Mitochondrial stress and aging: Lessons from C. elegans.

Aging is accompanied by a progressive decline in mitochondrial function, which in turn contributes to a variety of age-related diseases. Counterintuitively, a growing number of studies have found that disruption of mitochondrial function often leads to increased lifespan. This seemingly contradictory observation has inspired extensive research into genetic pathways underlying the mitochondrial basis of aging, particularly within the model organism Caenorhabditis elegans. The complex and antagonistic roles of mitochondria in the aging process have altered the view of mitochondria, which not only serve as simple bioenergetic factories but also as signaling platforms for the maintenance of cellular homeostasis and organismal health. Here, we review the contributions of C. elegans to our understanding of mitochondrial function in the aging process over the past decades. In addition, we explore how these insights may promote future research of mitochondrial-targeted strategies in higher organisms to potentially slow aging and delay age-related disease progression.

Real-time water/fat imaging at 0.55T with spiral out-in-out-in sampling.

PURPOSE: To develop an efficient and flexible water/fat separated real-time MRI (RT-MRI) method using spiral out-in-out-in (OIOI) sampling and balanced SSFP (bSSFP) at 0.55T. METHODS: A bSSFP sequence with golden-angle spiral OIOI readout was developed, capturing three echoes to allow water/fat separation. A low-latency reconstruction that combines all echoes was available for online visualization. An offline reconstruction provided water and fat RT-MRI in two steps: (1) image reconstruction with spatiotemporally constrained reconstruction (STCR) and (2) water/fat separation with hierarchical iterative decomposition of water and fat with echo asymmetry and least-squares estimation (HIDEAL). In healthy volunteers, spiral OIOI was acquired in the wrist during a radial-to-ulnar deviation maneuver, in the heart without breath-hold and cardiac gating, and in the lower abdomen during free-breathing for visualizing small bowel motility. RESULTS: We demonstrate successful water/fat separated RT-MRI for all tested applications. In the wrist, resulting images provided clear depiction of ligament gaps and their interactions during the radial-to-ulnar deviation maneuver. In the heart, water/fat RT-MRI depicted epicardial fat, provided improved delineation of epicardial coronary arteries, and provided high blood-myocardial contrast for ventricular function assessment. In the abdomen, water-only RT-MRI captured small bowel mobility clearly with improved water-fat contrast. CONCLUSIONS: We have demonstrated a novel and flexible bSSFP spiral OIOI sequence at 0.55T that can provide water/fat separated RT-MRI with a variety of application-specific temporal resolution and spatial resolution requirements.

T1 mapping of myocardium in rats using self-gated golden-angle acquisition.

PURPOSE: The aim of this study is to design a method of myocardial T1 quantification in small laboratory animals and to investigate the effects of spatiotemporal regularization and the needed acquisition duration. METHODS: We propose a compressed-sensing approach to T1 quantification based on self-gated inversion-recovery radial two/three-dimensional (2D/3D) golden-angle stack-of-stars acquisition with image reconstruction performed using total-variation spatiotemporal regularization. The method was tested on a phantom and on a healthy rat, as well as on rats in a small myocardium-remodeling study. RESULTS: The results showed a good match of the T1 estimates with the results obtained using the ground-truth method on a phantom and with the literature values for rats myocardium. The proposed 2D and 3D methods showed significant differences between normal and remodeling myocardium groups for acquisition lengths down to approximately 5 and 15 min, respectively. CONCLUSIONS: A new 2D and 3D method for quantification of myocardial T1 in rats was proposed. We have shown the capability of both techniques to distinguish between normal and remodeling myocardial tissue. We have shown the effects of image-reconstruction regularization weights and acquisition length on the T1 estimates.

Functional magnetic alginate/gelatin sponge-based flexible sensor with multi-mode response and discrimination detection properties for human motion monitoring.

The functional flexible sensors that can simultaneously detect multiple external excitations have exhibited great potential in the human-machine interaction and wearable electronics. However, it is still a primary challenge to develop a multi-mode sensor that can achieve sensitivity equilibrium towards different stimuli, and effectively recognize external stimulus while in a facile and cost-effective material and methodology. This study presented a functional flexible sensor based on natural polymer sodium alginate and gelatin sponge electrode which could detect both external mechanical and magnetic stimuli with superiorities of outstanding sensing capability and stability. With the optimal multilayered structure, it possessed high magnetic responsive sensitivity of 0.45 T-1, excellent stability and recoverability. Its electrical property variations also displayed high sensitivity and durability under cyclic stretching, bending and compressing stimuli for 1000 cycles. More importantly, the sensor could not only respond to magnetic field and compression stimuli with contrary electrical responses, but also recognize the respective input signals to decouple different stimuli in real time. Furthermore, it was developed as electronic skins and smart sensor arrays for human physiological signals and mechanical-magnetic detection. Based on excellent multifunctional response characteristics, the sensor showed significant potential in next-generation intelligent multifunctional electronic system and artificial intelligence.

Quality control of mass-encoded nanodevices by compartmented DNA origami frames for precision information coding and logic mapping.

Encoded nanostructures afford an ideal platform carrying multi-channel signal components for multiplexed assay and information security. However, with the demand on exclusivity and reproducibility of coding signals, precise control on the structure and composition of nanomaterials featuring fully distinguishable signals remains challenging. By using the multiplexing capability of mass spectrometry (MS) and spatial addressability of DNA origami nanostructures, we herein propose a quality control methodology for constructing mass-encoded nanodevices (namely MNTs-TDOFs) in the scaffold of compartmented tetrahedral DNA origami frames (TDOFs), in which the arrangement and stoichiometry of four types of mass nanotags (MNTs) can be finely regulated and customized to generate characteristic MS patterns. The programmability of combinatorial MNTs and orthogonality of individual compartments allows further evolution of MNTs-TDOFs to static tagging agents and dynamic nanoprobes for labeling and sensing of multiple targets. More importantly, structure control at single TDOF level ensures the constancy of prescribed MS outputs, by which a high-capacity coding system was established for secure information encryption and decryption. In addition to the multiplexed outputs in parallel, the nanodevices could also map logic circuits with interconnected complexity and logic events of c-Met recognition and dimerization on cell surface for signaling regulation by MS interrogation.

Lipid metabolism-associated genes serve as potential predictive biomarkers in neoadjuvant chemoradiotherapy combined with immunotherapy in rectal cancer.

BACKGROUND: The aim of this study was to investigate the potential role of lipid metabolism-associated genes (LMAGs) in neoadjuvant chemoradiotherapy (nCRT) and immunotherapy for rectal cancer. METHODS: Differential LMAGs were characterized and functional enrichment analysis was performed. Multiple machine learning algorithms were combined to explore candidate LMAGs. ROC analysis was performed to evaluate the predicting accuracy of candidate LMAGs. The expression patterns, prognostic value, genetic alterations, and immune cell infiltration of the top-ranked LMAGs were investigated. RESULTS: We identified 45 LMAGs that were differentially expressed in tumor samples of nCRT responders and non-responders. These LMAGs were closely associated with lipid metabolism-related biological processes and pathways. ROC analysis revealed that the SREBF2 gene, an important transcription factor in regulating lipid metabolism, was the highest predictor of nCRT in rectal cancer. SREBF2 was highly expressed in rectal cancer tissues and high expression of SREBF2 was associated with favorable prognosis. Multivariate analysis showed that SREBF2 was an independent prognostic factor, and we integrated it with other clinical factors to establish an effective prognostic nomogram. SREBF2 also played a synergistic role with its co-expressed genes in the prognostic process of rectal cancer. Furthermore, SREBF2 was demonstrated to be closely associated with multiple immune infiltrating cells, and immunotherapy-related genes and may be used to predict the response to immunotherapy. CONCLUSION: Our study suggests that LMAGs may serve as promising biomarkers in nCRT combined with immunotherapy for rectal cancer. However, large-scale clinical trials and biological experiments are necessary to demonstrate the efficacy and underlying mechanisms.

Intrinsic variability of fluorescence calibrators impacts the assignment of MESF or ERF values to nanoparticles and extracellular vesicles by flow cytometry.

Flow cytometry allows to characterize nanoparticles (NPs) and extracellular vesicles (EVs) but results are often expressed in arbitrary units of fluorescence. We evaluated the precision and accuracy of molecules of equivalent soluble fluorophores (MESF) beads for calibration of NPs and EVs. Firstly, two FITC-MESF bead sets, 2 and 6 um in size, were measured on three flow cytometers. We showed that arbitrary units could not be compared between instruments but after calibration, comparable FITC MESF units were achieved. However, the two calibration bead sets displayed varying slopes that were consistent across platforms. Further investigation revealed that the intrinsic uncertainty related to the MESF beads impacts the robust assignment of values to NPs and EVs based on extrapolation into the dim fluorescence range. Similar variations were found with PE MESF calibration. Therefore, the same calibration materials and numbers of calibration points should be used for reliable comparison of submicron sized particles.

Origami-inspired Bionic Soft Robot Stomach with Self-Powered Sensing.

The stomach is a vital organ in the human digestive system, and its digestive condition is critical to human health. The physical movement of the stomach during digestion is controlled by the circular and oblique muscles. Existing stomach simulators are unable to realistically reproduce the physical movement of the stomach. Due to the complexity of gastric motility, it is challenging to simulate and sense gastric motility. This paper proposes for the first time a bionic soft robotic stomach (BSRS) with an integrated drive and sensing structure inspired by origami and self-powered sensing technology. This soft stomach (SS) can realistically simulate and sense the movements of various parts of the human stomach in real-time. The contraction force and contraction rate of the BSRS are investigated with different viscosity contents, and the experimental values are similar to the physiological range (maximum contraction force is 3.2 N, and maximum contraction rate is 0.8). This paper provides an experimental basis for the study of gastric digestive medicine and food science by simulating the peristaltic motion of the BSRS according to the human stomach and by combining the triboelectric nanogenerator (TENG) sensing technology to monitor the motion of the BSRS in real-time. This article is protected by copyright. All rights reserved.

Photocatalytic water splitting properties of GeC/InS van der Waals heterostructure: First-principles calculations.

Based on first-principles, we conducted an in-depth study of the GeC/InS van der Waals heterostructure formed by GeC and InS and discussed its structure, electronic properties and optical properties. First, we observe that this heterostructure has negative binding energy, indicating that the interlayer interactions are mainly affected by van der Waals forces. Through band structure and density of state analysis, we confirmed its type-II band alignment characteristics, which means that photogenerated carriers have the ability to automatically separate in space. Moreover, the average charge density difference and Bader charge analysis show that there is a built-in electric field in the heterostructure, and further proves that GeC/InS forms a Z-scheme charge transfer mechanism. Interestingly, the band edge position spans the water redox potential and can fully induce the redox reaction of water splitting, indicating that it is a potential photocatalyst. The high light absorption coefficient shown in the absorption spectrum also further confirms its excellent photocatalytic activity. The most striking thing is that the solar hydrogen production efficiency of GeC/InS heterostructure is as high as 44.39%. Our research demonstrates the theoretical basis for GeC/InS heterostructure as a photocatalyst.

Comparison of detection methods for carbonation depth of concrete.

This paper presents comprehensive research of the advantages and applicability of various concrete carbonation detection methods. Employing a combination of Phenolphthalein indicator (PI), Thermogravimetric analysis (TGA), X-ray phase analysis (XRD), Fourier transform infrared spectroscopy (FTIR), and Quantitative calcium carbonate analysis (CA), a detailed comparison to determine the carbonation depth in the partial carbonation zone of concrete specimens is conducted. Among the quantitative analysis methods, CA measures CaCO3 content based on chemical reactions, while TGA obtains the concentration distribution of Ca(OH)2 and CaCO3. Among qualitative analysis methods, XRD tested the intensity distribution of Ca(OH)2 and CaCO3, while FTIR traced the characteristic peaks of C-O functional groups in a specific spectral range to determine the depth of carbonation of concrete. Results indicate that the depth of carbonation values measured by CA, TGA, XRDA, and FTIR are 2-3 times higher than those measured by PI. This research may provide valuable insights for the design of carbonation detection in concrete.

Multifunctional agents against Alzheimer's disease based on oxidative stress: Polysubstituted pyrazine derivatives synthesized by multicomponent reactions.

As Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathogenesis, the exploration of multi-target drugs may be an effective strategy for AD treatment. Multifunctional small molecular agents can be obtained by connecting two or more active drugs or privileged pharmacophores by multicomponent reactions (MCRs). In this paper, two series of polysubstituted pyrazine derivatives with multifunctional moieties were designed as anti-AD agents and synthesized by Passerini-3CR and Ugi-4CR. Since the oxidative stress plays an important role in the pathological process of AD, the antioxidant activities of the newly synthesized compounds were first evaluated. Subsequently, selected active compounds were further screened in a series of AD-related bioassays, including Aß1-42 self-aggregation and deaggregation, BACE-1 inhibition, metal chelation, and protection of SH-SY5Y cells from H2O2-induced oxidative damage. Compound A3B3C1 represented the best one with multifunctional potencies. Mechanism study showed that A3B3C1 acted on Nrf2/ARE signaling pathway, thus increasing the expression of related antioxidant proteins NQO1 and HO-1 to normal cell level. Furthermore, A3B3C1 showed good in vitro human plasma and liver microsome stability, indicating a potential for further development as multifunctional anti-AD agent.

PEX26 Functions as a Metastasis Suppressor in Colorectal Cancer.

BACKGROUND/AIMS: Aberrant Peroxisomal Biogenesis Factor 26 (PEX26) occurs in multiple cell process. However, the role of PEX26 in colorectal cancer (CRC) development remains unknown. We aimed to study PEX26 expression, regulation, and function in CRC cells. METHODS: Using the bioinformatic analysis, real-time quantitative PCR, and immunohistochemistry staining, we detected the expression of PEX26 in CRC and normal tissues. We performed functional experiments in vitro to elucidate the effect of PEX26 on CRC cells. We analyzed the RNA-seq data to reveal the downstream regulating network of PEX26. RESULTS: PEX26 is significantly down-regulated in CRC and its low expression correlates with the poor overall survival of CRC patients. We further demonstrated that PEX26 over-expression inhibits the ability of CRC cell migration, invasion, and epithelial-mesenchymal transition (EMT), while PEX26 knockdown promotes the malignant phenotypes of migration, invasion, and EMT via activating the Wnt pathway. CONCLUSION: Overall, our results showed that the loss of PEX26 contributes to the malignant phenotype of CRC. PEX26 may serve as a novel metastasis repressor for CRC.

Association of MMP3, MMP14, and MMP25 gene polymorphisms with cerebral stroke risk: a case-control study.

BACKGROUND: Cerebral stroke (CS) is the leading cause of death in China, and a complex disease caused by both alterable risk factors and genetic factors. This study intended to investigate the association of MMP3, MMP14, and MMP25 single nucleotide polymorphisms (SNPs) with CS risk in a Chinese Han population. METHODS: A total of 1,348 Han Chinese were recruited in this case-control study. Four candidate loci including rs520540 A/G and rs679620 T/C of MMP3, rs2236302 G/C of MMP14, and rs10431961 T/C of MMP25 were successfully screened. The correlation between the four SNPs and CS risk was assessed by logistic regression analysis. The results were analyzed by false-positive report probability (FPRP) for chance or significance. The interactions between four SNPs associated with CS risk were assessed by multifactor dimensionality reduction (MDR). RESULTS: rs520540 A/G and rs679620 C/T SNP in MMP3 were associated with risk of CS in allele, codominant, dominant and log-additive models. Ischemic stroke risk were significantly lower in carriers with rs520540-A allele and rs679620-T allele than those with G/G or C/C genotypes. However, rs520540-A allele and rs679620-T allele were associated with higher risk of hemorrhagic stroke. Stratified analysis showed that these two SNPs were associated with reduced risk of CS in aged < 55 years, non-smoking and non-drinking participants, and rs679620 SNP also reduced CS risk in male participants. The levels of uric acid, high-density lipoprotein cholesterol, and eosinophil were different among patients with different genotypes of rs520540 and rs679620. No statistically significant association was found between MMP14 rs2236302 G/C or MMP25 rs10431961 T/C with CS even after stratification by stroke subtypes, age, gender as well as smoking and drinking conditions in all the genetic models. CONCLUSION: MMP3 rs520540 A/G and rs679620 C/T polymorphisms were associated with CS risk in the Chinese Han population, which provides useful information for the prevention and diagnosis of CS.

NO-mediated protein S-nitrosylation under salt stress: Role and mechanism.

Salt stress is one of the major environmental stressors that remarkably hinders the processes of plant growth and development, thereby limiting crop productivity. An understanding of the molecular mechanisms underlying plant responses against salinity stimulus will help guide the rational design of crop plants to counter these challenges. Nitric oxide (NO) is a redox-related signaling molecule regulating diverse biological processes in plant. Accumulating evidences indicated NO exert its biological functions through posttranslational modification of proteins, notably via S-nitrosylation. During the past decade, the roles of S-nitrosylation as a regulator of plant and S-nitrosylated candidates have also been established and detected. Emerging evidence indicated that protein S-nitrosylation is ubiquitously involved in the regulation of plant response to salt stress. However, little is known about this pivotal molecular amendment in the regulation of salt stress response. Here, we describe current understanding on the regulatory mechanisms of protein S-nitrosylation in response to salt stress in plants and highlight key challenges in this field.

Zwitterionic Conductive Hydrogel-Based Nerve Guidance Conduit Promotes Peripheral Nerve Regeneration in Rats.

In recent years, conductive biomaterials have been widely used to enhance peripheral nerve regeneration. However, most biomaterials use electronic conductors to increase the conductivity of materials. As information carriers, electronic conductors always transmit discontinuous electrical signals, while biological systems essentially transmit continuous signals through ions. Herein, an ion-based conductive hydrogel was fabricated by simple copolymerization of the zwitterionic monomer sulfobetin methacrylate and hydroxyethyl methacrylate. Benefiting from the excellent mechanical stability, suitable electrical conductivity, and good cytocompatibility of the zwitterionic hydrogel, the Schwann cells cultured on the hydrogel could grow and proliferate better, and dorsal root ganglian had an increased neurite length. The zwitterionic hydrogel-based nerve guidance conduits were then implanted into a 10 mm sciatic nerve defect model in rats. Morphological analysis and electrophysiological data showed that the grafts achieved a regeneration effect close to that of the autologous nerve. Overall, our developed zwitterionic hydrogel facilitates efficient and efficacious peripheral nerve regeneration by mimicking the electrical and mechanical properties of the extracellular matrix and creating a suitable regeneration microenvironment, providing a new material reserve for the repair of peripheral nerve injury.

Efficiency trends of essential public health services and possible influencing factors since the new round health reform in China: a case study from Hainan Province.

Objective: This article aimed to evaluate the efficiency trends and influencing factors of essential public health services in Hainan Province after the healthcare reform launched in 2009 in China. Methods: The efficiency of essential public health services (EPHS) at primary health institutions was assessed using data envelopment analysis (DEA), and the efficiency change was analyzed by employing the Malmquist productivity index (MPI). We used Tobit regression to identify the influence of environmental factors on the efficiency of public health services. The bootstrap method was adopted to reduce the impact of random errors on the result. Results: The bootstrapping bias-corrected efficiency revealed that the average values of technical efficiency, pure technical efficiency, and scale efficiency were 0.7582, 0.8439, and 0.8997, respectively, which meant that the EPHS in Hainan Province were not at the most effective state. The average bias-corrected MPI was 1.0407 between 2010 and 2011 and 1.7404 between 2011 and 2012. MPIs were less than 1.0000 during other periods investigated, ranging from 0.8948 to 0.9714, indicating that the efficiency of EPHS has been decreasing since 2013. The Tobit regression showed that the regression coefficients of per capita GDP, population density, the proportion of older people aged over 65, and the proportion of ethnic minority population were 0.0286, -0.0003, -0.0316, and - 0.0041 respectively, which were statistically significant (p < 0.05). Conclusion: There was a short-term improvement in the efficiency of EPHS in Hainan after the launch of the new round of health reform. However, this trend has not been sustained after 2013. In particular, equalized financial investment in essential public health could not fulfill the needs of poor counties. This has resulted in the inability to improve scale efficiency in some counties, which in turn has affected the improvement of overall EPHS efficiency. Therefore, to promote EPHS efficiency sustainably, it is suggested that under this model of provincial control of counties, the equity of resource allocation should be effectively improved while further advancing the technology of service delivery.

Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models.

T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC' cleft of Tim-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells' killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3. ML-T7 strengthened DCs' functions through both Tim-3 and Tim-4, which is consistent with the fact that Tim-4 contains a similar FG-CC' loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to the Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wild-type and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti-PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.

Clinical and Temporal Radiological Findings from Critical Patients with COVID-19 Pneumonia: A Descriptive Study.

BACKGROUND: In late December 2019, Wuhan, the capital of Hubei Province, China, became the center of an outbreak of pneumonia caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). INTRODUCTION: The radiological changes in the lungs of critical people with coronavirus disease 2019 (COVID-19) pneumonia at different times have not been fully characterized. We aim to describe the computed tomography findings of patients with critical COVID-19 pneumonia at different disease stages. METHODS: Clinical and laboratory features of critical patients were assessed. CT scans were assigned to groups 1, 2, 3, or 4 based on the interval from symptom onset (within 2 weeks; ≥ 2-4 weeks; ≥ 4-6 weeks; or ≥ 6 weeks, respectively). Imaging features were analyzed and compared across the four groups. Total CT scores, corresponding periods of laboratory findings, and glucocorticoid dosages during the imaging intervals were longitudinally observed in five patients with complete data. RESULTS: All 11 critical patients (median age: 60 years [42-69]) underwent a total of 40 CT examinations, and the acquisition times ranged from 1-59 days after symptom onset. Median total CT scores were 18 (9-25.25); 44.5 (42.88-47.62); 43.75 (38.62-49.38); and 42 (32.25-53.25) in groups 1, 2, 3, and 4, respectively. The observed lesions were mainly bilateral (37 [92.5%]). The median values of involved lung segments were 10.5 (4.5-13.5); 17 (16-18.5); 18 (18-19.5); and 18 (18-19) in groups 1-4, respectively. The predominant patterns of observed abnormalities were ground-glass opacities (GGO) (9 [90%]); GGO with reticulation and mixed patterns (3 [37.5%] for both); GGO with consolidation (3 [30%]); and GGO with reticulation (8 [66.7%]) in groups 1-4, respectively. Patients developed fibrotic manifestations at later stages. CONCLUSION: Critical patients with COVID-19 infection generally presented with temporally changing abnormal CT features from focal unilateral to diffuse bilateral GGO and consolidation that progressed to or coexisted with reticulation in the long term after symptom onset. Low-dose glucocorticoids may be effective in patients with interstitial changes on CT findings.