PTCH1 mutation as a potential predictive biomarker for immune checkpoint inhibitors in gastrointestinal cancer.

Immune checkpoint inhibitors (ICIs) have become prominent therapies for gastrointestinal cancer (GC). However, it is urgent to screen patients who can benefit from ICIs. Protein patched homolog 1 (PTCH1) is a frequently altered gene in GC. We attempt to explore the association between PTCH1 mutation and immunotherapy efficacy. The Memorial Sloan Kettering Cancer Center (MSKCC) cohort (n = 236) with GC (esophageal, gastric and colorectal cancers) patients receiving ICIs was used for discovery and the Peking University Cancer Hospital (PUCH) GC cohort (n = 92) was used for validation. Overall survival (OS) and tumor mutational burden (TMB) of the PTCH1 mutant-type (PTCH1-MUT) and PTCH1 wild-type (PTCH1-WT) groups were compared. Furthermore, GC data were collected from The Cancer Genome Atlas to assess the potential mechanisms. In the MSKCC cohort, PTCH1-MUT group showed significantly better OS (P = 0.017) and higher TMB. Multivariate analysis showed that PTCH1 mutation was associated with better OS. In the PUCH cohort, PTCH1-MUT group showed significantly longer OS (P = 0.036) and progression-free survival, and higher durable clinical benefit and TMB. Immune cell infiltration analysis revealed that PTCH1-MUT group had significantly higher distributions of CD8 T cells, CD4 T cells, NK cells, mast cells and M1 cells. The PTCH1-MUT group showed significantly higher expression of most immune-related genes. Gene set enrichment analysis showed that the PTCH1-MUT group had enriched INF-γ response, INF-α response, glycolysis and reactive oxygen species pathway gene sets. PTCH1 mutation may represent a potential biomarker for predicting ICIs response in GC. Nevertheless, prospective cohort studies should be performed to further validate our results.

Research progress on the regulatory mechanisms of Irisin on cognitive dysfunction in patients with Alzheimer's disease and the interventional role of Irisin in associated diseases.

Irisin, a peptide produced during exercise, is believed to play a role in regulating energy levels within the body. Moreover, Irisin has the ability to traverse the blood-brain barrier and engage in various pathophysiological processes within the central nervous system. An increasing body of research identifies Irisin as a significant therapeutic target for neurodegenerative diseases, indicating a strong link between Irisin and the development of cognitive impairments. In this paper, we present a concise review of effects of different types of exercise on Irisin production, and the mechanisms underlying the Irisin's intervention in various diseases including metabolic diseases, kidney injury and depression. Following this, we delve into an in-depth exploration of its role in modulating cognitive dysfunction among patients with Alzheimer's disease (AD), focusing on recent advancements in three critical areas: neuroinflammation, mitochondrial dysfunction, and protein misfolding. Finally, we put forth 3 hypotheses: (1) exercise-induced fibronectin type III domain containing protein 5 (FNDC5) stimulation and subsequent Irisin cleavage may be associated with the stress response in energy metabolism; (2) Irisin, as a myokine, likely plays a role in mitochondrial repair mechanisms to ameliorate cognitive impairment in AD patients; (3) Irisin is a homeostatic factor that maintains energy homeostasis and is closely related to the dynamic stability of the body's internal environment.

Large-Scale Multiobjective Evolutionary Algorithm Guided by Low-Dimensional Surrogates of Scalarization Functions.

Recently, computationally intensive multiobjective optimization problems have been efficiently solved by surrogate-assisted multiobjective evolutionary algorithms. However, most of those algorithms can only handle no more than 200 decision variables. As the number of decision variables increases further, unreliable surrogate models will result in a dramatic deterioration of their performance, which makes large-scale expensive multiobjective optimization challenging. To address this challenge, we develop a large-scale multiobjective evolutionary algorithm guided by low-dimensional surrogate models of scalarization functions. The proposed algorithm (termed LDS-AF) reduces the dimension of the original decision space based on principal component analysis, and then directly approximates the scalarization functions in a decompositionbased multiobjective evolutionary algorithm. With the help of a two-stage modeling strategy and convergence control strategy, LDS-AF can keep a good balance between convergence and diversity, and achieve a promising performance without being trapped in a local optimum prematurely. The experimental results on a set of test instances have demonstrated its superiority over eight state-of-the-art algorithms on multiobjective optimization problems with up to 1000 decision variables using only 500 real function evaluations.

Contrasting ecological niches lead to great postzygotic ecological isolation: a case of hybridization between carnivorous and herbivorous cyprinid fishes.

BACKGROUND: Postzygote isolation is an important part of species isolation, especially for fish, and it can be divided into two aspects: genetic isolation and ecological isolation. With the increase in parental genetic distance, the intensity of genetic isolation between them also increases. Will the increase in parental ecological niche differences also lead to the increase in ecological isolation intensity between them? This question is difficult to answer based on the current literature due to the lack of hybridization cases of contrasting ecological niche parents. RESULTS: Cyprinid fish parents (Schizothorax wangchiachii and Percocypris pingi) with contrasting ecological niches (herbivorous and carnivorous) and their F1 hybrids were used as research objects. Fish and periphytic algae were selected as food corresponding to different parental resources. The foraging-related traits of these hybrids are generally the same between parents; however, the intermediate foraging traits of hybrids did not result in intermediate foraging performance for parental resources, and these hybrids could hardly forage for parental resources. The poor foraging performance of these hybrids for parental resources was caused not only by the decline in the foraging ability of these hybrids but, more importantly, by the decrease in foraging activity. Interestingly, these hybrids initially showed a high interest in foraging small fishes; however, after the first successful capture, these hybrids had difficulty ingesting fish and spit them out, which led to the subsequent decrease in foraging activity. We designed a series of experiments to explore the mechanism of the fish spitting of these hybrids, excluding the taste and the size of prey, and found that the decrease in their pharyngeal tooth puncture ability may be the reason. CONCLUSIONS: This study was the first to demonstrate that these parents with contrasting ecological niches will produce great postzygotic ecological isolation for parental resources. The poor foraging performance of these hybrids for parental resources is mainly due to the decrease in foraging activity. Interestingly, these hybrids have obvious fish-spitting behaviour, which is a typical example of the incompatibility between intermediate traits and genetic behaviors.

Chloroplast genomes in seven Lagerstroemia species provide new insights into molecular evolution of photosynthesis genes.

Lagerstroemia indica is an important commercial tree known for the ornamental value. In this study, the complete chloroplast genome sequence of Lagerstroemia indica "Pink Velour" (Lagerstroemia "Pink Velour") was 152,174 bp in length with a GC content of 39.50%. It contained 85 protein coding genes (PCGs), 37 tRNAs, and 8 rRNA genes. 207 simple sequence repeats (SSRs) and 31 codons with relative synonymous codon (RSCU)value > 1 were detected. Phylogenetic analysis divided 10 Lagerstroemia species into evolutionary branches of clade A and clade B. We conducted a comparative analysis of Lagerstroemia "Pink Velours" complete chloroplast genome with the genomes of six closely related Lagerstroemia species from different origins. The structural features of all seven species were similar, except for the deletion of ycf1 nucleobases at the JSA boundary. The large single-copy (LSC) and the small single-copy (SSC) had a higher sequence divergence than the IR region, and 8 genes that were highly divergent (trnK-UUU, petN, psbF, psbJ, ndhE, ndhD, ndhI, ycf1) had been identified and could be used as molecular markers in future studies. High nucleotide diversity was present in genes belonging to the photosynthesis category. Mutation of single nucleic acid was mainly influenced by codon usage. The value percentage of nonsynonymous substitutions (Ka) and synonymous substitutions (Ks) in 6 Lagerstroemia species revealed that more photosynthesis genes have Ka or Ks only in Lagerstroemia fauriei, Lagerstroemia limii, and Lagerstroemia subcostata. These advances will facilitate the breeding of closely related Lagerstroemia species and deepen understanding on climatic adaptation of Lagerstroemia plants.

Interspecific differences and ecological correlations between scale number and skin structure in freshwater fishes.

Fish skin is mainly composed of the epidermis, dermis, and its derivative scales. There is a wide diversity in scale number in fishes, but the diversity of skin structure lacks systematic histological comparison. This research aimed to improve our understanding of the functional relationship between the scale number and the skin structure in freshwater fishes and to determine which ecological factors affect the scale number and skin structure. First, we presented a method to quantify skin structure in fish and histologically quantified the skin structure of 54 freshwater fishes. Second, we collected the scale number and habitat information of 509 Cyprinidae fishes in China and explored which ecological factors were related to their scale number. Third, common carp and scaleless carp were used as models to study the effects of scale loss on swimming. We found a strong negative correlation between scale thickness and scale number. The main factor affecting the skin structure of fishes was the species' water column position, and the skin of benthic fishes was the most well-developed (thicker skin layers (dermis, epidermis) or more/larger goblet cells and club cells). The scale number was related to two factors, namely, temperature and water column position, and cold, benthic and pelagic adaptation may have contributed to increased scale numbers. Only in benthic fishes, the more well-developed their skin, the more scales. In common carp, scale loss did not affect its swimming performance. In summary, we suggest that there is a rich diversity of skin structure in freshwater fishes, and the scales of fish with well-developed skin tend to degenerate (greater number/smaller size/thinner, or even disappear), but the skin of fish with degenerated scales is not necessarily well developed.

Partial immune responses in Sichuan bream (Sinibrama taeniatus) after starvation.

Background: Food deprivation is a severe stress across multiple fields and it might be a challenge to immune system. Methods: In the present study, adult male Sinibrama taeniatus were deprived of feed for 7 to 28 days. We explored the effects of starvation on immunity in S. taeniatus through hematological analysis, antioxidant capacity analysis, detection of the content or activity of immune factors in plasma, and transcriptomic analysis. Results: The results indicated that biometric indexes significantly decreased in the fish after starvation, the proportion of thrombocyte, neutrophil and monocyte increased and, conversely, the proportion of lymphocyte decreased. The antioxidant indexes (SOD and CAT) and innate immune parameters (LZM, C3) were upregulated in fish suffering from a short period of starvation, while adaptive immune parameter (IgM) conversely declined. The transcriptome analysis revealed the changes of various metabolic regulatory pathways involved in fatty acids and amino acids, as well as the immune responses and antioxidant capacity. Conclusions: Taken together, this research in the present study suggested an induced innate immunity while a partly suppressed adaptive immunity under a short period starvation.

Integrated printed BDNF-stimulated HUCMSCs-derived exosomes/collagen/chitosan biological scaffolds with 3D printing technology promoted the remodelling of neural networks after traumatic brain injury.

The restoration of nerve dysfunction after traumatic brain injury (TBI) faces huge challenges due to the limited self-regenerative abilities of nerve tissues. In situ inductive recovery can be achieved utilizing biological scaffolds combined with endogenous human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomes (MExos). In this study, brain-derived neurotrophic factor-stimulated HUCMSCs-derived exosomes (BMExos) were composited with collagen/chitosan by 3D printing technology. 3D-printed collagen/chitosan/BMExos (3D-CC-BMExos) scaffolds have excellent mechanical properties and biocompatibility. Subsequently, in vivo experiments showed that 3D-CC-BMExos therapy could improve the recovery of neuromotor function and cognitive function in a TBI model in rats. Consistent with the behavioural recovery, the results of histomorphological tests showed that 3D-CC-BMExos therapy could facilitate the remodelling of neural networks, such as improving the regeneration of nerve fibres, synaptic connections and myelin sheaths, in lesions after TBI.

An exploration of challenges associated with machine learning for time series forecasting of COVID-19 community spread using wastewater-based epidemiological data.

Wastewater-based epidemiology (WBE) has gained increasing attention as a complementary tool to conventional surveillance methods with potential for significant resource and labour savings when used for public health monitoring. Using WBE datasets to train machine learning algorithms and develop predictive models may also facilitate early warnings for the spread of outbreaks. The challenges associated with using machine learning for the analysis of WBE datasets and timeseries forecasting of COVID-19 were explored by running Random Forest (RF) algorithms on WBE datasets across 108 sites in five regions: Scotland, Catalonia, Ohio, the Netherlands, and Switzerland. This method uses measurements of SARS-CoV-2 RNA fragment concentration in samples taken at the inlets of wastewater treatment plants, providing insight into the prevalence of infection in upstream wastewater catchment populations. RF's forecasting performance at each site was quantitatively evaluated by determining mean absolute percentage error (MAPE) values, which was used to highlight challenges affecting future implementations of RF for WBE forecasting efforts. Performance was generally poor using WBE datasets from Catalonia, Scotland, and Ohio with 'reasonable' or better forecasts constituting 0 %, 5 %, and 0 % of these regions' forecasts, respectively. RF's performance was much stronger with WBE data from the Netherlands and Switzerland, which provided 55 % and 45 % 'reasonable' or better forecasts respectively. Sampling frequency and training set size were identified as key factors contributing to accuracy, while inclusion of too many unnecessary variables (or e.g., flow data) was identified as a contributing factor to poor performance. The contribution of catchment population on forecast accuracy was more ambiguous. This study determined that the factors governing RF's forecast performance are complicated and interrelated, which presents challenges for further work in this space. A sufficiently accurate further iteration of the tool discussed within this study would provide significant but varying value for public health departments for monitoring future, or ongoing outbreaks, assisting the implementation of on-time health response measures.

Characterization of the complete mitochondrial genome of Glyptothorax minimaculatus and phylogenetic studies of Sisoridae.

The entire mitochondrial genome (mitogenome) of Glyptothorax minimaculatus was sequenced; it spanned 16,536 bp in length and contained 13 protein-coding genes (PCGs), 2 ribosomal RNAs, and 22 transfer RNA genes. A total of 37 genes formed a typical vertebrate mitochondrial gene arrangement. The phylogenetic tree of Sisoridae based on 13 PCGs was constructed and supported that G. minimaculatus was closely related to Glyptothorax sinensis, Glyptothorax zanaensis, Glyptothorax longinema, Glyptothorax granosus and Glyptothorax lanceatus. The mitogenome of G. minimaculatus described in this study provided molecular evidence for its current taxonomic status and laid a groundwork for further study concerning phylogenetics within Sisoridae.

The complete mitochondrial genome sequence of Schizothorax dulongensis (Cypriniformes, Cyprinidae) from Irrawaddy River in China.

Schizothorax dulongensis Huang (1985) is an endemic species in China, which is mainly distributed in the Irrawaddy River and its tributaries. In this study, the complete mitochondrial genome was sequenced. Its length is 16,579 bp, containing 22 tRNAs, two rRNAs, and 13 PCGs. The phylogenetic results showed that S. dulongensis and these species from Brahmaputra River clustered a clade, and supported the Brahmaputra River and the Irrawaddy River have been reorganized of drainage.

Collagen/heparin scaffold combined with vascular endothelial growth factor promotes the repair of neurological function in rats with traumatic brain injury.

The objective of this study was to evaluate the therapy effects of a novel biological scaffold containing heparin, collagen and vascular endothelial growth factor (VEGF) in treating traumatic brain injury (TBI). In our research, a functional composite scaffold constituted by collagen, heparin and vascular endothelial growth factor was used to stimulate angiogenesis and improve nerve-tissue regeneration in a rat model of TBI. The composite scaffold possessed excellent mechanical properties and good porosity, and could effectively control the release rate of VEGF. Motor and cognitive functions such as motor evoked potential, Morris water maze test and modified neurological severity score were evidently improved after the scaffold was grafted onto the injury site in the rat TBI model. There was clearly improved restoration of damaged nerve tissue at the injured site. Furthermore, brain edema and inflammatory reactions were significantly alleviated. Newly formed neurons with associated synaptic structures, nerve fibers, myelin sheaths and functional angiogenesis with intact endothelium at the injury site were observed. In conclusion, our data revealed that the collagen/heparin scaffold combined with VEGF could create excellent microenvironment stimuli for damaged nerve-tissue regeneration, providing a potential strategy for treating TBI.

Predictive Value of the Serum Matrix Metalloproteinase-9 Level on Hepatic Encephalopathy in Patients with Chronic Liver Disease.

BACKGROUND: Early diagnosis of hepatic encephalopathy (HE) in chronic liver disease (CLD) is difficult clinically. OBJECTIVE: The aim of this study was to evaluate whether serum matrix metalloproteinase-9 (MMP-9) levels could identify early HE in patients with CLD. METHODS: Serum MMP-9 levels in 1,187 patients with CLD were measured at baseline. A total of 1,187 patients with CLD were followed for a mean of 48 months (range: 4-50). The association between MMP-9 and the risk of HE was evaluated by logistic regression analysis and Cox regression analysis. RESULTS: Patients with higher serum MMP-9 levels had higher rates of HE history and HE events during follow-up (all P<0.001). The multivariate logistic regression analysis revealed that MMP-9 (OR=2.84, 95% CI 1.63-7.11, P=0.004) was independently associated with HE history, with an increased grade of aggravation on liver fibrosis at baseline. Multivariate Cox proportional hazard analysis revealed that MMP-9 (HR=2.21, 95% CI 1.09-5.02, P<0.001) was an independent predictor for HE events by sensitivity analysis. The Kaplan-Meier analysis demonstrated that patients with MMP-9 above the median value (176.2 mg/d) had a higher rate of new HE events than patients who had MMP-9 levels below the median value (P<0.001). CONCLUSIONS: Elevated serum RBP4 levels were associated with a higher risk of HE events during follow-up. These results may suggest that serum MMP-9 has good predictive value for detecting HE in patients with CLD, which provides some clinical reference value to clinicians for the early diagnosis of HE.

Chromosomal genome of Triplophysa bleekeri provides insights into its evolution and environmental adaptation.

BACKGROUND: Intense stresses caused by high-altitude environments may result in noticeable genetic adaptions in native species. Studies of genetic adaptations to high elevations have been largely limited to terrestrial animals. How fish adapt to high-elevation environments is largely unknown. Triplophysa bleekeri, an endemic fish inhabiting high-altitude regions, is an excellent model to investigate the genetic mechanisms of adaptation to the local environment. Here, we assembled a chromosomal genome sequence of T. bleekeri, with a size of ∼628 Mb (contig and scaffold N50 of 3.1 and 22.9 Mb, respectively). We investigated the origin and environmental adaptation of T. bleekeri based on 21,198 protein-coding genes in the genome. RESULTS: Compared with fish species living at low altitudes, gene families associated with lipid metabolism and immune response were significantly expanded in the T. bleekeri genome. Genes involved in DNA repair exhibit positive selection for T. bleekeri, Triplophysa siluroides, and Triplophysa tibetana, indicating that adaptive convergence in Triplophysa species occurred at the positively selected genes. We also analyzed whole-genome variants among samples from 3 populations. The results showed that populations separated by geological and artificial barriers exhibited obvious differences in genetic structures, indicating that gene flow is restricted between populations. CONCLUSIONS: These results will help us expand our understanding of environmental adaptation and genetic diversity of T. bleekeri and provide valuable genetic resources for future studies on the evolution and conservation of high-altitude fish species such as T. bleekeri.

Differences Between the "Chinese AMS Score" and the Lake Louise Score in the Diagnosis of Acute Mountain Sickness.

The Chinese AMS score (CAS) is used in clinical medicine and research to diagnosis acute mountain sickness (AMS). However, the Lake Louise Score (LLS) is the well-accepted standard for diagnosing AMS. The difference between the CAS and LLS questionnaires is that the CAS considers more nonspecific symptoms. The aim of the present study was to evaluate differences in AMS prevalence according to the LLS and CAS criteria. We surveyed 58 males who traveled from Chongqing (300 m) to Lhasa (3658 m) via the Qinghai-Tibet train. Cases of AMS were diagnosed using LLS and CAS questionnaires in a few railway stations at different evaluation areas along the road. We subsequently evaluated discrepancies in values related to the prevalence of AMS determined using the 2 types of questionnaires (CAS and LLS). The prevalence of CAS-diagnosed AMS indicated that the percentage of AMS cases among the 58 young men was 29.3% in Golmud, 60.3% in Tanggula, 63.8% in Lhasa, 22.4% on the first day after arrival in Lhasa, 27.6% on the second day, 24.1% on the third day, and 12.1% on the fourth day. The prevalence of LLS-diagnosed AMS in Golmud was 10.3%, 38% in Lhasa, and 6.9% on day 1, the prevalence in each station was lower than that as assessed by the CAS. Our experimental data indicate that AMS diagnoses ascertained using the CAS indicate a higher AMS prevalence than those ascertained using the LLS. Through statistical analysis, the CAS seems capable of effectively diagnosing AMS as validated by LLS (sensitivity 61.8%, specificity 92.7%).