Mitochondrial translational defect extends lifespan in C. elegans by activating UPRmt.

Aminoacyl-tRNA synthetases (aaRSs) are indispensable players in translation. Usually, two or three genes encode cytoplasmic and mitochondrial threonyl-tRNA synthetases (ThrRSs) in eukaryotes. Here, we reported that Caenorhabditis elegans harbors only one tars-1, generating cytoplasmic and mitochondrial ThrRSs via translational reinitiation. Mitochondrial tars-1 knockdown decreased mitochondrial tRNAThr charging and translation and caused pleotropic phenotypes of delayed development, decreased motor ability and prolonged lifespan, which could be rescued by replenishing mitochondrial tars-1. Mitochondrial tars-1 deficiency leads to compromised mitochondrial functions including the decrease in oxygen consumption rate, complex Ⅰ activity and the activation of the mitochondrial unfolded protein response (UPRmt), which contributes to longevity. Furthermore, deficiency of other eight mitochondrial aaRSs in C. elegans and five in mammal also caused activation of the UPRmt. In summary, we deciphered the mechanism of one tars-1, generating two aaRSs, and elucidated the biochemical features and physiological function of C. elegans tars-1. We further uncovered a conserved connection between mitochondrial translation deficiency and UPRmt.

Loss of threonyl-tRNA synthetase-like protein Tarsl2 has little impact on protein synthesis but affects mouse development.

Aminoacyl-tRNA synthetases (aaRSs) are essential components for mRNA translation. Two sets of aaRSs are required for cytoplasmic and mitochondrial translation in vertebrates. Interestingly, TARSL2 is a recently evolved duplicated gene of TARS1 (encoding cytoplasmic threonyl-tRNA synthetase) and represents the only duplicated aaRS gene in vertebrates. Although TARSL2 retains the canonical aminoacylation and editing activities in vitro, whether it is a true tRNA synthetase for mRNA translation in vivo is unclear. In this study, we showed that Tars1 is an essential gene since homozygous Tars1 KO mice were lethal. In contrast, when Tarsl2 was deleted in mice and zebrafish, neither the abundance nor the charging levels of tRNAThrs were changed, indicating that cells relied on Tars1 but not on Tarsl2 for mRNA translation. Furthermore, Tarsl2 deletion did not influence the integrity of the multiple tRNA synthetase complex, suggesting that Tarsl2 is a peripheral member of the multiple tRNA synthetase complex. Finally, we observed that Tarsl2-deleted mice exhibited severe developmental retardation, elevated metabolic capacity, and abnormal bone and muscle development after 3 weeks. Collectively, these data suggest that, despite its intrinsic activity, loss of Tarsl2 has little influence on protein synthesis but does affect mouse development.

The gut microbiota-astrocyte axis: Implications for type 2 diabetic cognitive dysfunction.

BACKGROUND: Diabetic cognitive dysfunction (DCD) is one of the most insidious complications of type 2 diabetes mellitus, which can seriously affect the ability to self-monitoring of blood glucose and the quality of life in the elderly. Previous pathological studies of cognitive dysfunction have focused on neuronal dysfunction, characterized by extracellular beta-amyloid deposition and intracellular tau hyperphosphorylation. In recent years, astrocytes have been recognized as a potential therapeutic target for cognitive dysfunction and important participants in the central control of metabolism. The disorder of gut microbiota and their metabolites have been linked to a series of metabolic diseases such as diabetes mellitus. The imbalance of intestinal flora has the effect of promoting the occurrence and deterioration of several diabetes-related complications. Gut microbes and their metabolites can drive astrocyte activation. AIMS: We reviewed the pathological progress of DCD related to the "gut microbiota-astrocyte" axis in terms of peripheral and central inflammation, intestinal and blood-brain barrier (BBB) dysfunction, systemic and brain energy metabolism disorders to deepen the pathological research progress of DCD and explore the potential therapeutic targets. CONCLUSION: "Gut microbiota-astrocyte" axis, unique bidirectional crosstalk in the brain-gut axis, mediates the intermediate pathological process of neurocognitive dysfunction secondary to metabolic disorders in diabetes mellitus.

[Effect and mechanism of Huangqi Shengmai Decoction in treatment of joint rat model of fatigue and myocardial injury].

This study aims to investigate the effects and the underlying mechanism of Huangqi Shengmai Decoction(HQSMD) in the treatment of fatigue and myocardial injury in a joint rat model. Wistar rats were assigned into 4 groups: sham, model, diltiazem hydrochloride(positive control), and HQSMD. The joint model of fatigue and myocardial injury was established by 14-day exhausted swimming followed by high ligation of the left anterior descending coronary artery. The rats in the sham group underwent a sham operation without coronary artery ligation or swimming. Since the fourth day after the ligation, swimming was continued in the model group and the drug-treated groups for the following 4 weeks. Meanwhile, the rats in the positive control group and the HQSMD group were respectively administrated intragastrically with diltiazem hydrochloride(20 mg·kg~(-1)·d~(-1)) and HQSMD(0.95 g·kg~(-1)·d~(-1)) for 4 weeks, while the shams and the models were given the same volume of normal saline. The left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS), grip strength, and myocardial pathophysiological changes were measured to evaluate the anti-fatigue and cardioprotective effects of HQSMD. The protein levels of PTEN-induced putative kinase 1(PINK1) and parkin in the myocardium were measured by Western blot to preliminarily elucidate the mechanism of HQSMD in ameliorating myocardial injury by suppressing mitochondrial autophagy. Compared with the shams, the models showed weakened heart function(LVEF and LVFS, P<0.01), decreased grasping ability(P<0.05), elevated blood urea nitrogen(BUN) and aldosterone(ALD) levels(P<0.01), aggravated myocardial fibrosis and connective tissue hyperplasia(P<0.01), and up-regulated protein levels of PINK1(P<0.01) and parkin(P<0.05). Four-week treatment with HQSMD increased the LVEF and LVFS levels(P<0.01), enhanced the grip strength(P<0.01), reduced the serum levels of BUN(P<0.01) and ALD(P<0.05), alleviated the pathological injury and fibrosis in the myocardium(P<0.01), and down-regulated the protein levels of PINK1(P<0.01) and parkin(P<0.05) in heart tissue. The results demonstrate that HQSMD may alleviate myocardial fibrosis and protect myocardium by suppressing the excessive mitochondrial auto-phagic activity and reducing the excessively elevated ALD level, thereby ameliorating fatigue and myocardial injury.

Proteomics as a tool to improve novel insights into skin diseases: what we know and where we should be going.

Background: Biochemical processes involved in complex skin diseases (skin cancers, psoriasis, and wound) can be identified by combining proteomics analysis and bioinformatics tools, which gain a next-level insight into their pathogenesis, diagnosis, and therapeutic targets. Methods: Articles were identified through a search of PubMed, Embase, and MEDLINE references dated to May 2022, to perform system data mining, and a search of the Web of Science (WoS) Core Collection was utilized to conduct a visual bibliometric analysis. Results: An increased trend line revealed that the number of publications related to proteomics utilized in skin diseases has sharply increased recent years, reaching a peak in 2021. The hottest fields focused on are skin cancer (melanoma), inflammation skin disorder (psoriasis), and skin wounds. After deduplication and title, abstract, and full-text screening, a total of 486 of the 7,822 outcomes met the inclusion/exclusion criteria for detailed data mining in the field of skin disease tooling with proteomics, with regard to skin cancer. According to the data, cell death, metabolism, skeleton, immune, and inflammation enrichment pathways are likely the major part and hotspots of proteomic analysis found in skin diseases. Also, the focuses of proteomics in skin disease are from superficial presumption to depth mechanism exploration within more comprehensive validation, from basic study to a combination or guideline for clinical applications. Furthermore, we chose skin cancer as a typical example, compared with other skin disorders. In addition to finding key pathogenic proteins and differences between diseases, proteomic analysis is also used for therapeutic evaluation or can further obtain in-depth mechanisms in the field of skin diseases. Conclusion: Proteomics has been regarded as an irreplaceable technology in the study of pathophysiological mechanism and/or therapeutic targets of skin diseases, which could provide candidate key proteins for the insight into the biological information after gene transcription. However, depth pathogenesis and potential clinical applications need further studies with stronger evidence within a wider range of skin diseases.

Prognostic Value of Drug Targets Predicted Using Deep Bioinformatic Analysis of m6A-Associated lncRNA-Based Pancreatic Cancer Model Characteristics and Its Tumour Microenvironment.

The role of N6-methyladenosine (m6A)-associated long-stranded non-coding RNA (lncRNA) in pancreatic cancer is unclear. Therefore, we analysed the characteristics and tumour microenvironment in pancreatic cancer and determined the value of m6A-related lncRNAs for prognosis and drug target prediction. An m6A-lncRNA co-expression network was constructed using The Cancer Genome Atlas database to screen m6A-related lncRNAs. Prognosis-related lncRNAs were screened using univariate Cox regression; patients were divided into high- and low-risk groups and randomised into training and test groups. In the training group, least absolute shrinkage and selection operator (LASSO) was used for regression analysis and to construct a prognostic model, which was validated in the test group. Tumor mutational burden (TMB), immune evasion, and immune function of risk genes were analysed using R; drug sensitivity and potential drugs were examined using the Genomics of Drug Sensitivity in Cancer database. We screened 129 m6A-related lncRNAs; 17 prognosis-related m6A-related lncRNAs were obtained using multivariate analysis and three m6A-related lncRNAs (AC092171.5, MEG9, and AC002091.1) were screened using LASSO regression. Survival rates were significantly higher (p < 0.05) in the low-risk than in the high-risk group. Risk score was an independent predictor affecting survival (p < 0.001), with the highest risk score being obtained by calculating the c-index. The TMB significantly differed between the high- and low-risk groups (p < 0.05). In the high- and low-risk groups, mutations were detected in 61 of 70 samples and 49 of 71 samples, respectively, with KRAS, TP53, and SMAD4 showing the highest mutation frequencies in both groups. A lower survival rate was observed in patients with a high versus low TMB. Immune function HLA, Cytolytic activity, and Inflammation-promoting, T cell co-inhibition, Check-point, and T cell co-stimulation significantly differed in different subgroups (p < 0.05). Immune evasion scores were significantly higher in the high-risk group than in the low-risk group. Eight sensitive drugs were screened: ABT.888, ATRA, AP.24534, AG.014699, ABT.263, axitinib, A.443654, and A.770041. We screened m6A-related lncRNAs using bioinformatics, constructed a prognosis-related model, explored TMB and immune function differences in pancreatic cancer, and identified potential therapeutic agents, providing a foundation for further studies of pancreatic cancer diagnosis and treatment.

Clinical online nomogram for predicting prognosis in recurrent hepatolithiasis after biliary surgery: A multicenter, retrospective study.

BACKGROUND: Methods for predicting the prognosis of patients undergoing surgery for recurrent hepatolithiasis after biliary surgery are currently lacking. AIM: To establish a nomogram to predict the prognosis of patients with recurrent hepatolithiasis after biliary surgery. METHODS: In this multicenter, retrospective study, data of consecutive patients in four large medical centers who underwent surgery for recurrent hepatolithiasis after biliary surgery were retrospectively analyzed. We constructed a nomogram to predict the prognosis of recurrent hepatolithiasis in a training cohort of 299 patients, following which we independently tested the nomogram in an external validation cohort of 142 patients. Finally, we used the concordance index (C-index), calibra-tion, area under curve, decision curve analysis, clinical impact curves, and visual fit indices to evaluate the accuracy of the nomogram. RESULTS: Multiple previous surgeries [2 surgeries: Odds ratio (95% confidence interval), 1.451 (0.719-2.932); 3 surgeries: 4.573 (2.015-10.378); ≥ 4 surgeries: 5.741 (1.347-24.470)], bilateral hepatolithiasis [1.965 (1.039-3.717)], absence of immediate clearance [2.398 (1.304-4.409)], neutrophil-to-lymphocyte ratio ≥ 2.462 [1.915 (1.099-3.337)], and albumin-to-globulin ratio ≤ 1.5 [1.949 (1.056-3.595)] were found to be independent factors influencing the prognosis. The nomogram constructed on the basis of these variables showed good reliability in the training (C-index: 0.748) and validation (C-index: 0.743) cohorts. Compared with predictions using traditional classification models, those using our nomogram showed better agreement with actual observations in the calibration curve for the probability of endpoints and the receiver operating characteristic curve. Dichloroacetate and clinical impact curves showed a larger net benefit of the nomogram. CONCLUSION: The nomogram developed in this study demonstrated superior performance and discriminative power compared to the three traditional classifications. It is easy to use, highly accurate, and shows excellent calibration.

Mutually exclusive substrate selection strategy by human m3C RNA transferases METTL2A and METTL6.

tRNAs harbor the most diverse posttranscriptional modifications. The 3-methylcytidine (m3C) is widely distributed at position C32 (m3C32) of eukaryotic tRNAThr and tRNASer species. m3C32 is decorated by the single methyltransferase Trm140 in budding yeasts; however, two (Trm140 and Trm141 in fission yeasts) or three enzymes (METTL2A, METTL2B and METTL6 in mammals) are involved in its biogenesis. The rationale for the existence of multiple m3C32 methyltransferases and their substrate discrimination mechanism is hitherto unknown. Here, we revealed that both METTL2A and METTL2B are expressed in vivo. We purified human METTL2A, METTL2B, and METTL6 to high homogeneity. We successfully reconstituted m3C32 modification activity for tRNAThr by METT2A and for tRNASer(GCU) by METTL6, assisted by seryl-tRNA synthetase (SerRS) in vitro. Compared with METTL2A, METTL2B exhibited dramatically lower activity in vitro. Both G35 and t6A at position 37 (t6A37) are necessary but insufficient prerequisites for tRNAThr m3C32 formation, while the anticodon loop and the long variable arm, but not t6A37, are key determinants for tRNASer(GCU) m3C32 biogenesis, likely being recognized synergistically by METTL6 and SerRS, respectively. Finally, we proposed a mutually exclusive substrate selection model to ensure correct discrimination among multiple tRNAs by multiple m3C32 methyltransferases.

Insight into the reversible conversion-(de)incorporation of redox-active dopants within a polymer-based electrode.

We combined a microporous polymer backbone with an organic redox-active dopant to construct a reversible electrode system based on the conversion-(de)incorporation behaviour of the dopant. The correspondence between the reversible conversion-(de)incorporation mechanism of the dopant and the electrochemical performance of the designed electrode system was established by electrochemical quartz crystal microbalance and in situ Fourier transform infrared spectroscopy.

Magnetic Anisotropy: Structural Correlation of a Series of Chromium(II)-Amidinate Complexes.

Systematic substituent variations on amidinate ligands bring delicate changes of CrN4 coordination in a family of chromium(II) complexes with the common formula of Cr(RNC(CH3)NR)2, where R = iPr (1), Cy (2), Dipp (Dipp = 2, 6-diisopropylphenyl) (3), and tBu (4). With the largest substituent group, 4 shows the largest distortion of the N4 coordination geometry from square-planar to seesaw shape, which leads to its field-induced single-molecule magnet (SMM) behavior. This is an indication that 4 has the strongest axial magnetic anisotropy and/or optimized magnetic relaxation process. Combined with high-frequency/field electron paramagnetic resonance (HF-EPR) experiments and ab initio calculations, we deduce that the smallest energy gap between ground 4Ψ0 and the first excited 4Ψ1 orbitals in 4 contributes the most to its strongest magnetic anisotropy. Moreover, the lower E value of 4 ensures its being a field-induced SMM. Specifically, the D and E values were found to be correlated to the dihedral angle between the ΔN1CrN2 and ΔN3CrN4 triangles, indicating that distortion from ideal square-planar geometry to the seesaw help increase axial magnetic anisotropy and suppress the transversal part. Thus, the study on this system not only expands the family of Cr(II)-based SMMs but also contributes to a deeper understanding of magneto-structural correlation in four-coordinate Cr(II) SMMs.

Nomogram based on inflammation-related markers for predicting survival of patients undergoing hepatectomy for hepatocellular carcinoma.

BACKGROUND: Previous nomograms for hepatocellular carcinoma (HCC) did not include the neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR). This study aimed to establish an effective nomogram capable of estimating the association between preoperative inflammatory factors and overall survival (OS) of HCC patients after hepatectomy. AIM: To analyse the factors affecting the prognosis of HCC and establish a nomogram. METHODS: A total of 626 HCC patients (410 training set patients from the First Affiliated Hospital of Anhui Medical University and 216 validation set patients from the First Affiliated Hospital of University of Science and Technology of China) underwent hepatectomy from January 2014 to December 2017 and were followed up every 3-6 mo. The nomogram was based on OS-related independent risk factors identified by Cox regression analysis. The C-index, calibration curve, and area under the curve (AUC) were used to evaluate the nomogram's accuracy. RESULTS: The 1-, 2- and 3-year OS rates were 79.0%, 68.0% and 45.4% in the training cohort (median OS = 34 mo) and 92.1%, 73.9% and 51.2% in the validation cohort (median OS = 38 mo). Higher α-fetoprotein [hazard ratio (HR) = 1.812, 95% confidence interval (CI): 1.343-2.444], NLR (HR = 2.480, 95%CI: 1.856-3.312) and PLR (HR = 1.974, 95%CI: 1.490-2.616), tumour size ≥ 5 cm (HR = 1.323, 95%CI: 1.002-1.747), and poor differentiation (HR = 3.207, 95%CI: 1.944-5.290) were significantly associated with shortened OS. The developed nomogram integrating these variables showed good reliability in both the training (C-index = 0.71) and validation cohorts (C-index = 0.75). For predicting 1-, 2- and 3-year OS, the nomogram had AUCs of 0.781, 0.743 and 0.706 in the training cohort and 0.789, 0.815 and 0.813 in the validation cohort. The nomogram was more accurate in predicting prognosis than the AJCC TNM staging system. CONCLUSION: The prognostic nomogram combining pathological characteristics and inflammation indicators could provide a more accurate individualized risk estimate for the OS of HCC patients with hepatectomy.

Dimerized p-Semiquinone Radical Anions Stabilized by a Pair of Rare-Earth Metal Ions.

Here we report stable p-quinone-radical-bridged rare-earth complexes involving the ligand tetramethylquinone (QMe4•-). The complexes, {Y[(QMe4)•-Cl2(THF)3]}2 (1) and {Gd[(QMe4)•-Cl2(THF)3]}2 (2), where THF = tetrahydrofuran, are sufficiently stable that we can measure the single-crystal structures and perform magnetic and electron paramagnetic resonance measurements. These studies show the presence of a semiquinone form and that the magnetic interaction between the radicals in the dimer is strong and antiferromagnetic.

Exchange-Biasing in a Dinuclear Dysprosium(III) Single-Molecule Magnet with a Large Energy Barrier for Magnetisation Reversal.

A dichlorido-bridged dinuclear dysprosium(III) single-molecule magnet [Dy2 L2 (µ-Cl)2 (thf)2 ] has been made by using a diamine-bis(phenolate) ligand, H2 L. Magnetic studies show an energy barrier for magnetisation reversal (Ueff ) around 1000 K. An exchange-biasing effect is clearly seen in magnetic hysteresis with steps up to 3 K. Ab initio calculations exclude the possibility of a pure dipolar origin of this effect leading to the conclusion that super-exchange through the chloride bridging ligands is important.

Air-Stable Hexagonal Bipyramidal Dysprosium(III) Single-Ion Magnets with Nearly Perfect D6h Local Symmetry.

Eight-coordinated DyIII centres with D6h symmetry are expected to act as high-performance single-molecule magnets (SMMs) due to the simultaneous fulfilment of magnetic axiality and a high coordination number (a requisite for air stability). But the experimental realization is challenging due to the requirement of six coordinating atoms in the equatorial plane of the hexagonal bipyramid; this is usually too crowded for the central DyIII ion. Here a hexaaza macrocyclic Schiff base ligand and finetuned axial alkoxide/phenol-type ligands are used to show that a family of hexagonal bipyramidal DyIII complexes can be isolated. Among them, three complexes possess nearly perfect D6h local symmetry. The highest effective magnetic reversal barrier is found at 1338(3) K and an open hysteresis temperature of 6 K at the field sweeping rate of 1.2 mT s-1 ; this represents a new record for D6h SMMs.

Disease-related stressors of caregiving burden among different types of family caregivers of persons with schizophrenia in rural China.

BACKGROUND: Little is known about the impacts of schizophrenia on different types of caregiving burden. AIM: This study aims to examine how the severity of schizophrenia, social functioning and aggressive behavior are associated with caregiving burden across different kinship types. METHOD: The analytic sample included 300 dyads of persons with schizophrenia and their family caregivers in Xinjin, Chengdu, China. The 10th edition of the International Classification of Diseases (ICD-10) was utilized to identify the patients, whose symptom severity, social functioning and aggressive behavior were measured. Caregiving burden was estimated using the Burden Scale for Family Caregivers-short (BSFC-s). RESULTS: A higher level of burden was significantly associated with female caregivers, larger family size, lower income, worse symptoms, poorer functional status and more aggressive behaviors. Parent caregivers showed greater burden if the patients had better functioning of social interest and concern or more aggression toward property. Mother caregivers showed greater burden than fathers. Spouses tended to perceive greater burden if the patients had better marital functioning, poorer occupational functioning or more aggressive behaviors toward property. Patients attacking others or a father with schizophrenia was related to a higher burden of child caregivers. A heavier burden of other relatives was correlated with patients' more verbal aggression and self-harm. CONCLUSION: This study shows the distinct impacts of disease-related factors on the caregiving burden across different kinship types. Our findings have implications for health-care professionals and practitioners in terms of developing more targeted family-based or individualized intervention to ameliorate burden according to kinship types and deal with behavioral and functional problems in schizophrenia.

A dichlorido-bridged dinuclear Dy(iii) single-molecule magnet with an effective energy barrier larger than 600 K.

We report a dichlorido-bridged dinuclear dysprosium(iii) single-molecule magnet [Dy(Cy2N)2(µ-Cl)(THF)]2 which shows an effective energy barrier for magnetization reversal (Ueff) of ca. 623 K. This is by far the largest Ueff barrier for any chlorido-bridged lanthanide single-molecule magnet. We observe two relaxation processes with near-identical temperature dependencies, one of which disappears upon magnetic dilution. We suspect that these two processes are the isolated and coupled relaxation processes.

[Research progress in effects of biochar application on crop growth and synergistic mechanism of biochar with fertilizer]. / ç”Ÿç‰©ç‚­å½±å“ä½œç‰©ç”Ÿé•¿åŠå ¶ä¸ŽåŒ–è‚¥æ··æ–½çš„å¢žæ•ˆæœºåˆ¶ç ”ç©¶è¿›å±•.

The application of biochar made from crop straw to soil has already become a research hotspot in the field of agriculture at home and abroad, because it can increase crop production capacity with specific environmental benefits. This review summarized the progress of recent research regarding the molecular mechanisms underlying the effects of biochar on crop growth, with particular emphasis on the interactions between crop roots and biochar in soil. The biological effects of the interactions between fertilizer and biochar application and the probable mechanisms underlying the synergistic effect were discussed. The current work proposed the prospects of biochar in agriculture and would promote the relative researches in China. The recent researches indicated that auxin and related signaling molecules play a key role in the growth stimulation in response to biochar application by promoting the expression of genes controlling cell expansion, loosening of the cell wall, and membrane transport for water and nutrients. Biochar and its interaction with plant roots could directly or indirectly influence the physical, chemical and biological properties of soil, which would regulate the function and synergistic effects of biochar coupled with fertilizer.