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice.

The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR in human and mouse cells. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair in humans and mice.

PML2-mediated thread-like nuclear bodies mark late senescence in Hutchinson-Gilford progeria syndrome.

Progerin accumulation disrupts nuclear lamina integrity and causes nuclear structure abnormalities, leading to premature aging, that is, Hutchinson-Gilford progeria syndrome (HGPS). The roles of nuclear subcompartments, such as PML nuclear bodies (PML NBs), in HGPS pathogenesis, are unclear. Here, we show that classical dot-like PML NBs are reorganized into thread-like structures in HGPS patient fibroblasts and their presence is associated with late stage of senescence. By co-immunoprecipitation analysis, we show that farnesylated Progerin interacts with human PML2, which accounts for the formation of thread-like PML NBs. Specifically, human PML2 but not PML1 overexpression in HGPS cells promotes PML thread development and accelerates senescence. Further immunofluorescence microscopy, immuno-TRAP, and deep sequencing data suggest that these irregular PML NBs might promote senescence by perturbing NB-associated DNA repair and gene expression in HGPS cells. These data identify irregular structures of PML NBs in senescent HGPS cells and support that the thread-like PML NBs might be a novel, morphological, and functional biomarker of late senescence.

Deacetylase-independent function of SIRT6 couples GATA4 transcription factor and epigenetic activation against cardiomyocyte apoptosis.

SIRT6 deacetylase activity improves stress resistance via gene silencing and genome maintenance. Here, we reveal a deacetylase-independent function of SIRT6, which promotes anti-apoptotic gene expression via the transcription factor GATA4. SIRT6 recruits TIP60 acetyltransferase to acetylate GATA4 at K328/330, thus enhancing its chromatin binding capacity. In turn, GATA4 inhibits the deacetylase activity of SIRT6, thus ensuring the local chromatin accessibility via TIP60-promoted H3K9 acetylation. Significantly, the treatment of doxorubicin (DOX), an anti-cancer chemotherapeutic, impairs the SIRT6-TIP60-GATA4 trimeric complex, blocking GATA4 acetylation and causing cardiomyocyte apoptosis. While GATA4 hyperacetylation-mimic retains the protective effect against DOX, the hypoacetylation-mimic loses such ability. Thus, the data reveal a novel SIRT6-TIP60-GATA4 axis, which promotes the anti-apoptotic pathway to prevent DOX toxicity. Targeting the trimeric complex constitutes a new strategy to improve the safety of DOX chemotherapy in clinical application.

Vascular endothelium-targeted Sirt7 gene therapy rejuvenates blood vessels and extends life span in a Hutchinson-Gilford progeria model.

Vascular dysfunction is a typical characteristic of aging, but its contributing roles to systemic aging and the therapeutic potential are lacking experimental evidence. Here, we generated a knock-in mouse model with the causative Hutchinson-Gilford progeria syndrome (HGPS) LmnaG609G mutation, called progerin. The Lmnaf/f ;TC mice with progerin expression induced by Tie2-Cre exhibit defective microvasculature and neovascularization, accelerated aging, and shortened life span. Single-cell transcriptomic analysis of murine lung endothelial cells revealed a substantial up-regulation of inflammatory response. Molecularly, progerin interacts and destabilizes deacylase Sirt7; ectopic expression of Sirt7 alleviates the inflammatory response caused by progerin in endothelial cells. Vascular endothelium-targeted Sirt7 gene therapy, driven by an ICAM2 promoter, improves neovascularization, ameliorates aging features, and extends life span in Lmnaf/f ;TC mice. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction.

HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration.

NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-ß signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-ß signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-ß signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-ß signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-ß signaling related diseases.

Wearable Sensor-Based Human Activity Recognition via Two-Layer Diversity-Enhanced Multiclassifier Recognition Method.

Sensor-based human activity recognition can benefit a variety of applications such as health care, fitness, smart homes, rehabilitation training, and so forth. In this paper, we propose a novel two-layer diversity-enhanced multiclassifier recognition method for single wearable accelerometer-based human activity recognition, which contains data-based and classifier-based diversity enhancement. Firstly, we introduce the kernel Fisher discriminant analysis (KFDA) technique to spatially transform the training samples and enhance the discrimination between activities. In addition, bootstrap resampling is utilized to increase the diversities of the dataset for training the base classifiers in the multiclassifier system. Secondly, a combined diversity measure for selecting the base classifiers with excellent performance and large diversity is proposed to optimize the performance of the multiclassifier system. Lastly, majority voting is utilized to combine the preferred base classifiers. Experiments showed that the data-based diversity enhancement can improve the discriminance of different activity samples and promote the generation of base classifiers with different structures and performances. Compared with random selection and traditional ensemble methods, including Bagging and Adaboost, the proposed method achieved 92.3% accuracy and 90.7% recall, which demonstrates better performance in activity recognition.

Lamin A buffers CK2 kinase activity to modulate aging in a progeria mouse model.

Defective nuclear lamina protein lamin A is associated with premature aging. Casein kinase 2 (CK2) binds the nuclear lamina, and inhibiting CK2 activity induces cellular senescence in cancer cells. Thus, it is feasible that lamin A and CK2 may cooperate in the aging process. Nuclear CK2 localization relies on lamin A and the lamin A carboxyl terminus physically interacts with the CK2α catalytic core and inhibits its kinase activity. Loss of lamin A in Lmna-knockout mouse embryonic fibroblasts (MEFs) confers increased CK2 activity. Conversely, prelamin A that accumulates in Zmpste24-deficent MEFs exhibits a high CK2α binding affinity and concomitantly reduces CK2 kinase activity. Permidine treatment activates CK2 by releasing the interaction between lamin A and CK2, promoting DNA damage repair and ameliorating progeroid features. These data reveal a previously unidentified function for nuclear lamin A and highlight an essential role for CK2 in regulating senescence and aging.