Heterogeneous hydrochlorination of lipids mediated by fatty acids in an indoor environment.

Fatty acids from cooking fumes and hypochlorous acid (HOCl) released from indoor cleaning adversely affect respiratory health, but the molecular-level mechanism remains unclear. Here, the effect of cooking oil fumes [palmitic acid (PA), oleic acid (OA), and linoleic acid (LA)] on lung model phospholipid (POPG) hydrochlorination mediated by HOCl at the air-water interface of the hanged droplets was investigated. Interfacial hydrochlorination of POPG was impeded by OA and LA, while that of POPG was facilitated by PA. The effect on POPG hydrochlorination increased with the decrease in oil fume concentration. A potential mechanism with respect to the chain length of these oil fumes, regardless of their saturation, was proposed. PA with a short carbon chain looses the POPG packing and leads to the exposure of the C=C double bonds of POPG, whereas OA and LA with a long carbon chain hinder HOCl from reaching the C=C bonds of POPG. These results for short chain and low concentration dependence suggest that the decay of oil fumes or the conversion of short-chain species by indoor interfacial chemistry might be adverse to lung health. These results provide insights into the relationship between indoor multicomponent pollutants and the respiratory system.

Early Therapeutic Drug Monitoring Optimizes Teicoplanin Use in Febrile Neutropenic Patients with Hematological Malignancies.

INTRODUCTION: A target trough concentration (Cmin) of teicoplanin ≥ 15-20 mg/L between the fourth and sixth day has been suggested for severe infections or management of febrile neutropenia (FN). Owing to no reports discussing the impact of early target attainment on treatment outcomes, this study aimed to evaluate the dose-Cmin relationship and clinical outcome and estimate the optimal early target Cmin for FN in patients with hematological malignancies. METHODS: This single-center, prospective study enrolled patients with hematological malignancies who were treated with teicoplanin either as an empirical antibiotic for FN or as targeted treatment for Gram-positive bacteria. Blood samples were collected on day three (48 h) post-loading doses, day 5 (96 h), and day 8 (when applicable) and determined by ultrahigh-pressure liquid chromatography-triple quadruple mass spectrometry. A total of 117 samples from 47 patients with FN (27 men, 20 women) were consecutively analyzed. A two-tailed α value of 0.05 was considered statistically significant. RESULTS: The mean Cmin values at 48 h, 96 h, and on day 8 were 23.4, 21.4, and 27.8 mg/L, respectively. The patients achieving Cmin ≥ 20 mg/L at 48 h had a higher likelihood of treatment success. The areas under the receiver operating characteristic curves were 0.71 for clinical efficacy and the cutoff value of Cmin at 48 h was 18.85 mg/L (95% confidence interval 0.55-0.87; P = 0.018). CONCLUSIONS: The Cmin of teicoplanin after completion of loading doses could predict the treatment response, with a target concentration ≥ 18.85 mg/L.

Study on the regulatory mechanism of latent membrane protein 2A on GCNT3 expression in nasopharyngeal carcinoma.

O-Glycan synthesis enzyme glucosaminyl (N-acetyl) transferase 3 (GCNT3) is closely related to the occurrence and development of various cancers. However, the regulatory mechanism and function of GCNT3 in nasopharyngeal carcinoma (NPC) are still poorly understood. This study aims to explore the regulatory mechanism of EBV-encoded latent membrane protein 2A (LMP2A) on GCNT3 and the biological role of GCNT3 in NPC. The results show that LMP2A can activate GCNT3 through the mTORC1 pathway, and there is a positive feedback between the mTORC1 and GCNT3. GCNT3 regulates EMT progression by forming a complex with ZEB1 to promote cell migration. GCNT3 can also promote cell proliferation. These findings indicate that targeting the LMP2A-mTORC1-GCNT3 axis may represent a novel therapeutic target in NPC.

Novel T cell exhaustion gene signature to predict prognosis and immunotherapy response in thyroid carcinoma from integrated RNA-sequencing analysis.

Exhausted CD8+ T lymphocytes and tumor-associated macrophages play critical roles in determining cancer prognosis and the efficacy of immunotherapy. Our study revealed a negative correlation between exhausted CD8+ T lymphocytes and prognosis in thyroid carcinoma (THCA). Consensus clustering divided patients into two subgroups of exhaustion with different prognoses, as defined by marker genes of exhausted CD8+ T cells. Subsequently, we constructed an eight-gene prognostic signature, and developed a risk score named the exhaustion-related gene score (ERGS) to forecast both prognosis and immunotherapy response in THCA. Bulk RNA sequencing analysis revealed a higher prevalence of M2 macrophages, indicative of an immunosuppressive tumor microenvironment (TME), in the high-ERGS group. Single-cell RNA sequencing showed that SPP1+ macrophages and CD14+ monocytes infiltrations were positively associated with higher ERGS. Functionally, it was determined that SPP1+ macrophages exert an immunosuppressive role, while CD14+ monocytes were implicated in promoting tumor progression and angiogenesis. Analysis of cell-cell interactions between SPP1+ macrophages and T cells highlighted the activation of the SPP1-CD44 and MIF-CD74 axes, both of which could foster an immunosuppressive TME. Therapeutic strategies that target SPP1+ macrophages, CD14+ monocytes, and the SPP1-CD44 and MIF-CD74 axes may potentially improve the prognosis and amplify the immunotherapy response in THCA patients.

Palmatine Alleviates Particulate Matter-Induced Acute Lung Injury by Inhibiting Pyroptosis via Activating the Nrf2-Related Pathway.

Particulate matter (PM) induces and enhances oxidative stress and inflammation, leading to a variety of respiratory diseases, including acute lung injury. Exploring new treatments for PM-induced lung injury has long been of interest to researchers. Palmatine (PAL) is a natural extract derived from plants that has been reported in many studies to alleviate inflammatory diseases. Our study was designed to explore whether PAL can alleviate acute lung injury caused by PM. The acute lung injury model was established by instilling PM (4 mg/kg) into the airway of mice, and PAL (50 mg/kg and 100 m/kg) was administrated orally as the treatment groups. The effect and mechanism of PAL treatment were examined by immunofluorescence, immunohistochemistry, Western Blotting, ELISA, and other experiments. The results showed that oral administration of PAL (50 mg/kg and 100 m/kg) could significantly alleviate lung inflammation and acute lung injury caused by PM. In terms of mechanism, we found that PAL (50 mg/kg) exerts anti-inflammatory and anti-damage effects mainly by enhancing the activation of the Nrf2-related antioxidant pathway and inhibiting the activation of the NLRP3-related pyroptosis pathway in mice. These mechanisms have also been verified in our cell experiments. Further cell experiments showed that PAL may reduce intracellular reactive oxygen species (ROS) by activating Nrf2-related pathways, thereby inhibiting the activation of NLRP3-related pyroptosis pathway induced by PM in Beas-2B cell. Our study suggests that PAL can be a new option for PM-induced acute lung injury.

The Significant Role of New Particle Composition and Morphology on the HNO3-Driven Growth of Particles down to Sub-10 nm.

New particle formation and growth greatly influence air quality and the global climate. Recent CERN Cosmics Leaving OUtdoor Droplets (CLOUD) chamber experiments proposed that in cold urban atmospheres with highly supersaturated HNO3 and NH3, newly formed sub-10 nm nanoparticles can grow rapidly (up to 1000 nm h-1). Here, we present direct observational evidence that in winter Beijing with persistent highly supersaturated HNO3 and NH3, nitrate contributed less than ∼14% of the 8-40 nm nanoparticle composition, and overall growth rates were only ∼0.8-5 nm h-1. To explain the observed growth rates and particulate nitrate fraction, the effective mass accommodation coefficient of HNO3 (αHNO3) on the nanoparticles in urban Beijing needs to be 2-4 orders of magnitude lower than those in the CLOUD chamber. We propose that the inefficient uptake of HNO3 on nanoparticles is mainly due to the much higher particulate organic fraction and lower relative humidity in urban Beijing. To quantitatively reproduce the observed growth, we show that an inhomogeneous "inorganic core-organic shell" nanoparticle morphology might exist for nanoparticles in Beijing. This study emphasized that growth for nanoparticles down to sub-10 nm was largely influenced by their composition, which was previously ignored and should be considered in future studies on nanoparticle growth.

Metabolism-dependent mutagenicity of two structurally similar tobacco-specific nitrosamines (N-nitrosonornicotine and N-nitrosoanabasine) in human cells, partially different CYPs being activating enzymes.

N-nitrosonornicotine (NNN) and N-nitrosoanabasine (NAB) are both tobacco-specific nitrosamines bearing two heterocyclic amino groups, NAB bearing an extra -CH2- group (conferring a hexa- rather than penta-membered cycle) but with significantly decreased carcinogenicity. However, their activating enzymes and related mutagenicity remain unclear. In this study, the chemical-CYP interaction was analyzed by molecular docking, thus the binding energies and conformations of NNN for human CYP2A6, 2A13, 2B6, 2E1 and 3A4 appeared appropriate as a substrate, so did NAB for human CYP1B1, 2A6, 2A13 and 2E1. The micronucleus test in human hepatoma (HepG2) cells with each compound (62.5-1000 µM) exposing for 48 h (two-cell cycle) was negative, however, pretreatment with bisphenol AF (0.1-100 nM, CYPs inducer) and ethanol (0.2% v:v, CYP2E1 inducer) potentiated micronucleus formation by both compounds, while CITCO (1 µM, CYP2B6 inducer) selectively potentiated that by NNN. In C3A cells (endogenous CYPs enhanced over HepG2) both compounds induced micronucleus, which was abolished by 1-aminobenzotriazole (60 µM, CYPs inhibitor) while unaffected by 8-methoxypsoralen (1 µM, CYP2A inhibitor). Consistently, NNN and NAB induced micronucleus in V79-derived recombinant cell lines expressing human CYP2B6/2E1 and CYP1B1/2E1, respectively, while negative in those expressing other CYPs. By immunofluorescent assay both compounds selectively induced centromere-free micronucleus in C3A cells. In PIG-A assays in HepG2 cells NNN and NAB were weakly positive and simply negative, respectively; however, in C3A cells both compounds significantly induced gene mutations, NNN being slight more potent. Conclusively, both NNN and NAB are mutagenic and clastogenic, depending on metabolic activation by partially different CYP enzymes.

Clinical data mining: challenges, opportunities, and recommendations for translational applications.

Clinical data mining of predictive models offers significant advantages for re-evaluating and leveraging large amounts of complex clinical real-world data and experimental comparison data for tasks such as risk stratification, diagnosis, classification, and survival prediction. However, its translational application is still limited. One challenge is that the proposed clinical requirements and data mining are not synchronized. Additionally, the exotic predictions of data mining are difficult to apply directly in local medical institutions. Hence, it is necessary to incisively review the translational application of clinical data mining, providing an analytical workflow for developing and validating prediction models to ensure the scientific validity of analytic workflows in response to clinical questions. This review systematically revisits the purpose, process, and principles of clinical data mining and discusses the key causes contributing to the detachment from practice and the misuse of model verification in developing predictive models for research. Based on this, we propose a niche-targeting framework of four principles: Clinical Contextual, Subgroup-Oriented, Confounder- and False Positive-Controlled (CSCF), to provide guidance for clinical data mining prior to the model's development in clinical settings. Eventually, it is hoped that this review can help guide future research and develop personalized predictive models to achieve the goal of discovering subgroups with varied remedial benefits or risks and ensuring that precision medicine can deliver its full potential.

Transcriptome sequencing analysis reveals miR-30c-5p promotes ferroptosis in cervical cancer and inhibits growth and metastasis of cervical cancer xenografts by targeting the METTL3/KRAS axis.

Cervical cancer is the most common malignant tumor in the female reproductive system worldwide, and its molecular mechanisms remain complex and poorly understood. Various techniques, including transcriptome sequencing, RT-qPCR, ELISA, immunofluorescence, Western blot, CCK-8 assay, Transwell assay, and xenograft models, were employed to investigate gene/miRNA expression, cellular proliferation, migration, and the interactions between miR-30c-5p, METTL3, and KRAS. Our transcriptome sequencing results demonstrated a significant downregulation of miR-30c-5p in cervical cancer cells. Further investigations using RNA pull-down, dual-luciferase reporter assay, Me-RIP, and PAR-CLIP confirmed METTL3 as one of the downstream targets of miR-30c-5p, while KRAS was identified as an iron-death suppressor gene susceptible to m6A modification. Notably, our Me-RIP analysis demonstrated the involvement of METTL3 in m6A modification of KRAS. In vitro experiments revealed that miR-30c-5p facilitated ferroptosis in cervical cancer cells by inhibiting the METTL3/KRAS axis, thus suppressing proliferation and migration. Additionally, in vivo studies demonstrated that miR-30c-5p repressed the growth and metastasis of cervical cancer xenografts through the inhibition of the METTL3/KRAS axis. Overall, this study highlights the critical role of miR-30c-5p in modulating cervical cancer progression by targeting the METTL3/KRAS axis, providing new insights into the molecular mechanisms underlying cervical cancer growth and metastasis.

Nicotiana alkaloids-intervened phospholipid ozonolysis at the air-water interface.

Cigarette nicotiana alkaloids associated with lung and cardiovascular diseases attack enormous attention. However, the mechanism at the molecular level between nicotiana alkaloids and phospholipid ozonolysis remains elusive. Herein, we investigated the interfacial ozonolysis of a hung droplet containing 1-palmitoyl-2-oleoyl-sn-phosphatidylglycerol (POPG) intervened by nicotiana alkaloids (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK; rac-N'-nitrosonornicotine, NNN; nicotine; and (R,S)-N-nitrosoanasabine, NAT) and followed by on-line mass spectrometry analysis. NNK and NNN showed an acceleration on the interfacial ozonolysis, while nicotine and NAT inhibited this chemistry. Such acceleration/inhibition on POPG ozonolysis was positively correlated with nicotiana alkaloid concentrations. The reaction rate constants suggested that the ozonolysis of lung phospholipids exposed to cigarette smoke at the air-water interface occurred rapidly. A possible mechanism of the hydrophilic/oleophilic nature of nicotiana alkaloids mediating the packing density of POPG was proposed. NNK and NNN with a hydrophilic nature inserted into the POPG monolayer loosed the packing, but nicotine and NAT with an oleophilic nature let the POPG closely pack and shield the CC double bonds exposed to ozone (O3). These results gain the knowledge of nicotiana alkaloids mediated phospholipid ozonolysis at the molecule level and provide a method for online interfacial reaction studies associated with elevated indoor pollutants on public health.

Gut microbiota-driven metabolic alterations reveal gut-brain communication in Alzheimer's disease model mice.

The gut microbiota (GM) and its metabolites affect the host nervous system and are involved in the pathogeneses of various neurological diseases. However, the specific GM alterations under pathogenetic pressure and their contributions to the "microbiota - metabolite - brain axis" in Alzheimer's disease (AD) remain unclear. Here, we investigated the GM and the fecal, serum, cortical metabolomes in APP/PS1 and wild-type (WT) mice, revealing distinct hub bacteria in AD mice within scale-free GM networks shared by both groups. Moreover, we identified diverse peripheral - central metabolic landscapes between AD and WT mice that featured bile acids (e.g. deoxycholic and isodeoxycholic acid) and unsaturated fatty acids (e.g. 11Z-eicosenoic and palmitoleic acid). Machine-learning models revealed the relationships between the differential/hub bacteria and these metabolic signatures from the periphery to the brain. Notably, AD-enriched Dubosiella affected AD occurrence via cortical palmitoleic acid and vice versa. Considering the transgenic background of the AD mice, we propose that Dubosiella enrichment impedes AD progression via the synthesis of palmitoleic acid, which has protective properties against inflammation and metabolic disorders. We identified another association involving fecal deoxycholic acid-mediated interactions between the AD hub bacteria Erysipelatoclostridium and AD occurrence, which was corroborated by the correlation between deoxycholate levels and cognitive scores in humans. Overall, this study elucidated the GM network alterations, contributions of the GM to peripheral - central metabolic landscapes, and mediatory roles of metabolites between the GM and AD occurrence, thus revealing the critical roles of bacteria in AD pathogenesis and gut - brain communications under pathogenetic pressure.

Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease of lipid metabolism mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Genetic detection of patients with FH help with precise diagnosis and treatment, thus reducing the risk of coronary heart disease (CHD) and other related diseases. The study aimed to identify the causative gene mutations in a Chinese FH family and reveal the pathogenicity and the mechanism of these mutations. METHODS AND RESULTS: Whole exome sequencing was performed in a patient with severe lipid metabolism dysfunction seeking fertility guidance from a Chinese FH family. Two LDLR variants c.1875 C > G (p.N625K; novel variant) and c.1448G > A (p.W483*) were identified in the family. Wildtype and mutant LDLR constructs were established by the site-direct mutagenesis technique. Functional studies were carried out by cell transfection to evaluate the impact of detected variants on LDLR activity. The two variants were proven to affect LDL uptake and binding, resulting in cholesterol clearance reduction to different degrees. According to The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, the W483* variant was classified as "Pathogenic", while the N625K variant as "VUS". CONCLUSIONS: Our results provide novel experimental evidence of functional alteration by LDLR variants identified in our study and expand the mutational spectrum of LDLR mutation induced FH.

Molecular Engineering of Perylene Diimide Polymers with a Robust Built-in Electric Field for Enhanced Solar-Driven Water Splitting.

The built-in electric field of the polymer semiconductors could be regulated by the dipole moment of its building blocks, thereby promoting the separation of photogenerated carriers and achieving efficient solar-driven water splitting. Herein, three perylene diimide (PDI) polymers, namely oPDI, mPDI and pPDI, are synthesized with different phenylenediamine linkers. Notably, the energy level structure, light-harvesting efficiency, and photogenerated carrier separation and migration of polymers are regulated by the orientation of PDI unit. Among them, oPDI enables a large dipole moment and robust built-in electric field, resulting in enhanced solar-driven water splitting performance. Under simulated sunlight irradiation, oPDI exhibits the highest photocurrent of 115.1 µA cm-2 for photoelectrochemical oxygen evolution, which is 11.5 times that of mPDI, 26.8 times that of pPDI and 104.6 times that of its counterparts PDI monomer at the same conditions. This work provides a strategy for designing polymers by regulating the orientation of structural units to construct efficient solar energy conversion systems.

Exploring the extensin gene family: an updated genome-wide survey in plants and algae.

Extensins (EXTs), a class of hydroxyproline-rich glycoprotein with multiple Ser-Pro3-5 motifs, are known to play roles in cell wall reinforcement and environmental responses. EXTs with repetitive Tyr-X-Tyr (YXY) motifs for crosslinking are referred as crosslinking EXTs. Our comprehensive study spanned 194 algal and plant species, categorizing EXTs into seven subfamilies: classical extensins (EXT I and II), arabinogalactan-protein extensins (AGP-EXTs), proline-rich extensin-like receptor kinases (PERKs), leucine-rich repeat extensins (LRX I and II), formin homology (FH) domain-containing extensins (FH-EXTs), proline-rich, arabinogalactan proteins, conserved cysteines (PAC) domain-containing extensins (PAC I and II), and eight-cysteine motif (8CM)-containing extensins (8CM-EXTs). In the examined dataset, EXTs were detected ubiquitously in plants but infrequently in algae, except for one Coccomyxa and four Chlamydomonadales species. No crosslinking EXTs were found in Poales or certain Zingiberales species. Notably, the previously uncharacterized EXT II, PAC II, and liverwort-specific 8CM-EXTs were found to be crosslinking EXTs. EXT II, featuring repetitive YY motifs instead of the conventional YXY motif, was exclusively identified in Solanaceae. Furthermore, tandem genes encoding distinctive 8CM-EXTs specifically expressed in the germinating spores of Marchantia polymorpha. This updated classification of EXT types allows us to propose a plausible evolutionary history of EXT genes during the course of plant evolution.

Enhancing the identification of voriconazole-associated hepatotoxicity by targeted metabolomics.

Voriconazole-associated hepatotoxicity is a common condition that generally manifests as elevated liver enzymes and can lead to drug discontinuation. Careful monitoring of voriconazole-associated hepatotoxicity is needed but there are no specific plasma biomarkers for this condition. Metabolomics has emerged as a promising technique for investigating biomarkers associated with drug-induced toxicity. The aim of this study was to use targeted metabolomics to evaluate seven endogenous metabolites as potential biomarkers of voriconazole-associated hepatotoxicity. Patients undergoing therapeutic drug monitoring of voriconazole were classified into a hepatotoxicity group (18 patients) or a control group (153 patients). Plasma samples were analysed using ultra-high-performance liquid chromatography coupled to mass spectrometry. Metabolite concentrations in the two groups were compared. Areas under the receiver operating characteristic (AUROC) curves generated from logistic regressions were used to correlate the concentrations of these seven metabolites with voriconazole trough concentrations and conventional liver biochemistry tests. Glycocholate and α-ketoglutarate levels were significantly higher in the hepatotoxicity group compared with the control group (false discovery rate-corrected P < 0.001 and P = 0.024, respectively). The metabolites glycocholate (AUROC = 0.795) and α-ketoglutarate (AUROC = 0.696) outperformed voriconazole trough concentrations (AUROC = 0.555) and approached the performance of alkaline phosphatase (AUROC = 0.876) and total bilirubin (AUROC = 0.815). A panel of glycocholate combined with voriconazole trough concentrations (AUROC = 0.827) substantially improved the performance of voriconazole trough concentrations alone in predicting hepatotoxicity. In conclusion, the panel integrating glycocholate with voriconazole trough concentrations has great potential for identifying voriconazole-associated hepatotoxicity.

Intrinsic mechanisms and spatial effects of multidimensional urbanization and carbon emissions.

Existing studies on urbanization and carbon emissions are mostly based on a single pathway and lack the support of a theoretical framework. This study innovatively integrates Grossman's perspective of environmental effects analysis to develop a new framework to interpret the mechanism of multidimensional urbanization (MU) and carbon emissions (CEs). We first explored the spatial effects of MUs and CEs in the Yangtze River Delta urban agglomeration (YRDUA) and then introduced the "population-land-economic" urbanization variables into the S-STIRPAT model to determine the impact mechanisms of each factor on CEs under different urbanization dimensions. The results show that the spatiotemporal development patterns of MUs and CEs overlap to some extent. The Shanghai-Nanjing line is a high-value area of urbanization with different dimensions, as some edge cities are in low-value areas. However, there are local differences in the different dimensions of urbanization, e.g., population urbanization in the southern area is in a high-value area. CEs show a core-edge structure of "high in the center and low in the north and south". All factors, except for population urbanization, affect CEs locally, and their spillover effects are all positive, except for energy intensity, which has a negative influence on CEs in neighboring regions. Land urbanization has the largest positive impact on CEs, with a total effect coefficient of 0.409; economic urbanization has a coefficient of 0.195, and population urbanization has a coefficient of only 0.070. The findings can help to maximize urbanization growth while minimizing harmful environmental externalities.

Association between increased C-reactive protein and cardiovascular disease among patients with rectal cancer.

Purpose: This study aimed to investigate the association between increased C-reactive protein (CRP) and cardiovascular disease (CVD) in individuals with rectal cancer, as well as to understand the effect of chemotherapy for cancer on increasing CRP and its underlying mechanisms. Patients and methods: From January 1, 2010 to December 31, 2020, individuals with rectal cancer were evaluated at the First Affiliated Hospital of Gannan Medical University. Then, in patients with rectal cancer, the relationship between increased CRP and CVD attributes was summarized, and the impact of chemotherapy on CRP levels was qualitatively assessed. For further investigation into potential regulatory mechanisms of CRP, differentially expressed genes (DEGs), GO and KEGG enrichment analyses were conducted. Results: A total of 827 individuals were included in the study, including 175 with CVD (21.16%) and 652 without CVD. A significant association between increased CRP and CVD events was observed in rectal cancer patients (p < 0.01), and it significantly improved the classification performance of the CVD predictive model in the AUC (0.724 vs 0.707) and NRI (0.069, 95% CI 0.05-0.14). Furthermore, a comparison of CRP levels before and after chemotherapy revealed a significant increase among rectal cancers post-treatment (p < 0.001). Analysis of differentially expressed genes and co-expression indicated that 96 DEGs were involved in the pathophysiology of increased CRP after chemotherapy, and three hub genes were implicated in atherosclerotic susceptibility. Conclusion: In conclusion, our findings indicated that increased CRP levels following chemotherapy profoundly impacted CVD events in individuals with rectal cancer, and may be beneficial in promoting CVD prediction in clinical practice.

Exploration of the truncated cytosolic Hsp70 in plants - unveiling the diverse T1 lineage and the conserved T2 lineage.

The 70-kDa heat shock proteins (Hsp70s) are chaperone proteins involved in protein folding processes. Truncated Hsp70 (Hsp70T) refers to the variant lacking a conserved C-terminal motif, which is crucial for co-chaperone interactions or protein retention. Despite their significance, the characteristics of Hsp70Ts in plants remain largely unexplored. In this study, we performed a comprehensive genome-wide analysis of 192 sequenced plant and green algae genomes to investigate the distribution and features of Hsp70Ts. Our findings unveil the widespread occurrence of Hsp70Ts across all four Hsp70 forms, including cytosolic, endoplasmic reticulum, mitochondrial, and chloroplast Hsp70s, with cytosolic Hsp70T being the most prevalent and abundant subtype. Cytosolic Hsp70T is characterized by two distinct lineages, referred to as T1 and T2. Among the investigated plant and green algae species, T1 genes were identified in approximately 60% of cases, showcasing a variable gene count ranging from one to several dozens. In contrast, T2 genes were prevalent across the majority of plant genomes, usually occurring in fewer than five gene copies per species. Sequence analysis highlights that the putative T1 proteins exhibit higher similarity to full-length cytosolic Hsp70s in comparison to T2 proteins. Intriguingly, the T2 lineage demonstrates a higher level of conservation within their protein sequences, whereas the T1 lineage presents a diverse range in the C-terminal and SBDα region, leading to categorization into four distinct subtypes. Furthermore, we have observed that T1-rich species characterized by the possession of 15 or more T1 genes exhibit an expansion of T1 genes into tandem gene clusters. The T1 gene clusters identified within the Laurales order display synteny with clusters found in a species of the Chloranthales order and another species within basal angiosperms, suggesting a conserved evolutionary relationship of T1 gene clusters among these plants. Additionally, T2 genes demonstrate distinct expression patterns in seeds and under heat stress, implying their potential roles in seed development and stress response.

RAI2 acts as a tumor suppressor with functional significance in gastric cancer.

Metastasis of gastric cancer (GC) is one of the major causes of death among GC patients. GC metastasis involves numerous biological processes, yet the specific molecular biological mechanisms have not been elucidated. Here, we report a novel tumor suppressor, retinoic acid-induced 2 (RAI2), which is located in the Xp22 region of the chromosome and plays a role in inhibiting GC growth and invasion. In this study, integrated analysis of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets and immunohistochemistry staining data suggested that RAI2 expression in GC samples was low. Moreover, the immune infiltration analysis indicated that low expression of RAI2 in GC was associated with a higher intensity of tumor-infiltrating lymphocytes (TILs) and an abundance of Programmed death ligand 1 (PD-L1) expression. Gene set enrichment analysis (GSEA) analysis further revealed that RAI2 regulated some pathways including the GAP junction, focal adhesion and ECM receptor interaction pathway, immune regulation, PI3K-Akt signaling, MAPK signaling, cell cycle, and DNA replication. Furthermore, the knockdown of RAI2 promoted GC cell proliferation, migration, and invasion in vitro. Taken together, these results suggest that the tumor suppressor RAI2 could be a potential target for the development of anti-cancer strategies in GC.

Vessels characteristics in familial exudative vitreoretinopathy and retinopathy of prematurity based on deep convolutional neural networks.

Purpose: The purpose of this study was to investigate the quantitative retinal vascular morphological characteristics of Retinopathy of Prematurity (ROP) and Familial Exudative Vitreoretinopathy (FEVR) in the newborn by the application of a deep learning network with artificial intelligence. Methods: Standard 130-degree fundus photographs centered on the optic disc were taken in the newborns. The deep learning network provided segmentation of the retinal vessels and the optic disc (OD). Based on the vessel segmentation, the vascular morphological characteristics, including avascular area, vessel angle, vessel density, fractal dimension (FD), and tortuosity, were automatically evaluated. Results: 201 eyes of FEVR, 289 eyes of ROP, and 195 eyes of healthy individuals were included in this study. The deep learning system of blood vessel segmentation had a sensitivity of 72% and a specificity of 99%. The vessel angle in the FEVR group was significantly smaller than that in the normal group and ROP group (37.43 ± 5.43 vs. 39.40 ± 5.61, 39.50 ± 5.58, P = 0.001, < 0.001 respectively). The normal group had the lowest vessel density, the ROP group was in between, and the FEVR group had the highest (2.64 ± 0.85, 2.97 ± 0.92, 3.37 ± 0.88 respectively). The FD was smaller in controls than in the FEVR and ROP groups (0.984 ± 0.039, 1.018 ± 0.039 and 1.016 ± 0.044 respectively, P < 0.001). The ROP group had the most tortuous vessels, while the FEVR group had the stiffest vessels, the controls were in the middle (11.61 ± 3.17, 8.37 ± 2.33 and 7.72 ± 1.57 respectively, P < 0.001). Conclusions: The deep learning technology used in this study has good performance in the quantitative analysis of vascular morphological characteristics in fundus photography. Vascular morphology was different in the newborns of FEVR and ROP compared to healthy individuals, which showed great clinical value for the differential diagnosis of ROP and FEVR.