Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.

Vestibular Rehabilitation: Intelligent or Traditional?

Null.

Proteomics reveals the mechanism of protein degradation and its relationship to sensorial and texture characteristics in dry-cured squid during processing.

Proteolysis in dry-cured squid contributes to the development of sensory and textural attributes. In this study, label-free quantitative proteomics was conducted to study the mechanism of proteolysis and its correlation with quality changes. The results showed that the protein profile of dry-cured squid changed markedly during processing, which was confirmed by the quantification of myofibrillar protein, amino nitrogen and total free acids, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. Thirty-two key differentially abundant proteins were found to be correlated with sensory and texture characteristics, including myofibrillar protein, tubulin beta chain, collagens, heat shock proteins and cytochrome c. The correlation analysis indicated that myosin regulatory light chain and tubulin beta chain played the most important role in the development of texture and sensory attributes in squid samples during the dry-curing process. The results offered novel insights into proteolysis in dry-cured squid and its relationship to quality changes.

Seed germination demonstrates inter-annual variations in alkaline tolerance: a case study in perennial Leymus chinensis.

BACKGROUND AND AIMS: The escalating issue of soil saline-alkalization poses a growing global challenge. Leymus chinensis is a perennial grass species commonly used in the establishment and renewal of artificial grasslands that is relatively tolerant of saline, alkaline, and drought conditions. Nonetheless, reduced seed setting rates limit its propagation, especially on alkali-degraded grassland. Inter-annual variations have an important effect on seed yield and germination under abiotic stress, and we therefore examined the effect of planting year on seed yield components of L. chinensis. METHODS: We grew transplanted L. chinensis seedlings in pots for two (Y2), three (Y3), or four (Y4) years and collected spikes for measurement of seed yield components, including spike length, seed setting rate, grain number per spike, and thousand seed weight. We then collected seeds produced by plants from different planting years and subjected them to alkaline stress (25 mM Na2CO3) for measurement of germination percentage and seedling growth. RESULTS: The seed setting rate of L. chinensis decreased with an increasing number of years in pot cultivation, but seed weight increased. Y2 plants had a higher seed setting rate and more grains per spike, whereas Y4 plants had a higher thousand seed weight. The effects of alkaline stress (25 mM Na2CO3) on seed germination were less pronounced for the heavier seeds produced by Y4 plants. Na2CO3 caused a 9.2% reduction in shoot length for seedlings derived from Y4 seeds but a 22.3% increase in shoot length for seedlings derived from Y3 seeds. CONCLUSIONS: Our findings demonstrate significant differences in seed yield components among three planting years of L. chinensis under pot cultivation in a finite space. Inter-annual variation in seed set may provide advantages to plants. Increased alkalinity tolerance of seed germination was observed for seeds produced in successive planting years.

City level water withdrawal and scarcity accounts of China.

In the context of China's freshwater crisis high-resolution data are critical for sustainable water management and economic growth. Yet there is a dearth of data on water withdrawal and scarcity regardless of whether total or subsector amount, for prefectural cities. In administrative and territorial scope, we accounted for water withdrawal of all 63 economic-socio-environmental sectors for all 343 prefectural cities in China, based on a general framework and 2015 data. Spatial and economic-sector resolution is improved compared with previous studies by partitioning general sectors into industrial and agricultural sub-sectors. Construction of these datasets was based on selection of 16 driving forces. We connected a size indicator with corresponding water-withdrawal efficiency. We further accounted for total blue-water withdrawal and quantitative water scarcity status. Then we compared different scopes and methods of official accounts and statistics from various water datasets. These disaggregated and complete data could be used in input-output models for municipal design and governmental planning to help gain in-depth insights into subsector water-saving priorities from local economic activities.

Chimonobambusapleiacantha (Poaceae, Bambusoideae), a new species from southeast Sichuan, China.

Chimonobambusapleiacantha, a newly-identified species of the genus Chimonobambusa Makino from southeast Sichuan, China, is meticulously described and illustrated herein. It is morphologically similar to Ch.tuberculata, but differs in having 4-angled internodes, thicker wall to 4.5-8.5 mm, more reclinate and elongated root thorns to 5-8 mm long, culm internodes with three grooves and two longitudinal ridges on the branch-bearing side, persistent culm leaves, densely brown-purple setose at the bottom of culm leaf sheaths together with sheath scar, developed foliage leaf fimbriae, 6-8 on each shoulder, ca. 3-8 mm long, abaxially white pubescent foliage leaf blades. Phenologically, new shoots usually appear in September to October. In the light of these key morphological and phenological characteristics, Ch.pleiacantha was identified as a new species of the genus Ch. Makino which is different from published species of this genus.

Idebenone ameliorates statin-induced myotoxicity in atherosclerotic ApoE-/- mice by reducing oxidative stress and improving mitochondrial function.

Statins are the first line of choice for the treatment for atherosclerosis, but their use can cause myotoxicity, a common side effect that may require dosage reduction or discontinuation. The exact mechanism of statin-induced myotoxicity is unknown. Previous research has demonstrated that the combination of idebenone and statin yielded superior anti-atherosclerotic outcomes. Here, we investigated the mechanism of statin-induced myotoxicity in atherosclerotic ApoE-/- mice and whether idebenone could counteract it. After administering simvastatin to ApoE-/- mice, we observed a reduction in plaque formation as well as a decrease in their exercise capacity. We observed elevated levels of lactic acid and creatine kinase, along with a reduction in the cross-sectional area of muscle fibers, an increased presence of ragged red fibers, heightened mitochondrial crista lysis, impaired mitochondrial complex activity, and decreased levels of CoQ9 and CoQ10. Two-photon fluorescence imaging revealed elevated H2O2 levels in the quadriceps, indicating increased oxidative stress. Proteomic analysis indicated that simvastatin inhibited the tricarboxylic acid cycle. Idebenone treatment not only further reduced plaque formation but also ameliorated the impaired exercise capacity caused by simvastatin. Our study represents the inaugural comprehensive investigation into the mechanisms underlying statin-induced myotoxicity. We have demonstrated that statins inhibit CoQ synthesis, impair mitochondrial complex functionality, and elevate oxidative stress, ultimately resulting in myotoxic effects. Furthermore, our research marks the pioneering identification of idebenone's capability to mitigate statin-induced myotoxicity by attenuating oxidative stress, thereby safeguarding mitochondrial complex functionality. The synergistic use of idebenone and statin not only enhances the effectiveness against atherosclerosis but also mitigates statin-induced myotoxicity.

Household Environments and Functional Decline Among Middle-Aged and Older Adults in China: Variations by Gender, Age, and Residence.

This study examined the associations between household social, economic, and physical environments and the trajectory of functional limitations over time among middle-aged and older adults in China, and how this relationship differs by gender, age, and residence. Linear growth curve models were applied to a sample of 13,564 respondents aged 45 years and older from four waves of the China Health and Retirement Longitudinal Study (CHARLS 2011-2018). Living alone, particularly for rural, female, and older respondents, was associated with a faster functional decline when compared to living with a spouse and without children. Improved housing quality was associated with a slower functional decline. Living with young descendants and without adult children for urban residents and a lower expenditure per capita for younger respondents were associated with a faster functional decline. These findings suggest that policies aimed at enhancing living conditions have the potential to improve physical functioning of older adults.

[Correlation Analysis of Peripheral Blood B Cell Count with Clinical Features and Prognosis in Patients Newly Diagnosed with Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To explore the correlation between peripheral blood B cell count and clinical features and prognosis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). METHODS: The relationship of peripheral blood B cell count with clinical features, laboratory indexes and prognosis in 67 patients with newly diagnosed DLBCL was retrospectively analyzed. RESULTS: Patients were divided into low B-cell count group (B cell＜0.1×109/L, n=34) and high B-cell count group (B cell≥0.1×109/L, n=33) according to the median B cell count values. Compared with the high B cell count group, the low B cell count group had a higher proportion of patients with Lugano stage III-IV, elevated LDH, elevated ß2-MG and IPI score 3-5 and increased CRP (P =0.033, 0.000, 0.023, 0.001, 0.033). The peripheral CD3+ and CD4+ cell counts of patients in the low B cell count group were significantly lower than those in the high B cell count group (P =0.010, 0.017). After initial treatment, overall response rate (ORR) and complete remission (CR) rate in high B cell count group were significantly higher than those in low B cell count group (P =0.032, 0.013). The median follow-up time of patients was 23(2-77) months, progression-free survival (PFS) and overall survival (OS) of patients in the high B cell count group were significantly better than those in the low B cell count group (P =0.001, 0.002). Univariate analysis showed that pretreatment low B cell count in the peripheral blood was associated with shortened PFS and OS (HR=4.108, P =0.002; HR=8.218, P =0.006). Multivariate analysis showed that low B cell count was an independent prognostic factor for shortened PFS (HR=3.116, P =0.037). CONCLUSION: Decreased peripheral blood B cell count in newly diagnosed DLBCL patients is associated with high-risk clinical features and may affect the efficacy of immunochemotherapy, which is associated with poor clinical prognosis.

BMSC-derived exosomes regulate the Treg/Th17 balance through the miR-21-5p/TLR4/MyD88/NF-κB pathway to alleviate dry eye symptoms in mice.

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-Exos) have a variety of biological functions and are extensively involved in the regulation of inflammatory diseases, as well as tissue repair and regeneration. However, the mechanism of action of these compounds in dry eye disease (DED) in mice is still unclear. This study demonstrated that the Treg/Th17 ratio was strongly imbalanced in DED clinical samples. BMSC-Exos can modulate the Treg/Th17 balance, improve the integrity of the corneal epithelial layer, and ameliorate DED progression in mice. Mechanistically, BMSC-Exos dramatically decreased the levels of IL-17 and IL-22; increased the levels of IL-4, IL-10, and TGF-ß1; and increased tear secretion and the number of goblet cells in the conjunctiva in mice, thus alleviating the progression of DED. This effect is achieved by BMSC-Exos through the delivery of miR-21-5p to target and restrain TLR4, thereby restraining the MyD88/NF-κB pathway. Our study showed that the upregulation of miR-21-5p in BMSC-Exos may be a therapeutic target for DED. These findings support new ideas and a basis for treating DED, as well as for further study of the application value of exosomes in alleviating DED.

Enhancing water retention and mechanisms of citrus and soya bean dietary fibres in pre-fermented frozen dough.

In recent years, the production of prepared and frozen foods has increased with economic development. However, during freezing, moisture migration forms ice crystals that damage food structure and reduce quality. This study investigates moisture migration changes in pre-fermented dough during frozen storage and effectiveness of Citrus fibre (CF) and Soya dietary fibre (SDF) on quality improvement. Pre-fermented frozen dough properties were evaluated at different freezing storage days with CF and SDF. Results showed frozen storage reduced water retention, converting deeply bound water to weakly bound and free water. Freezable water content increased significantly from 53% (fresh) to 56.95% (60d-control), forming disruptive ice crystals in gluten protein structure. SDF had superior water flow restriction compared to CF, preventing large ice crystal accumulation, enhancing water-holding capacity, and maintaining gluten protein structure. These findings lay a theoretical foundation for improving quality and industrial applications of pre-fermented frozen dough.

Cnidii Fructus: A traditional Chinese medicine herb and source of antiosteoporotic drugs.

BACKGROUND: Osteoporosis (OP) is a prevalent chronic metabolic bone disease for which limited countermeasures are available. Cnidii Fructus (CF), primarily derived from Cnidium monnieri (L.) Cusson., has been tested in clinical trials of traditional Chinese medicine for the management of OP. Accumulating preclinical studies indicate that CF may be used against OP. MATERIALS AND METHODS: Comprehensive documentation and analysis were conducted to retrieve CF studies related to its main phytochemical components as well as its pharmacokinetics, safety and pharmacological properties. We also retrieved information on the mode of action of CF and, in particular, preclinical and clinical studies related to bone remodeling. This search was performed from the inception of databases up to the end of 2022 and included PubMed, China National Knowledge Infrastructure, the National Science and Technology Library, the China Science and Technology Journal Database, Weipu, Wanfang, the Web of Science and the China National Patent Database. RESULTS: CF contains a wide range of natural active compounds, including osthole, bergapten, imperatorin and xanthotoxin, which may underlie its beneficial effects on improving bone metabolism and quality. CF action appears to be mediated via multiple processes, including the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK), Wnt/ß-catenin and bone morphogenetic protein (BMP)/Smad signaling pathways. CONCLUSION: CF and its ingredients may provide novel compounds for developing anti-OP drugs.

Generation of human vascularized and chambered cardiac organoids for cardiac disease modelling and drug evaluation.

Human induced pluripotent stem cell (hiPSC)-derived cardiac organoids (COs) have shown great potential in modelling human heart development and cardiovascular diseases, a leading cause of global death. However, several limitations such as low reproducibility, limited vascularization and difficulty in formation of cardiac chamber were yet to be overcome. We established a new method for robust generation of COs, via combination of methodologies of hiPSC-derived vascular spheres and directly differentiated cardiomyocytes from hiPSCs, and investigated the potential application of human COs in cardiac injury modelling and drug evaluation. The human COs we built displayed a vascularized and chamber-like structure, and hence were named vaschamcardioids (vcCOs). These vcCOs exhibited approximately 90% spontaneous beating ratio. Single-cell transcriptomics identified a total of six cell types in the vcCOs, including cardiomyocytes, cardiac precursor cells, endothelial cells, fibroblasts, etc. We successfully recaptured the processes of cardiac injury and fibrosis in vivo on vcCOs, and showed that the FDA-approved medication captopril significantly attenuated cardiac injury-induced fibrosis and functional disorders. In addition, the human vcCOs exhibited an obvious drug toxicity reaction to doxorubicin in a dose-dependent manner. We developed a three-step method for robust generation of chamber-like and vascularized complex vcCOs, and our data suggested that vcCOs might become a useful model for understanding pathophysiological mechanisms of cardiovascular diseases, developing intervention strategies and screening drugs.

BMSC Alleviates Dry Eye by Inhibiting the ROS-NLRP3-IL-1ß Signaling Axis by Reducing Inflammation Levels.

PURPOSE: Bone marrow mesenchymal stem cells (BMSC) have multiple biological functions and are widely involved in regulating inflammatory diseases, tissue repair and regeneration. However, the mechanism of their action in dry eye disease (DED) is currently unclear. The purpose of this study was to investigate the effect of BMSCs in the treatment of dry eye mice and to explore its specific therapeutic mechanism. METHODS: Mouse corneal epithelial cells (MCECs) were treated with 500 mOsM sodium chloride hypertonic solution to induce a DED cell model. The dry eye animal model was constructed by adding 5 µL 0.2% benzalkonium chloride solution to mouse eyes. Western blotting was used to detect the expression of related proteins, and flow cytometry, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, hematoxylin-eosin (HE) staining, and periodic acid schiff (PAS) staining were used to detect cell and eye tissue damage. RESULTS: The experimental results showed that BMSCs can reduce the levels of reactive oxygen species (ROS) and inflammatory factors in MCECs, promote cell proliferation, inhibit cell apoptosis, improve the integrity of the corneal epithelial layer in vivo, promote an increase in the number of goblet cells, and alleviate DED. Further exploration of the molecular mechanism of BMSCs treatment revealed that BMSCs alleviate the progression of DED by inhibiting the ROS-NLRP3-IL-1ß signaling pathway. CONCLUSION: BMSCs inhibit ROS-NLRP3-IL-1ß signaling axis, reducing inflammation levels and alleviating dry eye symptoms. These findings provide new ideas and a basis for the treatment of DED and provide an experimental basis for further research on the application value of BMSCs in alleviating DED.

Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity.

Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

Early life exposure to Chinese famine and risk of digestive system cancer in midlife.

To investigate whether early-life exposure to the Great Famine of 1959-1961 in China was associated with the risk of digestive system cancer. The prospective cohort study involved 17 997 participants from the Kailuan Study (Tangshan, China) that began in 2006. All participants were divided into three groups based on their date of birth. The unexposed group (born from 1 October 1962 to 30 September 1964), fetal-exposed group (born from 1 October 1959 to 30 December 1961), and early-childhood-exposed group (born from 1 October 1956 to 30 December 1958). The Cox proportional hazards model was used to analyze the association between early famine exposure and digestive system cancer. During the mean follow-up period of (10.4 ± 2.2) years, a total of 223 digestive system cancer events occurred. Including 54 cases in the unexposed group (62.14/100 000 person-years), 57 cases in the fetal-exposed group (114.8/100 000 person-years), and 112 cases in the early-childhood-exposure group (122.2/100 000 person-years). After adjusting covariates, compared with the unexposed group, the HR and 95% CI were 1.85 (1.28, 2.69) for participants in the fetal-exposed group and 1.92 (1.38, 2.66) for participants in the early-childhood-exposed group. No interactions were observed in our study. After classifying digestive system cancers, the HR and 95% CI were 2.02 (1.03, 3.97) for colorectal cancer for participants in the fetal-exposed group and 2.55 (1.43, 4.55) for participants in the early-childhood-exposed group. The HR and 95% CI were (1.13, 3.83) of liver cancer for participants in the fetal-exposed group and 1.15 (0.63, 2.10) for participants in the early-childhood-exposed group. Early-life famine exposure was associated with a higher risk of digestive system cancer in adulthood. Fetal-exposed individuals might increase the risk of colorectal cancer and liver cancer, and early childhood-exposed might increase the risk of colorectal cancer.

State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is initiated and maintained by BCR::ABL which is clinically targeted using tyrosine kinase inhibitors (TKIs). TKIs can induce long-term remission but are also not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. We collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR::ABL-inducible transgenic mice and wild-type controls. From the transcriptome, we constructed a CML state-space and a three-well leukemogenic potential landscape. The potential's stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemia; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as drivers of disease transition. Re-introduction of tetracycline to silence the BCR::ABL gene returned diseased mice transcriptomes to a near healthy state, without reaching it, suggesting parts of the transition are irreversible. TKI only reverted the transcriptome to an intermediate disease state, without approaching a state of health; disease relapse occurred soon after treatment. Using only the earliest time-point as initial conditions, our state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention, before phenotypic changes become detectable.

Characteristics and phylogenetic analysis of the complete mitochondrial genome of Erasmia pulchella Hope, 1840 (lepidoptera: zygaenidae).

Erasmia pulchella has brightly colored wings and releases toxic cyanide as a defense against predation. At present, the molecular phylogenetic status of this species is still unclear. Here, we presented the first complete mitochondrial genome of the genus Erasmia, which was assembled from data generated using a genome skimming method. The assembled mitogenome was 15,197 bp in length and consists of 37 genes, including 13 protein-coding genes, two rRNAs, 22 tRNAs, and a control region. Phylogenetic analysis based on both maximum likelihood (ML) and Bayesian inference (BI) revealed that E. pulchella was most closely related to Amesia sanguiflua.

A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene.

Lipid storage myopathy (LSM) is a heterogeneous group of lipid metabolism disorders predominantly affecting skeletal muscle by triglyceride accumulation in muscle fibers. Riboflavin therapy has been shown to ameliorate symptoms in some LSM patients who are essentially concerned with multiple acyl-CoA dehydrogenation deficiency (MADD). It is proved that riboflavin responsive LSM caused by MADD is mainly due to ETFDH gene variant (ETFDH-RRMADD). We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants (c.1588 C > T p.Arg530Cys and c.1589 G > C p.Arg530Pro, FLAD1-RRMADD). And we compared our patient together with 9 FLAD1-RRMADD cases from literature to 106 ETFDH-RRMADD cases in our neuromuscular center on clinical history, laboratory investigations and pathological features. Furthermore, the transcriptomics study on FLAD1-RRMADD and ETFDH-RRMADD were carried out. On muscle pathology, both FLAD1-RRMADD and ETFDH-RRMADD were proved with lipid storage myopathy in which atypical ragged red fibers were more frequent in ETFDH-RRMADD, while fibers with faint COX staining were more common in FLAD1-RRMADD. Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups. Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features.