Arabinosylation of cell wall extensin is required for the directional response to salinity in roots.

Soil salinity is a major contributor to crop yield losses. To improve our understanding of root responses to salinity, we developed and exploited a real-time salt-induced tilting assay. This assay follows root growth upon both gravitropic and salt challenges, revealing that root bending upon tilting is modulated by Na+ ions, but not by osmotic stress. Next, we measured this salt-specific response in 345 natural Arabidopsis (Arabidopsis thaliana) accessions and discovered a genetic locus, encoding the cell wall-modifying enzyme EXTENSIN ARABINOSE DEFICIENT TRANSFERASE (ExAD) that is associated with root bending in the presence of NaCl (hereafter salt). Extensins are a class of structural cell wall glycoproteins known as hydroxyproline (Hyp)-rich glycoproteins, which are posttranslationally modified by O-glycosylation, mostly involving Hyp-arabinosylation. We show that salt-induced ExAD-dependent Hyp-arabinosylation influences root bending responses and cell wall thickness. Roots of exad1 mutant seedlings, which lack Hyp-arabinosylation of extensin, displayed increased thickness of root epidermal cell walls and greater cell wall porosity. They also showed altered gravitropic root bending in salt conditions and a reduced salt-avoidance response. Our results suggest that extensin modification via Hyp-arabinosylation is a unique salt-specific cellular process required for the directional response of roots exposed to salinity.

Root branching under high salinity requires auxin-independent modulation of LATERAL ORGAN BOUNDARY DOMAIN 16 function.

Salinity stress constrains lateral root (LR) growth and severely affects plant growth. Auxin signaling regulates LR formation, but the molecular mechanism by which salinity affects root auxin signaling and whether salt induces other pathways that regulate LR development remains unknown. In Arabidopsis thaliana, the auxin-regulated transcription factor LATERAL ORGAN BOUNDARY DOMAIN 16 (LBD16) is an essential player in LR development under control conditions. Here, we show that under high-salt conditions, an alternative pathway regulates LBD16 expression. Salt represses auxin signaling but, in parallel, activates ZINC FINGER OF ARABIDOPSIS THALIANA 6 (ZAT6), a transcriptional activator of LBD16. ZAT6 activates LBD16 expression, thus contributing to downstream cell wall remodeling and promoting LR development under high-salt conditions. Our study thus shows that the integration of auxin-dependent repressive and salt-activated auxin-independent pathways converging on LBD16 modulates root branching under high-salt conditions.

Balancing growth amidst salt stress - lifestyle perspectives from the extremophyte model Schrenkiella parvula.

Schrenkiella parvula, a leading extremophyte model in Brassicaceae, can grow and complete its lifecycle under multiple environmental stresses, including high salinity. Yet, the key physiological and structural traits underlying its stress-adapted lifestyle are unknown along with trade-offs when surviving salt stress at the expense of growth and reproduction. We aimed to identify the influential adaptive trait responses that lead to stress-resilient and uncompromised growth across developmental stages when treated with salt at levels known to inhibit growth in Arabidopsis and most crops. Its resilient growth was promoted by traits that synergistically allowed primary root growth in seedlings, the expansion of xylem vessels across the root-shoot continuum, and a high capacity to maintain tissue water levels by developing thicker succulent leaves while enabling photosynthesis during salt stress. A successful transition from vegetative to reproductive phase was initiated by salt-induced early flowering, resulting in viable seeds. Self-fertilization in salt-induced early flowering was dependent upon filament elongation in flowers otherwise aborted in the absence of salt during comparable plant ages. The maintenance of leaf water status promoting growth, and early flowering to ensure reproductive success in a changing environment, were among the most influential traits that contributed to the extremophytic lifestyle of S. parvula.

A New and Practical Model of Human-like Ascending Aorta Aneurysm in Rats.

INTRODUCTION: Ascending aortic aneurysm is a serious health risk. In order to study ascending aortic aneurysms, elastase and calcium ion treatment for aneurysm formation are mainly used, but their aneurysm formation time is long, the aneurysm formation rate is low. Thus, this study aimed to construct a rat model of ascending aorta aneurysm with a short modeling time and high aneurysm formation rate, which may mimic the pathological processes of human ascending aorta aneurysm. METHODS: Cushion needles with different pipe diameters (1.0, 1.2, 1.4 and 1.6 mm) were used to establish a human-like rat model of ascending aortic aneurysm by narrowing the ascending aorta of rats and increasing the force of blood flow on the vessel wall. The vascular diameters were evaluated using color Doppler ultrasonography after two weeks. The characteristics of ascending aortic aneurysm in rats were detected by Masson's trichrome staining, Verhoeff's Van Gieson staining and hematoxylin and eosin staining while RT-PCR were utilized to assess the total RNA of cytokine interleukin-1ß, interleukin 6, transforming growth factor-beta1 and metalloproteinase 2. RESULTS: Two weeks after surgery, the ultrasound images and the statistical analysis demonstrated that the diameter of the ascending aorta in rats increased more than 1.5 times, similar to that in humans, indicating the success of animal modeling of ascending aortic aneurysm. Moreover, the optimal constriction diameter of the ascending aortic aneurysm model is 1.4 mm by the statistical analysis of the rate of ascending aortic aneurysm and mortality rate in rats with different constriction diameters. CONCLUSIONS: The human-like ascending aortic aneurysm model developed in this study can be used for the studies of the pathological processes and mechanisms in ascending aortic aneurysm in a more clinically relevant fashion.

Centennial Records of Microplastics in Lake Cores in Huguangyan Maar Lake, China.

Microplastic records from lake cores can reconstruct the plastic pollution history. However, the associations between anthropogenic activities and microplastic accumulation are not well understood. Huguangyan Maar Lake (HML) is a deep-enclosed lake without inlets and outlets, where the sedimentary environment is ideal for preserving a stable and historical microplastic record. Microplastic (size: 10-500 µm) characteristics in the HML core were identified using the Laser Direct Infrared Imaging system. The earliest detectable microplastics appeared unit in 1955 (1.1 items g-1). The microplastic abundance ranged from n.d. to 615.2 items g-1 in 1955-2019 with an average of 134.9 items g-1. The abundance declined slightly during the 1970s and then increased rapidly after China's Reform and Opening Up in 1978. Sixteen polymer types were detectable, with polyethylene and polypropylene dominating, accounting for 23.5 and 23.3% of the total abundance, and the size at 10-100 µm accounted for 80%. Socioeconomic factors dominated the microplastic accumulation based on the random forest modeling, and the contributions of GDP per capita, plastic-related industry yield, and total crop yield were, respectively, 13.9, 35.1, and 9.3% between 1955-2019. The total crop yield contribution further increased by 1.7% after 1978. Coarse sediment particles increased with soil erosion exacerbated microplastics discharging into the sediment.

Risk factors and a nomogram for prediction of post-endoscopic submucosal dissection electrocoagulation syndrome for superficial colorectal lesions.

BACKGROUND: Post-endoscopic submucosal dissection electrocoagulation syndrome (PEECS) is an uncommon complication after colorectal endoscopic submucosal dissection (ESD). This study aimed to explore the risk factors of PEECS for superficial colorectal lesions based on the latest and consistent diagnostic criteria and to establish a predictive nomogram model. METHODS: This retrospective analysis included patients with superficial colorectal lesions who underwent endoscopic submucosal dissection (ESD) between June 2008 and December 2021 in our center. The independent risk factors of PEECS for superficial colorectal lesions were identified using least absolute shrinkage and selection operator (LASSO) logistic regression analysis, as well as univariate analysis and multivariate logistic regression, and derived predictive nomogram model was constructed. RESULTS: Among the 555 patients with superficial colorectal lesions enrolled, PEECS occurred in 45 (8.1%) patients. Multivariate logistic regression revealed that female sex (OR 3.94, P < 0.001), age > 50 years (OR 4.28, P = 0.02), injury to muscle layer (OR 10.38, P < 0.001), non-lifting sign (OR 2.20, P = 0.04) and inadequate bowel preparation (OR 5.61, P < 0.001) were independent risk factors of PEECS for superficial colorectal lesions. A predictive nomogram model was constructed based on the above five predictors. For this model, the area under the receiver operating characteristic (ROC) curve was 0.855, the calibration curve exhibited good consistency between the prediction and the actual observation, and the C-index was confirmed as 0.843 by bootstrap method. CONCLUSION: Female sex, age > 50 years, injury to muscle layer, non-lifting sign and inadequate bowel preparation were independent risk factors of PEECS for superficial colorectal lesions. The proposed nomogram could accurately predict the risk of PEECS for superficial colorectal lesions.

The efficacy of sclerotherapy as the initial treatment in patients with bleeding from Dieulafoy's lesion of the upper gastrointestinal tract.

BACKGROUND: Dieulafoy's lesion (DL) is a rare and important cause of acute nonvariceal upper gastrointestinal bleeding (ANVUGIB), however, there is a lack of clear guidelines focus on the endoscopic hemostasis treatment for DL. Sclerotherapy, as the ANVUGIB guideline recommended endoscopic hemostasis method, is widely used in clinical practice. The aim of this study is to investigate the efficacy of sclerotherapy as the initial treatment for Dieulafoy's lesion of the upper gastrointestinal tract (UDL). METHODS: Patients with UDL who underwent the ANVUGIB standard endoscopic hemostasis between April 2007 and January 2023 were enrolled. The endoscopic therapy method was left to the discretion of the endoscopist. RESULTS: In total, 219 patients were finally obtained, with 74 (33.8%) receiving sclerotherapy and 145 (66.2%) receiving other standard endoscopic therapy. The rebleeding within 30 days was significantly lower in the sclerotherapy group compared to the other standard group (5.8% vs. 16.8%, p = 0.047). There were no significant differences between the two groups in terms of successful hemostasis rate (93.2% vs. 94.5%, p = 0.713), median number of red blood cell transfusions (3.5 vs. 4.0 units, p = 0.257), median hospital stay (8.0 vs. 8.0 days, p = 0.103), transferred to ICU rate (8.1% vs. 6.2%, p = 0.598), the need for embolization or surgery rate (12.2% vs. 9.7%, p = 0.567) and 30-day mortality (0 vs. 2.1%, p = 0.553). In addition, we found no difference in efficacy between sclerotherapy alone and combination (3.1% vs. 8.1%, p = 0.714). Further analysis revealed that thermocoagulation for hemostasis was associated with a higher rate of rebleeding (28.6% vs. 3.1%, p = 0.042) and longer hospital stay (11.5 vs. 7.5 days, p = 0.005) compared to sclerotherapy alone. CONCLUSION: Sclerotherapy represents an effective endoscopic therapy for both alone and combined use in patients with upper gastrointestinal Dieulafoy's lesion. Therefore, sclerotherapy could be considered as initial treatment in patients with bleeding of UDL.

Clinical value of echocardiography combined with serum Cav-1, NFATc1, and PAI-1 in the diagnosis of Kawasaki disease complicated with coronary artery lesions.

To analyze the clinical value of echocardiography combined with serum lacuna protein-1 (Cav-1), activated T cell nuclear factor C1 (NFATc1), and plasminogen activator inhibitor-1 (PAI-1) in the diagnosis of Kawasaki disease (KD) complicated with coronary artery lesions (CAL). A total of 200 children with KD treated in our hospital from January 2019 to October 2021 were grouped as the KD alone group (n = 56) and the KD complicated with CAL group (n = 144) according to the results of coronary angiography. The levels of Cav-1, NFATc1, and PAI-1 were detected by enzyme-linked immunosorbent assay. Echocardiography was performed and the internal diameters of left and right coronary arteries were compared between the two groups. The area under the curve (AUC), sensitivity, and specificity of echocardiography combined with serum Cav-1, NFATc1, and PAI-1 in the diagnosis of KD complicated with CAL were analyzed with receiver operating characteristic (ROC) curve. Coronary angiography, as the gold standard, showed that the sensitivity of echocardiography in diagnosing KD with CAL was 88.19% (127/144), the specificity was 66.07% (37/56), and the accuracy was 82.00% (164/200). ROC curve analysis revealed that the AUC of KD complicated with CAL diagnosed by echocardiography, Cav-1, NFATc1, and PAI-1 was 0.819, 0.715, 0.688, and 0.663, respectively, and the AUC of combined diagnosis of the four was 0.896. The combination of echocardiography, Cav-1, NFATc1, and PAI-1 has high value in diagnosing KD complicated with CAL, which can be widely used in clinical practice.

Knowledge, attitudes, and practices of primary healthcare practitioners regarding pharmacist clinics: a cross-sectional study in Shanghai.

BACKGROUND: Pharmacist clinics offer professional pharmaceutical services that can improve public health outcomes. However, primary healthcare staff in China face various barriers and challenges in implementing such clinics. To identify existing problems and provide recommendations for the implementation of pharmacist clinics, this study aims to assess the knowledge, attitudes, and practices of pharmacist clinics among primary healthcare providers. METHODS: A cross-sectional survey based on the Knowledge-Attitude-Practice (KAP) model, was conducted in community health centers (CHCs) and private hospitals in Shanghai, China in May, 2023. Descriptive analytics and the Pareto principle were used to multiple-answer questions. Chi-square test, Fisher's exact test, and binary logistic regression models were employed to identify factors associated with the knowledge, attitudes, and practices of pharmacist clinics. RESULTS: A total of 223 primary practitioners participated in the survey. Our study revealed that most of them had limited knowledge (60.1%, n = 134) but a positive attitude (82.9%, n = 185) towards pharmacist clinics, with only 17.0% (n = 38) having implemented them. The primary goal of pharmacist clinics was to provide comprehensive medication guidance (31.5%, n = 200), with medication education (26.3%, n = 202) being the primary service, and special populations (24.5%, n = 153) identified as key recipients. Logistic regression analysis revealed that education, age, occupation, position, work seniority, and institution significantly influenced their perceptions. Practitioners with bachelor's degrees, for instance, were more likely than those with less education to recognize the importance of pharmacist clinics in medication guidance (aOR: 7.130, 95%CI: 1.809-28.099, p-value = 0.005) and prescription reviews (aOR: 4.675, 95% CI: 1.548-14.112, p-value = 0.006). Additionally, practitioners expressed positive attitudes but low confidence, with only 33.3% (n = 74) feeling confident in implementation. The confidence levels of male practitioners surpassed those of female practitioners (p-value = 0.037), and practitioners from community health centers (CHCs) exhibited higher confidence compared to their counterparts in private hospitals (p-value = 0.008). Joint physician-pharmacist clinics (36.8%, n = 82) through collaboration with medical institutions (52.0%, n = 116) emerged as the favored modality. Daily sessions were preferred (38.5%, n = 86), and both registration and pharmacy service fees were considered appropriate for payment (42.2%, n = 94). The primary challenge identified was high outpatient workload (30.9%, n = 69). CONCLUSIONS: Although primary healthcare practitioners held positive attitudes towards pharmacist clinics, limited knowledge, low confidence, and high workload contributed to the scarcity of their implementation. Practitioners with diverse sociodemographic characteristics, such as education, age, and institution, showed varying perceptions and practices regarding pharmacist clinics.

KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation.

Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan-Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

Metformin alleviates benzo[a]pyrene-induced alveolar injury by inhibiting necroptosis and protecting AT2 cells.

Exposure to benzo[a]pyrene (B[a]P) has been linked to lung injury and carcinogenesis. Airway epithelial cells express the B[a]P receptor AHR, so B[a]P is considered to mainly target airway epithelial cells, whereas its potential impact on alveolar cells remains inadequately explored. Metformin, a first-line drug for diabetes, has been shown to exert anti-inflammatory and tissue repair-promoting effects under various injurious conditions. Here, we explored the effect of chronic B[a]P exposure on alveolar cells and the impact of metformin on B[a]P-induced lung injury by examining the various parameters including lung histopathology, inflammation, fibrosis, and related signal pathway activation. MLKL knockout (Mlkl-/-) and AT2-lineage tracing mice (SftpcCre-ERT2;LSL-tdTomatoflox+/-) were used to delineate the role of necroptosis in B[a]P-induced alveolar epithelial injury and repair. Mice receiving weekly administration of B[a]P for 6 weeks developed a significant alveolar damaging phenotype associated with pulmonary inflammation, fibrosis, and activation of the necroptotic cell death pathway. These effects were significantly relieved in MLKL null mice. Furthermore, metformin treatment, which were found to promote AMPK phosphorylation and inhibit RIPK3, as well as MLKL phosphorylation, also significantly alleviated B[a]P-induced necroptosis and lung injury phenotype. However, the protective efficacy of metformin was rendered much less effective in Mlkl null mice or by blocking the necroptotic pathway with RIPK3 inhibitor. Our findings unravel a potential protective efficacy of metformin in mitigating the detrimental effects of B[a]P exposure on lung health by inhibiting necroptosis and protecting AT2 cells.

Oridonin ameliorates renal fibrosis in diabetic nephropathy by inhibiting the Wnt/ß-catenin signaling pathway.

Diabetic nephropathy (DN) is one of the most serious and frequent complications among diabetes patients and presently constitutes vast the cases of end-stage renal disease worldwide. Tubulointerstitial fibrosis is a crucial factor related to the occurrence and progression of DN. Oridonin (Ori) is a diterpenoid derived from rubescens that has diverse pharmacological properties. Our previous study showed that Ori can protect against DN by decreasing the inflammatory response. However, whether Ori can alleviate renal fibrosis in DN remains unknown. Here, we investigated the mechanism through which Ori affects the Wnt/ß-catenin signaling pathway in diabetic rats and human proximal tubular epithelial cells (HK-2) exposed to high glucose (HG) levels. Our results revealed that Ori treatment markedly decreased urinary protein excretion levels, improved renal function and alleviated renal fibrosis in diabetic rats. In vitro, HG treatment increased the migration of HK-2 cells while reducing their viability and proliferation rate, and treatment with Ori reversed these changes. Additionally, the knockdown of ß-catenin arrested cell migration and reduced the expression levels of Wnt/ß-catenin signaling-related molecules (Wnt4, p-GSK3ß and ß-catenin) and fibrosis-related molecules (α-smooth muscle actin, collagen I and fibronectin), and Ori treatment exerted an effect similar to that observed after the knockdown of ß-catenin. Furthermore, the combination of Ori treatment and ß-catenin downregulation exerted more pronounced biological effects than treatment alone. These findings may provide the first line of evidence showing that Ori alleviates fibrosis in DN by inhibiting the Wnt/ß-catenin signaling pathway and thereby reveal a novel therapeutic avenue for treating tubulointerstitial fibrosis.

Improvement of biotic nitrate reduction in constructed photoautotrophic biofilm-soil microbial fuel cells.

The biotic nitrate reduction rate in freshwater ecosystems is typically constrained by the scarcity of carbon sources. In this study, 'two-chambers' - 'two-electrodes' photoautotrophic biofilm-soil microbial fuel cells (P-SMFC) was developed to accelerate nitrate reduction by activating in situ electron donors that originated from the soil organic carbon (SOC). The nitrate reduction rate of P-SMFC (0.1341 d-1) improved by âˆ¼ 1.6 times on the 28th day compared to the control photoautotrophic biofilm. The relative abundance of electroactive bacterium increased in the P-SMFC and this bacterium contributed to obtain electrons from SOC. Biochar amendment decreased the resistivity of P-SMFC, increased the electron transferring efficiency, and mitigated anodic acidification, which continuously facilitated the thriving of putative electroactive bacterium and promoted current generation. The results from physiological and ecological tests revealed that the cathodic photoautotrophic biofilm produced more extracellular protein, increased the relative abundance of Lachnospiraceae, Magnetospirillaceae, Pseudomonadaceae, and Sphingomonadaceae, and improved the activity of nitrate reductase and ATPase. Correspondingly, P-SMFC in the presence of biochar achieved the highest reaction rate constant for nitrate reduction (kobs) (0.2092 d-1) which was 2.4 times higher than the control photoautotrophic biofilm. This study provided a new strategy to vitalize in situ carbon sources in paddy soil for nitrate reduction by the construction of P-SMFC.

The OsWRKY72-OsAAT30/OsGSTU26 module mediates reactive oxygen species scavenging to drive heterosis for salt tolerance in hybrid rice.

Hybrid rice (Oryza sativa) generally outperforms its inbred parents in yield and stress tolerance, a phenomenon termed heterosis, but the underlying mechanism is not completely understood. Here, we combined transcriptome, proteome, physiological, and heterosis analyses to examine the salt response of super hybrid rice Chaoyou1000 (CY1000). In addition to surpassing the mean values for its two parents (mid-parent heterosis), CY1000 exhibited a higher reactive oxygen species scavenging ability than both its parents (over-parent heterosis or heterobeltiosis). Nonadditive expression and allele-specific gene expression assays showed that the glutathione S-transferase gene OsGSTU26 and the amino acid transporter gene OsAAT30 may have major roles in heterosis for salt tolerance, acting in an overdominant fashion in CY1000. Furthermore, we identified OsWRKY72 as a common transcription factor that binds and regulates OsGSTU26 and OsAAT30. The salt-sensitive phenotypes were associated with the OsWRKY72paternal genotype or the OsAAT30maternal genotype in core rice germplasm varieties. OsWRKY72paternal specifically repressed the expression of OsGSTU26 under salt stress, leading to salinity sensitivity, while OsWRKY72maternal specifically repressed OsAAT30, resulting in salinity tolerance. These results suggest that the OsWRKY72-OsAAT30/OsGSTU26 module may play an important role in heterosis for salt tolerance in an overdominant fashion in CY1000 hybrid rice, providing valuable clues to elucidate the mechanism of heterosis for salinity tolerance in hybrid rice.

KCNN1 promotes proliferation and metastasis of breast cancer via ERLIN2-mediated stabilization and K63-dependent ubiquitination of Cyclin B1.

Potassium Calcium-Activated Channel Subfamily N1 (KCNN1), an integral membrane protein, is thought to regulate neuronal excitability by contributing to the slow component of synaptic after hyperpolarization. However, the role of KCNN1 in tumorigenesis has been rarely reported, and the underlying molecular mechanism remains unclear. Here, we report that KCNN1 functions as an oncogene in promoting breast cancer cell proliferation and metastasis. KCNN1 was overexpressed in breast cancer tissues and cells. The pro-proliferative and pro-metastatic effects of KCNN1 were demonstrated by CCK8, clone formation, Edu assay, wound healing assay and transwell experiments. Transcriptomic analysis using KCNN1 overexpressing cells revealed that KCNN1 could regulate key signaling pathways affecting the survival of breast cancer cells. KCNN1 interacts with ERLIN2 and enhances the effect of ERLIN2 on Cyclin B1 stability. Overexpression of KCNN1 promoted the protein expression of Cyclin B1, enhanced its stability and promoted its K63 dependent ubiquitination, while knockdown of KCNN1 had the opposite effects on Cyclin B1. Knockdown (or overexpression) ERLNI2 partially restored Cyclin B1 stability and K63 dependent ubiquitination induced by overexpression (or knockdown) of KCNN1. Knockdown (or overexpression) ERLIN2 also partially neutralizes the effects of overexpression (or knockdown) KCNN1-induced breast cancer cell proliferation, migration and invasion. In paired breast cancer clinical samples, we found a positive expression correlations between KCNN1 and ERLIN2, KCNN1 and Cyclin B1, as well as ERLIN2 and Cyclin B1. In conclusion, this study reveals, for the first time, the role of KCNN1 in tumorigenesis and emphasizes the importance of KCNN1/ERLIN2/Cyclin B1 axis in the development and metastasis of breast cancer.

Identification of Alkoxy Radicals as Hydrogen Atom Transfer Agents in Ce-Catalyzed C-H Functionalization.

The intermediacy of alkoxy radicals in cerium-catalyzed C-H functionalization via H-atom abstraction has been unambiguously confirmed. Catalytically relevant Ce(IV)-alkoxide complexes have been synthesized and characterized by X-ray diffraction. Operando electron paramagnetic resonance and transient absorption spectroscopy experiments on isolated pentachloro Ce(IV) alkoxides identified alkoxy radicals as the sole heteroatom-centered radical species generated via ligand-to-metal charge transfer (LMCT) excitation. Alkoxy-radical-mediated hydrogen atom transfer (HAT) has been verified via kinetic analysis, density functional theory (DFT) calculations, and reactions under strictly chloride-free conditions. These experimental findings unambiguously establish the critical role of alkoxy radicals in Ce-LMCT catalysis and definitively preclude the involvement of chlorine radical. This study has also reinforced the necessity of a high relative ratio of alcohol vs Ce for the selective alkoxy-radical-mediated HAT, as seemingly trivial changes in the relative ratio of alcohol vs Ce can lead to drastically different mechanistic pathways. Importantly, the previously proposed chlorine radical-alcohol complex, postulated to explain alkoxy-radical-enabled selectivities in this system, has been examined under scrutiny and ruled out by regioselectivity studies, transient absorption experiments, and high-level calculations. Moreover, the peculiar selectivity of alkoxy radical generation in the LMCT homolysis of Ce(IV) heteroleptic complexes has been analyzed and back-electron transfer (BET) may have regulated the efficiency and selectivity for the formation of ligand-centered radicals.

A novel gain-of-function PIP4K2A mutation elevates the expression of ß-globin and aggravates the severity of α-thalassemia.

Haemoglobin H (Hb H) disease (intermediate status of α-thalassemia) shows marked phenotypic variability from asymptomatic to severe anaemia. Apart from the combined ß-thalassemia allele ameliorating clinical severity, reports of genetic modifier genes affecting the phenotype of Hb H disease are scarce which bring inconvenience to precise diagnosis and genetic counselling of the patients. Here, we present a novel mutation (c.948C>A, p.S316R) in the PIP4K2A gene in a female Hb H disease patient who displayed moderate anaemia and a relatively high Hb H level. Haematological analysis in her family members revealed that individuals carrying this mutation have upregulated ß-globin expression, leading to a more imbalanced ß/α-globin ratio and more Hb H inclusion bodies in peripheral red blood cells. According to functional experiments, the mutant PIP4K2A protein exhibits enhanced protein stability, increased kinase activity and a stronger regulatory effect on downstream proteins, suggesting a gain-of-function mutation. Moreover, introduction of the S316R mutation into HUDEP-2 cells increased expression of ß-globin, further inhibiting erythroid differentiation and terminal enucleation. Thus, the S316R mutation is a novel genetic factor associated with ß-globin expression, and the PIP4K2A gene is a new potential modifier gene affecting the α-thalassemia phenotype.

Investigation of the mechanism of copy number variations involving the α-globin gene cluster on chromosome 16: two case reports and literature review.

Thalassemia is one of the most common single-gene disorder worldwide. An important genetic cause of thalassemia is copy number variations (CNVs) in the α-globin gene cluster. However, there is no unified summary and discussion on the detailed information and mechanisms of these CNVs. In this study, two novel CNVs, a tandem duplication (αααα159) and deletion (--259), were identified in two Chinese families with thalassemia patients, according to the results of hematologic analysis, routine genetic testing for thalassemia, multiplex ligation-dependent probe amplification (MLPA), next-generation sequencing (NGS) and other molecular methods. Co-inherited with ßCD41-42 mutation and --SEA deletion separately, αααα159 and --259 resulted in a patient with ß-thalassemia intermedia and a lethal fetus with Hb Bart's hydrops fetalis syndrome, respectively. Next, a literature review was performed to summarize all known CNVs involving the α-globin gene cluster. The molecular structure characteristics of these CNVs were analyzed and the possible mechanism was explored. It is the first time to analyze the generation mechanism of genome arrangements in the α-globin gene cluster systematically.

Inhibition of endogenous hydrogen sulfide production suppresses the growth of nasopharyngeal carcinoma cells.

Hydrogen sulfide (H2 S) has been widely recognized as one of gasotransmitters. Endogenous H2 S plays a crucial role in the progression of cancer. However, the effect of endogenous H2 S on the development of nasopharyngeal carcinoma (NPC) is still unknown. In this study, aminooxyacetic acid (AOAA, an inhibitor of cystathionine-ß-synthase), dl-propargylglycine (PAG, an inhibitor of cystathionine-γ-lyase), and l-aspartic acid (l-Asp, an inhibitor of 3-mercaptopyruvate sulfurtransferase) were adopted to detect the role of endogenous H2 S in NPC growth. The results indicated that the combine (PAG + AOAA + l-Asp) group had higher inhibitory effect on the growth of NPC cells than the PAG, AOAA, and l-Asp groups. There were similar trends in the levels of apoptosis and reactive oxygen species (ROS). In addition, the combine group exhibited lower levels of phospho (p)-extracellular signal-regulated protein kinase but higher expressions of p-p38 and p-c-Jun N-terminal kinase than those in the AOAA, PAG, and l-Asp groups. Furthermore, the combine group exerted more potent inhibitory effect on NPC xenograft tumor growth without obvious toxicity. In summary, suppression of endogenous H2 S generation could dramatically inhibit NPC growth via the ROS/mitogen-activated protein kinase pathway. Endogenous H2 S may be a novel therapeutic target in human NPC cells. Effective inhibitors for H2 S-producing enzymes could be designed and developed for NPC treatment.

Effective root responses to salinity stress include maintained cell expansion and carbon allocation.

Acclimation of root growth is vital for plants to survive salt stress. Halophytes are great examples of plants that thrive even under severe salinity, but their salt tolerance mechanisms, especially those mediated by root responses, are still largely unknown. We compared root growth responses of the halophyte Schrenkiella parvula with its glycophytic relative species Arabidopsis thaliana under salt stress and performed transcriptomic analysis of S. parvula roots to identify possible gene regulatory networks underlying their physiological responses. Schrenkiella parvula roots do not avoid salt and experience less growth inhibition under salt stress. Salt-induced abscisic acid levels were higher in S. parvula roots compared with Arabidopsis. Root transcriptomic analysis of S. parvula revealed the induction of sugar transporters and genes regulating cell expansion and suberization under salt stress. 14 C-labeled carbon partitioning analyses showed that S. parvula continued allocating carbon to roots from shoots under salt stress while carbon barely allocated to Arabidopsis roots. Further physiological investigation revealed that S. parvula roots maintained root cell expansion and enhanced suberization under severe salt stress. In summary, roots of S. parvula deploy multiple physiological and developmental adjustments under salt stress to maintain growth, providing new avenues to improve salt tolerance of plants using root-specific strategies.