Unravelling the metabolic landscape of cutaneous melanoma: Insights from single-cell sequencing analysis and machine learning for prognostic assessment of lactate metabolism.

This manuscript presents a comprehensive investigation into the role of lactate metabolism-related genes as potential prognostic markers in skin cutaneous melanoma (SKCM). Bulk-transcriptome data from The Cancer Genome Atlas (TCGA) and GSE19234, GSE22153, and GSE65904 cohorts from GEO database were processed and harmonized to mitigate batch effects. Lactate metabolism scores were assigned to individual cells using the 'AUCell' package. Weighted Co-expression Network Analysis (WGCNA) was employed to identify gene modules correlated with lactate metabolism. Machine learning algorithms were applied to construct a prognostic model, and its performance was evaluated in multiple cohorts. Immune correlation, mutation analysis, and enrichment analysis were conducted to further characterize the prognostic model's biological implications. Finally, the function of key gene NDUFS7 was verified by cell experiments. Machine learning resulted in an optimal prognostic model, demonstrating significant prognostic value across various cohorts. In the different cohorts, the high-risk group showed a poor prognosis. Immune analysis indicated differences in immune cell infiltration and checkpoint gene expression between risk groups. Mutation analysis identified genes with high mutation loads in SKCM. Enrichment analysis unveiled enriched pathways and biological processes in high-risk SKCM patients. NDUFS7 was found to be a hub gene in the protein-protein interaction network. After the expression of NDUFS7 was reduced by siRNA knockdown, CCK-8, colony formation, transwell and wound healing tests showed that the activity, proliferation and migration of A375 and WM115 cell lines were significantly decreased. This study offers insights into the prognostic significance of lactate metabolism-related genes in SKCM.

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.

An assessment system for clinical and biological interpretability in ulcerative colitis.

Ulcerative colitis (UC) is a serious inflammatory bowel disease (IBD) with high morbidity and mortality worldwide. As the traditional diagnostic techniques have various limitations in the practice and diagnosis of early ulcerative colitis, it is necessary to develop new diagnostic models from molecular biology to supplement the existing methods. In this study, we developed a machine learning-based synthesis to construct an artificial intelligence diagnostic model for ulcerative colitis, and the correctness of the model is verified using an external independent dataset. According to the significantly expressed genes related to the occurrence of UC in the model, an unsupervised quantitative ulcerative colitis related score (UCRScore) based on principal coordinate analysis was established. The UCRScore is not only highly generalizable across UC bulk cohorts at different stages, but also highly generalizable across single-cell datasets, with the same effect in terms of cell numbers, activation pathways and mechanisms. As an important role of screening genes in disease occurrence, based on connectivity map analysis, 5 potential targeting molecular compounds were identified, which can be used as an additional supplement to the therapeutic of UC. Overall, this study provides a potential tool for differential diagnosis and assessment of bio-pathological changes in UC at the macroscopic level, providing an opportunity to optimize the diagnosis and treatment of UC.

Assessment of CircRNA Expression Profiles and Potential Functions in Brown Adipogenesis.

Brown adipose tissue (BAT) is specialized for energy expenditure, thus a better understanding of the regulators influencing BAT development could provide novel strategies to defense obesity. Many protein-coding genes, miRNAs, and lncRNAs have been investigated in BAT development, however, the expression patterns and functions of circRNA in brown adipogenesis have not been reported yet. This study determined the circRNA expression profiles across brown adipogenesis (proliferation, early differentiated, and fully differentiated stages) by RNA-seq. We identified 3,869 circRNAs and 36.9% of them were novel. We found the biogenesis of circRNA was significantly related to linear mRNA transcription, meanwhile, almost 70% of circRNAs were generated by alternative back-splicing. Next, we examined the cell-specific and differentiation stage-specific expression of circRNAs. Compared to white adipocytes, nearly 30% of them were specifically expressed in brown adipocytes. Further, time-series expression analysis showed circRNAs were dynamically expressed, and 117 differential expression circRNAs (DECs) in brown adipogenesis were identified, with 77 upregulated and 40 downregulated. Experimental validation showed the identified circRNAs could be successfully amplified and the expression levels detected by RNA-seq were reliable. For the potential functions of the circRNAs, GO analysis suggested that the decreased circRNAs were enriched in cell proliferation terms, while the increased circRNAs were enriched in development and thermogenic terms. Bioinformatics predictions showed that DECs contained numerous binding sites of functional miRNAs. More interestingly, most of the circRNAs contained multiple binding sites for the same miRNA, indicating that they may facilitate functions by acting as microRNA sponges. Collectively, we characterized the circRNA expression profiles during brown adipogenesis and provide numerous novel circRNAs candidates for future brown adipogenesis regulating studies.

Noninvasive assessment of age-related stiffness of crystalline lenses in a rabbit model using ultrasound elastography.

BACKGROUND: The pathological or physiological changes of a crystalline lens directly affect the eye accommodation and transmittance, and then they increase the risk of presbyopia and cataracts for people in the middle and old age groups. There is no universally accepted quantitative method to measure the lens' mechanical properties in vivo so far. This study aims to investigate the possibility of assessing the age-related stiffness change of crystalline lens by acoustic-radiation-force-based ultrasound elastography (ARF-USE) in a rabbit model in vivo. METHODS: There were 13 New Zealand white rabbits that were divided into four groups and fed normally until they were 60 (n = 4), 90 (n = 2), 120 (n = 4), and 150 (n = 3) days old, respectively. An ARF-USE platform was built based on the Verasonics™ Vantage 256 system. The shear waves were excited and traced in the lens by a linear ultrasound probe after a rabbit was anaesthetized. RESULTS: The average group velocities were 1.38 ± 0.2 m/s, 2.06 ± 0.3 m/s, 2.07 ± 0.29 m/s, and 2.30 ± 0.28 m/s, respectively, for the four groups of rabbits. The results shows that the group velocity has a strong correlation with the day age (r = 0.84, p < 1 × 10-7) and the weight (r = 0.83, p < 1×10-7) of the rabbits while the maximum displacement has no correlations with the day age (r = 0.27, p > 0.1) and the weight (r = 0.32, p > 0.1). CONCLUSION: This study demonstrated that the group velocity measured by ARF-USE had a strong correlation with age-related stiffness in a rabbit model, suggesting that group velocity is a good biomarker to characterize the stiffness of a crystalline lens. This study also demonstrated the feasibility of using this USE technique to assess the mechanical properties of the lens in vivo for clinical or research purposes.

Dynamic development of metabolic syndrome and its risk prediction in Chinese population: a longitudinal study using Markov model.

BACKGROUND: With the increasing prevalence of metabolic syndrome (MS), there is a need to track and predict the development of MS. In this study, we established a Markov model to explore the natural history and predict the risk of MS. METHODS: A total of 21,777 Chinese individuals who had at least two consecutive health check-ups between 2010 and 2015 were studied. MS was defined using the Chinese Diabetes Society criteria. Twelve metabolic abnormal states (the no component state, four isolated component states, six 2-component states, and the MS state) were contained in each Markov chain. The transition probability was the mean of five probabilities for the transition between any two states in 2 consecutive years. RESULTS: The dyslipidemia or overweight/obesity components were most likely to initiate the progress of MS in individuals aged 18-49. However, for individuals over 50 years old, the most likely initiating component of MS was dyslipidemia or hypertension. People who initially had dyslipidemia were most likely to develop the combined state of dyslipidemia with overweight/obesity before the age of 50, but after 50 years of age, the state of dyslipidemia merged with hypertension was the most common. Subjects (with the exception of males over 50 years of age who initially had an isolated state of hyperglycemia) who initially had an isolated state of overweight/obesity, hypertension, or hyperglycemia were most likely to develop a combination of one of these initial states with dyslipidemia. Males who initially had isolated hyperglycemia tended to develop hypertension after age 50. There was a greater chance for subjects who initially had an isolated hyperglycemia state or 2-component state that contained hyperglycemia to develop MS within 10 years compared to those who initially had other abnormal metabolic states. CONCLUSIONS: The occurrence of MS primarily began with overweight/obesity or dyslipidemia in people aged 18-49. However, for those over 50 years old, MS primarily initiated under the conditions of dyslipidemia or hypertension. When MS started under the conditions of overweight/obesity, hypertension or hyperglycemia, dyslipidemia tended to occur next. People who initially had isolated hyperglycemia or a 2-component state that contained hyperglycemia had a higher risk of developing MS than those with other initiating states.

Assessment of myoblast circular RNA dynamics and its correlation with miRNA during myogenic differentiation.

Myoblast differentiation is a highly complex process that is regulated by proteins as well as by non-coding RNAs. Circular RNAs have been identified as an emerging new class of non-coding RNA in the modulation of skeletal muscle development, whereas their expression profiles and functional regulation in myoblast differentiation remain unknown. In the present study, we performed deep RNA-sequencing of C2C12 myoblasts during cell differentiation and uncovered 37,751 unique circular RNAs derived from 6943 hosting genes. The ensuing qRT-PCR and RNA fluorescence in situ hybridization verification were carried out to confirm the RNA-sequencing results. An unbiased analysis demonstrated dynamic circular RNA expression changes in the process of myoblast differentiation, and the circular RNA abundances were independent from their cognate linear RNAs. Gene ontology analysis showed that many down-regulated circular RNAs were exclusive to cell division and the cell cycle, whereas up-regulated circular RNAs were related to the cell development process. Furthermore, interaction networks of circular RNA-microRNA were constructed. Several microRNAs well-known for myoblast regulation, such as miR-133, miR-24 and miR-23a, were in this network. In summary, this study showed that circular RNA expression dynamics changed during myoblast differentiation. Circular RNAs play a role in regulating the myoblast cell cycle and development by acting as microRNA binding sites to facilitate their regulation of gene expression during myoblast differentiation. These findings open a new avenue for future investigation of this emerging RNA class in skeletal muscle growth and development.

Description and prediction of the development of metabolic syndrome in Dongying City: a longitudinal analysis using the Markov model.

BACKGROUND: Metabolic Syndrome (MS) is increasingly becoming a major worldwide clinical and public health issue. Thus it is extremely important to study the history of MS and search for the most likely component contributing to start the cascade of confusions of MS. METHODS: A longitudinal cohort was involved which included the data of 7510 individuals who had at least two routine health check-ups in a six-year follow-up. Based on the data, a Markov model with each chain containing seven states (no component state, four isolated states, 2-component state, and MS state) was built. Annual transition probability was the mean of five probabilities for the transition between the given states between each pair of consecutive years. RESULTS: The transition probabilities from the no component state to MS were higher in men than that in women in four age groups. In the young people (men <60 years and women <50 years), the probabilities to the overweight or obesity state and dyslipidemia state were the first two biggest probabilities in transition from no component to the rest six states. However, in the elderly population, the probabilities to hypertension state and 2-component state increased, even surpassed the above two states. The individuals initiating with 2-component states and the isolated hyperglycemia state were more likely to develop MS than the others. CONCLUSIONS: The Markov model was able to give a better description of the evolutionary history of MS, and to predict the future course based on past evidence. The occurrence of the MS process mostly began with overweight or obesity and dyslipidemia in young people. In the elderly population, many individuals initiating with hypertension or 2 components besides the above two states. Individuals with the isolated hyperglycemia had greater chances to develop MS than other isolated MS' components.

Implementation and validation of an ultrasonic tissue characterization technique for quantitative assessment of normal-tissue toxicity in radiation therapy.

The goal of this study was to implement and validate a noninvasive, quantitative ultrasonic technique for accurate and reproducible measurement of normal-tissue toxicity in radiation therapy. The authors adapted an existing ultrasonic tissue characterization (UTC) technique that used a calibrated 1D spectrum based on region-of-interest analysis. They modified the calibration procedure by using a reference phantom instead of a planar reflector. This UTC method utilized ultrasonic radiofrequency echo signals to generate spectral parameters related to the physical properties (e.g., size, shape, and relative acoustic impedance) of tissue microstructures. Three spectral parameters were investigated for quantification of normal-tissue injury: Spectral slope, intercept, and midband fit. They conducted a tissue-mimicking phantom study to verify the reproducibility of UTC measurements and initiated a clinical study of radiation-induced breast-tissue toxicity. Spectral parameter values from measurements on two phantoms were reproducible within 1% of each other. Eleven postradiation breast-cancer patients were studied and significant differences between the irradiated and untreated (contralateral) breasts were observed for spectral intercept (p = 0.003) and midband fit (p < 0.001) but not for slope (p = 0.14). In comparison to the untreated breast, the average difference in the spectral intercept was 2.99 +/- 0.75 dB and the average difference in the midband fit was 3.99 +/- 0.65 dB. The preliminary clinical study demonstrated the feasibility of using the quantitative ultrasonic method to evaluate normal-tissue toxicity in radiation therapy.