ALTA: a simple nutritional prognostic score for patients with hepatitis B virus-related acute-on-chronic liver failure.

Background: Malnutrition, despite being a common complication, is often neglected in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). The objective of this study was to develop a simplified nutritional prognostic score to accurately predict mortality in HBV-ACLF patients. Methods: In this multicenter retrospective study, clinical data from 530 HBV-ACLF patients were used to create a new prognostic score, which was then validated in two external cohorts (n = 229 and 248). Results: Four independent factors were significantly associated with 28-day mortality in HBV-ACLF patients, forming a novel prognostic score (ALTA score = 0.187 × age-0.849 × lymphocyte count-2.033 × total cholesterol-0.148 × albumin-0.971). Notably, the AUROC of ALTA score for 28/90-day mortality (0.950/0.967) were significantly higher than those of three other ACLF prognostic scores (COSSH-ACLF II, 0.864/0.734; MELD, 0.525/0.488; MELD-Na, 0.546/0.517; all P < 0.001), and three known nutritional scores (CONUT, 0.739/0.861; OPNI, 0.279/0.157; NRS-2002, 0.322/0.286; all P < 0.001). The prediction error rates of ALTA score for 28-day mortality were significantly lower than COSSH-ACLF II (7.3%), MELD (14.4%), MELD-Na (12.7%), CONUT (9.0%), OPNI (30.6%), and NRS2002 (34.1%) scores. Further classifying ALTA score into two strata, the hazard ratios of mortality at 28/90 days were notably increased in the high-risk groups compared to the low-risk group (15.959 and 5.740). These results were then validated in two external cohorts. Conclusion: ALTA, as a simplified nutritional prognostic score for HBV-ACLF, demonstrates superiority over the COSSH-ACLF II and other scores in predicting short-term mortality among HBV-ACLF patients. Therefore, it may be used to guide clinical management, particularly in primary care settings.

Emission Wavelength-Tunable Bicyclic Dioxetane Chemiluminescent Probes for Precise In Vitro and In Vivo Imaging.

Chemiluminescent probes have become increasingly popular in various research areas including precise tumor imaging and immunofluorescence analysis. Nevertheless, previously developed chemiluminescence probes are mainly limited to studying oxidation reaction-associated biological events. This study presents the first example of bioimaging applicable bicyclic dioxetane chemiluminescent probes with tunable emission wavelengths that range from 525 to 800 nm. These newly developed probes were able to detect the analytes of ß-Gal, H2O2, and superoxide with high specificity and a limit of detection of 77 mU L-1, 96, and 28 nM, respectively. The bioimaging application of the probes was verified in ovarian and liver cancer cells and macrophage cells, allowing the detection of the content of ß-Gal, H2O2, and superoxide inside the cells. The high specificity allowed us to image the xenografted tumor in mice. We expect that our probes will receive extensive applications in recording complex biomolecular events using noninvasive imaging techniques.

Ni-Catalyzed Protecting Group Free Diphenic Acid Analog Synthesis.

Severe side effects and drug resistance are major drawbacks of Pt-based chemotherapy in clinical practice, leading to the search for new Pt-based drugs through the tuning of coordination ligands. Therefore, seeking appropriate ligands has attracted significant interest in this area. In this study, we report a Ni-catalyzed coupling strategy for the divergent synthesis of diphenic acid derivatives and the application of these newly prepared acids in Pt(II) agent synthesis.

Identification of novel urine proteomic biomarkers for high stamina in high-altitude adaptation.

Introduction: We aimed to identify urine biomarkers for screening individuals with adaptability to high-altitude hypoxia with high stamina levels. Although most non-high-altitude natives experience rapid decline in physical ability when ascending to high altitudes, some individuals with high-altitude adaptability continue to maintain high endurance levels. Methods: We divided the study population into two groups: the LC group (low change in endurance from low to high altitude) and HC group (high change in endurance from low to high altitude). We performed blood biochemistry testing for individuals at high altitudes and sea level. We used urine peptidome profiling to compare the HH (high-altitude with high stamina) and HL (high-altitude with low stamina) groups and the LC and HC groups to identify urine biomarkers. Results: Routine blood tests revealed that the concentration of white blood cells, lymphocytes and platelets were significantly higher in the HH group than in the HL group. Urine peptidome profiling showed that the proteins ITIH1, PDCD1LG2, NME1-NME2, and CSPG4 were significantly differentially expressed between the HH and HL groups, which was tested using ELISA. Urine proteomic analysis showed that LRG1, NID1, VASN, GPX3, ACP2, and PRSS8 were urine proteomic biomarkers of high stamina during high-altitude adaptation. Conclusion: This study provides a novel approach for identifying potential biomarkers for screening individuals who can adapt to high altitudes with high stamina.

Genomic and RNA-Seq profiling of patients with HFrEF unraveled OAS1 mutation and aggressive expression.

BACKGROUND: Heart failure (HF) is a complex pathophysiological state characterized by inadequate delivery of blood and nutrients to the cardiac tissues. It is rarely curable and is commonly associated with a poor prognosis. In this study, we aimed to analyse exomic and RNA-Seq data from patients with HF to identify the key altered pathways in HF. METHODS: Whole blood samples were collected from patients with HF and subjected to whole exome sequencing (WES) and RNA-Seq analysis. The gene expression and RNA-Seq data obtained were verified using gene chip analysis and RT-PCR. RESULTS: Both exomic and RNA-Seq data confirmed the dysregulation of phosphorylation and immune signalling in patients with HF. Specifically, exomic analysis showed that TITIN, OBSCURIN, NOD2, CDH2, MAP3K5, and SLC17A4 mutations were associated with HF, and RNA-Seq revealed that S100A12, S100A8, S100A9, PFDN5, and TMCC2, were upregulated in patients with HF. Additionally, comparison between RNA-seq and WES data showed that OAS1 mutations are associated with HF. CONLCUSION: Our findings indicated that patients with HF show an overall disruption of key phosphorylation and immune signalling pathways. Based on RNA-seq and WES, OAS1 mutations may be primarily responsible for these changes.

Calsyntenin-1 Promotes Doxorubicin-induced Dilated Cardiomyopathy in Rats.

PURPOSE: Doxorubicin is an important cancer chemotherapeutic agent with severe cardiotoxic effects that eventually lead to dilated cardiomyopathy (DCM). Calsyntenin-1(CLSTN1) plays a critical role in the nervous system, but its relevance in cardiovascular diseases is unknown. We investigated the significance of CLSTN1 in doxorubicin-induced DCM. METHODS: CLSTN1 expression in doxorubicin-induced DCM rats and H9c2 cells was determined using western blotting. To further explore the functions of CLSTN1, a cardiac-specific CLSTN1 overexpression rat model was constructed. The rats were subjected to analysis using echocardiographic, hemodynamic, and electrocardiographic parameters. Potential downstream molecules in CLSTN1 overexpression heart tissue were investigated using proteomics and western blotting. Finally, a knockdown of CLSTN1 was constructed to investigate the rescue function on doxorubicin-induced cell toxicity. RESULTS: CLSTN1 protein expression increased drastically in doxorubicin-induced DCM rats and H9c2 cells. Under doxorubicin treatment, CLSTN1 protein-specific overexpression in the heart muscle promoted cardiac chamber enlargement and heart failure, while the knockdown of CLSTN1 reduced doxorubicin-induced cardiomyocyte toxicity in vitro. At the mechanistic level, overexpression of CLSTN1 downregulated SERCA2 expression and increased the phosphorylation levels of PI3K-Akt and CaMK2. CONCLUSION: Our findings demonstrated that CLSTN1 promotes the pathogenesis of doxorubicin-induced DCM. CLSTN1 could be a therapeutic target to prevent the development of doxorubicin-induced DCM.

Perk heterozygosity ameliorates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in male rats.

BACKGROUND: Pulmonary hypertension (PH) is a rare and deadly disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. hypobaric pulmonary hypertension (HPH) is clinically classified as group 4 of pulmonary hypertension and has a poor prognosis . Previous reports showed that HPH was associated with increased endoplasmic reticulum (ER) stress. The protein kinase R-like endoplasmic reticulum kinase (PERK) is an ER-associated stress protein. However, to date, its physiological effects on HPH and RVF development remains unknown. This study aimed to assess PERK's role in HPH and RV function using in vivo experimental model. METHODS: Perk-knockout male Sprague-Dawley rats were generated and were housed in either a hypobaric chamber or in a normoxic environment. After stimulation for 4 weeks, the hemodynamic parameters of the rats were measured. The heart and lungs were harvested for pathological observation. Blood was collected for the detection of inflammatory indexes. The right ventricle tissue was collected to assess phosphorylated-AKT, ROCK1, ET1, and MMP2 protein expression. RESULTS: WE FIRSTLY GENERATED PERK+/− RATS,: Under normal conditions, Perk+/- rats showed no changes in mPAP(mean pulmonary artery pressure), RVHI(Right ventricular hypertrophy index), cardiomyocyte size and interstitial fibrosis, and pulmonary vascular remodeling. However, in response to chronic hypoxia, Perk+/- rats exhibited decreased in mPAP, RVHI, ventricular fibrosis, and lung remodeling compared to wild-type rats. Perk+/- rats also showed lower expression of phosphor-AKT, ROCK1, ET1, and MMP2 protein in response to chronic hypoxia. CONCLUSIONS: These findings suggest that Perk heterozygosity protects against HPH and Perk may be a suitable target for treating HPH.

Novel Targets in a High-Altitude Pulmonary Hypertension Rat Model Based on RNA-seq and Proteomics.

High-altitude pulmonary hypertension (HAPH) is a complication arising from an inability to acclimatize to high altitude and is associated with high morbidity and mortality. We aimed to analyze the effects of macitentan, selexipag, riociguat, and reoxygenation on HAPH, and to screen possible targets of these treatments for future drug screening. Rats were subjected to hypobaric hypoxia for 35 days to induce HAPH, and treated with vehicle or selexipag, macitentan, riociguat, or with reoxygenation, from days 21 to 35. Selexipag, macitentan, and reoxygenation prevented an increase in mean pulmonary artery pressure and hypoxia-induced right ventricular hypertrophy, compared to the vehicle. Riociguat had little effect. RNA-seq and proteomics revealed strong correlations between responses to the three drugs, which had almost identical effects. GO-enrichment revealed that the differentially expressed genes included those involved in metabolic regulation, transcription, and translation. Various molecular pathways were annotated. Selexipag, macitentan, and reoxygenation ameliorated HAPH. Serpina1, Cryz, and Cmc1 were identified, via multi-omics screening, as key genes involved in HAPH. These findings provide new insights into the targeted drug mechanisms in HAPH.

Clinical and Genetic Predictive Models for the Prediction of Pathological Complete Response to Optimize the Effectiveness for Trastuzumab Based Chemotherapy.

BACKGROUND: Trastuzumab shows excellent benefits for HER2+ breast cancer patients, although 20% treated remain unresponsive. We conducted a retrospective cohort study to optimize neoadjuvant chemotherapy and trastuzumab treatment in HER2+ breast cancer patients. METHODS: Six hundred patients were analyzed to identify clinical characteristics of those not achieving a pathological complete response (pCR) to develop a clinical predictive model. Available RNA sequence data was also reviewed to develop a genetic model for pCR. RESULTS: The pCR rate was 39.8% and pCR was associated with superior disease free survival and overall survival. ER negativity and PR negativity, higher HER2 IHC scores, higher Ki-67, and trastuzumab use were associated with improved pCR. Weekly paclitaxel and carboplatin had the highest pCR rate (46.70%) and the anthracycline+taxanes regimen had the lowest rate (11.11%). Four published GEO datasets were analyzed and a 10-gene model and immune signature for pCR were developed. Non-pCR patients were ER+PR+ and had a lower immune signature and gene model score. Hormone receptor status and immune signatures were independent predictive factors of pCR. CONCLUSION: Hormone receptor status and a 10-gene model could predict pCR independently and may be applied for patient selection and drug effectiveness optimization.

Effects of Intermittent Normoxia on Chronic Hypoxic Pulmonary Hypertension and Right Ventricular Hypertrophy in Rats.

Liu, Chunlei, Xu Chen, Ge Guo, Xiang Xu, Xin Li, Qingxia Wei, Yanying Shen, Hanlu Li, Jianxiu Hao, Ya Ping Tian, and Kunlun He. Effects of intermittent normoxia on chronic hypoxic pulmonary hypertension and right ventricular hypertrophy in rats. High Alt Med Biol. 22: 184-192, 2021. Background: Individuals with chronically low arterial oxygen tension owing to high altitude develop elevated rates of pulmonary hypertension (PH) and right ventricular (RV) hypertrophy. However, the effects of the frequency and duration of normoxic exposure on PH and RV hypertrophy have not been adequately assessed; thus, we aimed to analyze the same. Materials and Methods: PH and RV hypertrophy were induced in 60 rats using a hypobaric chamber. Of these 60 rats, every 10 were exposed to normoxic conditions for 30 minutes once (1T/D), three times (3T/D), or five times daily (5T/D), or for one 150-minute recovery daily (1LT/D). Furthermore, 10 rats were housed in a normoxic environment, and another 10 were subjected to continuous hypoxia. After 4 weeks, hemodynamic measurements were recorded, and the hearts were harvested for pathomorphological observations. Results: Average pulmonary arterial pressures (PAP) of control rats and those exposed to hypobaric hypoxia were 14.1 and 32.3 mmHg, respectively. After 30 minutes of exposure to normoxia 3T/D, 5T/D, or 1LT/D, PAP values were reduced to 27.1, 27.9, or 26.8 mmHg, respectively. Four weeks of hypoxic exposure elevated the RV/heart weight (HW) ratios, while exposure to normoxia 3T/D, 5T/D, and 1LT/D significantly reduced RV/HW. In addition, exposure to normoxia 3T/D, 5T/D, 1LT/D reduced the percentage wall thickness of the pulmonary artery as well as the hypertrophy indices of atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain 7 (MYH-7). Conclusions: Thirty-minute exposure to normoxic conditions of 3T/D, 5T/D, or 1LT/D effectively ameliorates PH and RV thickening.

Ursolic Acid Improves Monocrotaline-Induced Right Ventricular Remodeling by Regulating Metabolism.

Pulmonary arterial hypertension (PAH) is a progressive and malignant disease characterized by pulmonary small arteries and right ventricle (RV) remodeling that can lead to severe RV dysfunction and death. The current therapeutic targets for RV dysfunction, which is strongly linked to mortality, are far from adequate. Therefore, we investigated the effect of ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, on PAH-induced RV remodeling and its underlying mechanism. We established a PAH model by injecting Sprague Dawley rats with monocrotaline (MCT, 60 mg/kg, ip), as verified by echocardiography and hemodynamic examination. Proteomic analysis was performed on RV samples using a Q Exactive high-field mass spectrometer, followed by KEGG enrichment analysis. The effect of 4 weeks of UA (50 mg/kg) treatment on RV remodeling was explored based on ultrasound, hemodynamic parameters, and histological changes, with the mechanism verified in vivo and in vitro by qRT-PCR and western blotting. RV hypertrophy, fibrosis, increased apoptosis, and abnormal metabolism were induced by MCT and suppressed by UA via a mechanism that changed the expression of key markers. UA also attenuated the Phenylephrine-induced hypertrophy of neonatal rat ventricular myocytes and upregulated peroxisome proliferator-activated receptor-alpha (PPARα), a key fatty acid metabolism regulator, and its downstream factor carnitine palmitoyl transferase 1b. In conclusion, UA exerts beneficial effects on PAH-induced RV dysfunction and remodeling by regulating PPARα-dependent fatty acid metabolism.

Conserved expression of ultra-conserved noncoding RNA in mammalian nervous system.

T-UCRs, a class of long non-coding RNAs that are transcribed from ultra-conserved regions (UCRs), might play an important role in development and diseases. However, the amount of T-UCRs that are conservatively expressed in the developing nervous systems of mice, monkeys and humans is still unknown. In this study, we screened the RNA sequence signals of 481 identified UCRs in an E14.5 mouse brain from the ENCODE database and found 76 UCRs that may be transcribed into T-UCRs. To verify the expression of these potential T-UCRs, we used an RT-PCR experiment and identified that 60 T-UCRs can be expressed in the E14.5 mouse brain. Furthermore, we detected the expression conservation of 76 potential T-UCRs in two comparisons: postnatal day 0 brains of a mouse and a rhesus monkey and neural stem cells of mouse and human by RT-PCR experimentation. It was found that up to 65% of these T-UCRs were expressed in mouse, rhesus monkey and human nervous systems. Next, by testing the spatiotemporal expression pattern of these T-UCRs expressed in mouse, rhesus monkey and human nervous systems, we found that approximately 30% of the T-UCRs showed a relatively high and dynamical expression during mouse brain development. Finally, through biological process and molecular function gene ontology analysis of the host genes of intronic or exonic-antisense T-UCRs, it was discovered that most of the genes were involved in RNA splicing or RNA binding. These results suggest that T-UCRs are likely to participate in nervous system development through RNA processing.

GPU acceleration of Dock6's Amber scoring computation.

Dressing the problem of virtual screening is a long-term goal in the drug discovery field, which if properly solved, can significantly shorten new drugs' R&D cycle. The scoring functionality that evaluates the fitness of the docking result is one of the major challenges in virtual screening. In general, scoring functionality in docking requires a large amount of floating-point calculations, which usually takes several weeks or even months to be finished. This time-consuming procedure is unacceptable, especially when highly fatal and infectious virus arises such as SARS and H1N1, which forces the scoring task to be done in a limited time. This paper presents how to leverage the computational power of GPU to accelerate Dock6's (http://dock.compbio.ucsf.edu/DOCK_6/) Amber (J. Comput. Chem. 25: 1157-1174, 2004) scoring with NVIDIA CUDA (NVIDIA Corporation Technical Staff, Compute Unified Device Architecture - Programming Guide, NVIDIA Corporation, 2008) (Compute Unified Device Architecture) platform. We also discuss many factors that will greatly influence the performance after porting the Amber scoring to GPU, including thread management, data transfer, and divergence hidden. Our experiments show that the GPU-accelerated Amber scoring achieves a 6.5× speedup with respect to the original version running on AMD dual-core CPU for the same problem size. This acceleration makes the Amber scoring more competitive and efficient for large-scale virtual screening problems.