Cystathionine-ß-synthase expression correlates with tumour progression and adverse prognosis in patients with colon cancer.

OBJECTIVE: To investigate the levels of cystathionine-ß-synthase (CBS) in colon cancer tissues compared with adjacent control tissues; and to examine the relationship between CBS level and clinical characteristics and prognosis. METHODS: This retrospective study enrolled patients with primary colon cancer. Paraffin-embedded specimens were used to create pathological tissue microarrays. Immunohistochemistry was performed on the microarray to detect the levels of CBS in colon cancer tissues and normal adjacent tissues. Analyses were undertaken to examine the relationship between the level of CBS and clinical characteristics and prognosis. RESULTS: A total of 216 patients (107 males and 109 females) were included in the study. The level of CBS in cancer tissues was found to be significantly increased compared with normal adjacent control tissues. There were significant differences in tumour location, tumour-node-metastasis stage and survival rate between the CBS-negative and CBS-positive groups. Positive CBS immunostaining was associated with decreased survival in colon cancer patients. The results of multivariate Cox regression analysis revealed that tumour location and positive CBS immunostaining were independent prognostic factors for survival. CONCLUSION: Positive CBS immunostaining was closely associated with colon cancer and high levels of CBS might accelerate tumour development and affect patient prognosis in colon cancer.

Localized nitrogen management strategies can halve fertilizer use in Chinese staple crop production.

Nitrogen (N) management is the key to achieving food security and environmental sustainability. Here we analyse N flows using a localized N management model for wheat, maize and rice in 1,690 Chinese counties, with a breakdown of multiple reactive N (Nr) loss pathways. Results show that the total N input for producing these three staple crops in China was 22.2 Tg N in 2015, of which 7.4 Tg N was harvested as grain N and 4.0 Tg N was Nr losses in the forms of NH3 (47%), NOx (10%), N2O (3%), and leaching and runoff (40%). By assuming a production level equivalent to that of the top 10% of counties with the highest N use efficiency and yields surpassing the regional average, we reveal the possibility of achieving national staple crop production targets while improving net ecosystem economic benefit in 2050 through a 49% reduction (10.4 Tg N) in synthetic N fertilizer inputs and a 52% decrease (2.9 Tg N) in Nr losses.

Chronic abdominal distention caused by diffuse nodular ileal and mesenteric lipomatosis: A case report.

RATIONALE: Diffuse intestinal and mesenteric lipomatosis is a rare condition characterized by the overgrowth of adipose tissue in the intestines and mesentery. This case report aims to highlight the rare occurrence of chronic abdominal distention caused by this disease and its unique invasion into the muscle layer, which has not been previously reported. PATIENT CONCERNS: A 36-year-old woman with a 7-year history of abdominal distension was admitted to our hospital's Department of Gastrointestinal Surgery. DIAGNOSE: Abdominal and pelvic computed tomography revealed diffuse small intestinal lipomatosis. INTERVENTIONS: The patient underwent surgery. We performed an open-field ilectomy involving removal of all lipomatous intestines (250 cm). OUTCOMES: During the surgery, diffuse nodular ileal and mesenteric lipomatosis was confirmed, characterized by the presence of multiple nodular lipomas within the submucosal and muscular layers. The surgical intervention involved the resection of 250 cm of the affected ileum, followed by jejunoileal anastomosis. Postoperative pathology confirmed the diagnosis, with lesions observed in both the submucosa and muscle layers. The patient showed significant improvement in symptoms, with normal intestinal function and weight gain observed over a 10-month follow-up period, and no signs of recurrence. LESSONS: Diffuse intestinal and mesenteric lipomatosis can lead to long-term abdominal distension. Additionally, it may be involved in the muscle layer of the intestinal wall. Surgery is the primary treatment option for symptomatic intestinal lipomatosis.

Allosteric Activation of Protein Phosphatase 5 with Small Molecules.

The activation of PP5 is essential for a variety of cellular processes, as it participates in a variety of biological pathways by dephosphorylating substrates. However, activation of PP5 by small molecules has been a challenge due to its native "self-inhibition" mechanism, which is controlled by the N-terminal TPR domain and the C-terminal αJ helix. Here, we reported the discovery of DDO-3733, a well-identified TPR-independent PP5 allosteric activator, which facilitates the dephosphorylation process of downstream substrates. Considering the negative regulatory effect of PP5 on heat shock transcription factor HSF1, pharmacologic activation of PP5 by DDO-3733 was found to reduce the HSP90 inhibitor-induced heat shock response. These results provide a chemical tool to advance the exploration of PP5 as a potential therapeutic target and highlight the value of pharmacological activation of PP5 to reduce heat shock toxicity of HSP90 inhibitors.

Hsa_circ_0070440 mediates the prognosis and progress of human prostate cancer.

BACKGROUND: This study was designed to explore whether hsa_circ_0070440 was dysregulated in prostate cancer (PCa), and assess the effects of hsa_circ_0070440 alteration on PCa prognosis and cell function. METHODS: The expression levels of hsa_circ_0070440 were assessed in PCa tissues and cell lines. After the classification of patients with PCa based on mean hsa_circ_0070440 level in 138 cases, Chi-square test and survival analyses (Kaplan-Meier method and multivariable Cox proportional hazards analysis) were performed to assess the predictive value of hsa_circ_0070440 in treatment failure (TTF), time to PSA progression (TTPP) and overall survival time. To examine the function of hsa_circ_0070440 in PCa cells, 22Rv1 and C4-2B cells were used for CCK-8 proliferation and Transwell migration assays. Hsa_circ_0070440- and TXNDC5-specific bindings with miR-382/383-5p were validated by bioinformatic analysis and luciferase gene reporter assay. RESULTS: An increased expression of hsa_circ_0070440 was found in PCA tissues and cell lines, associated with clinical T stage (p=0.021) and lymph node metastasis. Hsa_circ_0070440 predicted poor overall survival, TTPP, and TTF, acting as independent prognostic factors for overall survival, TTPP, and TTF in patients with PCa. Knockdown of hsa_circ_0070440 inhibited cell proliferation and migration in vitro. Furthermore, hsa_circ_0070440 could sponge miR-382/383-5p. TXNDC5 was a common target gene for miR-382/383-5p in PCa cells. CONCLUSION: This study demonstrated that hsa_circ_0070440 can predict the prognosis of PCa patients. Hsa_circ_0070440 can facilitate the proliferation and migration of PCa cells, possibly by sponging miR-382/383-5p.

Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate ageing in mice.

One of the basic questions in the ageing field is whether there is fundamental difference between the ageing of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-ageing Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at early age was observed, indicating its involvement in normal ageing of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal ageing. AAV-delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan (Stern 2017). These findings demonstrate the complexity of ageing in mammals, and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.

Food-energy-water nexus optimization brings substantial reduction of urban resource consumption and greenhouse gas emissions.

Urban sustainability is a key to achieving the UN sustainable development goals (SDGs). Secure and efficient provision of food, energy, and water (FEW) resources is a critical strategy for urban sustainability. While there has been extensive discussion on the positive effects of the FEW nexus on resource efficiency and climate impacts, measuring the extent to which such synergy can benefit urban sustainability remains challenging. Here, we have developed a systematic and integrated optimization framework to explore the potential of the FEW nexus in reducing urban resource demand and greenhouse gas (GHG) emissions. Demonstrated using the Metropolis Beijing, we have identified that the optimized FEW nexus can reduce resource consumption and GHG emissions by 21.0 and 29.1%, respectively. These reductions come with increased costs compared to the siloed FEW management, but it still achieved a 16.8% reduction in economic cost compared to the business-as-usual scenario. These findings underscore the significant potential of FEW nexus management in enhancing urban resource efficiency and addressing climate impacts, while also identifying strategies to address trade-offs and increase synergies.

ANT2 functions as a translocon for mitochondrial cross-membrane translocation of RNAs.

Bidirectional transcription of mammalian mitochondrial DNA generates overlapping transcripts that are capable of forming double-stranded RNA (dsRNA) structures. Release of mitochondrial dsRNA into the cytosol activates the dsRNA-sensing immune signaling, which is a defense mechanism against microbial and viral attack and possibly cancer, but could cause autoimmune diseases when unchecked. A better understanding of the process is vital in therapeutic application of this defense mechanism and treatment of cognate human diseases. In addition to exporting dsRNAs, mitochondria also export and import a variety of non-coding RNAs. However, little is known about how these RNAs are transported across mitochondrial membranes. Here we provide direct evidence showing that adenine nucleotide translocase-2 (ANT2) functions as a mammalian RNA translocon in the mitochondrial inner membrane, independent of its ADP/ATP translocase activity. We also show that mitochondrial dsRNA efflux through ANT2 triggers innate immunity. Inhibiting this process alleviates inflammation in vivo, providing a potential therapeutic approach for treating autoimmune diseases.

Associations between remnant cholesterol levels and mortality in patients with diabetes.

BACKGROUND: Dyslipidemia is frequently present in patients with diabetes. The associations of remnant cholesterol and mortality remains unclear in patients with diabetes. AIM: To explore the associations of remnant cholesterol with all-cause and cardiovascular mortality in patients with diabetes. METHODS: This prospective cohort study included 4740 patients with diabetes who participated in the National Health and Nutrition Examination Survey from 1999 through 2018. Remnant cholesterol was used as the exposure variable, and all-cause and cardiovascular mortality were considered outcome events. Outcome data were obtained from the National Death Index, and all participants were followed from the interview date until death or December 31, 2019. Multivariate proportional Cox regression models were used to explore the associations between exposure and outcomes, in which remnant cholesterol was modeled as both a categorical and a continuous variable. Restricted cubic splines (RCSs) were calculated to assess the nonlinearity of associations. Subgroup (stratified by sex, age, body mass index, and duration of diabetes) and a series of sensitivity analyses were performed to evaluate the robustness of the associations. RESULTS: During a median follow-up duration of 83 months, 1370 all-cause deaths and 389 cardiovascular deaths were documented. Patients with remnant cholesterol levels in the third quartile had a reduced risk of all-cause mortality [hazard ratio (HR) 95% confidence interval (CI): 0.66 (0.52-0.85)]; however, when remnant cholesterol was modeled as a continuous variable, it was associated with increased risks of all-cause [HR (95%CI): 1.12 (1.02-1.21) per SD] and cardiovascular [HR (95%CI): 1.16 (1.01-1.32), per SD] mortality. The RCS demonstrated nonlinear associations of remnant cholesterol with all-cause and cardiovascular mortality. Subgroup and sensitivity analyses did not reveal significant differences from the above results. CONCLUSION: In patients with diabetes, higher remnant cholesterol was associated with increased risks of all-cause and cardiovascular mortality, and diabetes patients with slightly higher remnant cholesterol (0.68-1.04 mmol/L) had a lower risk of all-cause mortality.