The complete chloroplast genome sequences of three Pedicularis species (Orobanchaceae).

Pedicularis L., a generally bothersome genus of hemiparasitic plants, is primarily native to southwestern China. The phylogenetic relationship and evolutionary history of this genus have not yet been fully resolved. In this study, we sequenced and assembled chloroplast genomes of three Pedicularis species, P. chinensis, P. melampyriflora, and P. striata using high-throughput Illumina sequencing. The assembled plastomes were 142,059 bp (P. chinensis) to 152,146 bp (P. striata) in size, containing 110 (P. chinensis) to 117 (P. striata) genes. Moreover, we identified 13-15 pseudogenes within the three plastomes, nine of which were pseudogenized in all three species. The three plastomes exhibited a similar codon usage pattern. Moreover, the plastomes contained abundant simple sequence repeats and long repeats, which showed slight variations between the three species. A maximum likelihood analysis was performed to elucidate the phylogenetic positions of the three species within the Pedicularis genus. The plastomes presented in our study can be used as valuable genomic resources for further genetic and genomic studies of the Pedicularis genus.

Comprehensive pan-cancer analysis reveals prognostic implications of TMEM92 in the tumor immune microenvironment.

BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.

Kindlin-2 in myoepithelium controls luminal progenitor commitment to alveoli in mouse mammary gland.

Myoepithelium plays an important role in mammary gland development, but less is known about the molecular mechanism underlying how myoepithelium controls acinus differentiation during gestation. Herein, we found that loss of Kindlin-2 in myoepithelial cells impaired mammary morphogenesis, alveologenesis, and lactation. Using five genetically modified mouse lines combined with single-cell RNA sequencing, we found a Kindlin-2-Stat3-Dll1 signaling cascade in myoepithelial cells that inactivates Notch signaling in luminal cells and consequently drives luminal progenitor commitment to alveolar cells identity. Single-cell profiling revealed that Kindlin-2 loss significantly reduces the proportion of matured alveolar cells. Mechanistically, Kindlin-2 depletion in myoepithelial cells promotes Stat3 activation and upregulates Dll1, which activates the Notch pathway in luminal cells and inhibits luminal progenitor differentiation and maturation during gestation. Inhibition of Notch1 with tangeretin allowed luminal progenitors to regain commitment ability in the pregnant mice with Kindlin-2 depletion in myoepithelium. Taken together, we demonstrated that Kindlin-2 is essential to myoepithelium-controlled luminal progenitors to alveoli transition during gestation.

Structural variation underlies functional diversity at methyl salicylate loci in tomato.

Methyl salicylate is an important inter- and intra-plant signaling molecule, but is deemed undesirable by humans when it accumulates to high levels in ripe fruits. Balancing the tradeoff between consumer satisfaction and overall plant health is challenging as the mechanisms regulating volatile levels have not yet been fully elucidated. In this study, we investigated the accumulation of methyl salicylate in ripe fruits of tomatoes that belong to the red-fruited clade. We determine the genetic diversity and the interaction of four known loci controlling methyl salicylate levels in ripe fruits. In addition to Non-Smoky Glucosyl Transferase 1 (NSGT1), we uncovered extensive genome structural variation (SV) at the Methylesterase (MES) locus. This locus contains four tandemly duplicated Methylesterase genes and genome sequence investigations at the locus identified nine distinct haplotypes. Based on gene expression and results from biparental crosses, functional and non-functional haplotypes for MES were identified. The combination of the non-functional MES haplotype 2 and the non-functional NSGT1 haplotype IV or V in a GWAS panel showed high methyl salicylate levels in ripe fruits, particularly in accessions from Ecuador, demonstrating a strong interaction between these two loci and suggesting an ecological advantage. The genetic variation at the other two known loci, Salicylic Acid Methyl Transferase 1 (SAMT1) and tomato UDP Glycosyl Transferase 5 (SlUGT5), did not explain volatile variation in the red-fruited tomato germplasm, suggesting a minor role in methyl salicylate production in red-fruited tomato. Lastly, we found that most heirloom and modern tomato accessions carried a functional MES and a non-functional NSGT1 haplotype, ensuring acceptable levels of methyl salicylate in fruits. Yet, future selection of the functional NSGT1 allele could potentially improve flavor in the modern germplasm.

Long noncoding RNA HOTAIR promotes breast cancer development through the lncRNA HOTAIR/miR-1/GOLPH3 axis.

BACKGROUND: The lncRNA HOTAIR is frequently overexpressed in breast cancer tissues and plays an important role in the development of breast cancer. Here, we investigated the effect of the lncRNA HOTAIR on the biological behaviour of breast cancer cells and its molecular mechanism. METHODS: We investigated the level of HOTAIR in breast cancer and its clinical pathological characteristics by bioinformatic methods. Then, we evaluated the effects of HOTAIR and miRNA-1 expression on the biological behaviour of breast cancer cells by qPCR, Cell Counting Kit-8 (CCK-8) assay, clonogenic assays, Transwell assay and flow cytometry for cell proliferation, invasion migration and apoptosis, and cell cycle analysis. Finally, the target genes of the lncRNA HOTAIR/miR-1/GOLPH3 regulatory axis were validated by luciferase reports. RESULTS: The expression of HOTAIR in breast cancer tissues was significantly higher than that in normal breast tissues (P < 0.05). Silencing of HOTAIR suppressed cell proliferation, invasion and migration, promoted apoptosis and induced G1 phase block in breast cancer (P < 0.0001). We also verified that miR-1 is a target of HOTAIR and that GOLPH3 is a target of miR-1 by luciferase reporter assays (P < 0.001). CONCLUSIONS: The expression of HOTAIR was significantly elevated in breast cancer tissues. Reducing the expression of HOTAIR inhibited the proliferation, invasion and migration of breast cancer cells and promoted apoptosis, and the mechanism was mainly the effect of the lncRNA HOTAIR/miR-1/GOLPH3 regulatory axis on the biological behaviour of breast cancer cells.

miR-6216 regulates neural stem cell proliferation by targeting RAB6B.

Neural stem cells (NSCs) are a class of self-renewing, multipotent and undifferentiated progenitor cells that retain the capacity to both glial and neuronal lineages. MicroRNAs (miRNAs) are small non-coding RNAs that play an important role in stem cell fate determination and self-renewal. Our previous RNA-seq data indicated that the expression of miR-6216 was decreased in denervated hippocampal exosomes compared with normal. However, whether miR-6216 participates in regulating NSC function remains to be elucidated. In this study, we demonstrated that miR-6216 negatively regulates RAB6B expression. Forced overexpression of miR-6216 inhibited NSC proliferation, and overexpression of RAB6B promoted NSC proliferation. These findings suggest that miR-6216 played an important role in regulating NSC proliferation via targeting RAB6B, and improve the understanding of the miRNA-mRNA regulatory network that affects NSC proliferation.

The ubiquitin E3 ligase TRIM10 promotes STING aggregation and activation in the Golgi apparatus.

STING is an endoplasmic reticulum-resident protein regulating innate immunity. After binding with cyclic guanosine monophosphate-AMP (cGAMP), STING translocates from the endoplasmic reticulum (ER) to the Golgi apparatus to stimulate TBK1 and IRF3 activation, leading to expression of type I interferon. However, the exact mechanism concerning STING activation remains largely enigmatic. Here, we identify tripartite motif 10 (TRIM10) as a positive regulator of STING signaling. TRIM10-deficient macrophages exhibit reduced type I interferon production upon double-stranded DNA (dsDNA) or cGAMP stimulation and decreased resistance to herpes simplex virus 1 (HSV-1) infection. Additionally, TRIM10-deficient mice are more susceptible to HSV-1 infection and exhibit faster melanoma growth. Mechanistically, TRIM10 associates with STING and catalyzes K27- and K29-linked polyubiquitination of STING at K289 and K370, which promotes STING trafficking from the ER to the Golgi apparatus, formation of STING aggregates, and recruitment of TBK1 to STING, ultimately enhancing the STING-dependent type I interferon response. Our study defines TRIM10 as a critical activator in cGAS-STING-mediated antiviral and antitumor immunity.

Neuro-protective effect of Linalool against spinal cord injury in rats and the mechanism involved / Efecto neuroprotector del Linalool contra la lesión de la médula espinal en ratas y el mecanismo involucrado

The current study was conducted to determine the neuroprotective role and mechanism of action of Linalool (LIN) in SCI. The SCI in Sprague-Dawley (SD) rats was induced by weight-drop contusion model. Results of the suggested that LIN showed improvement in the locomotor function of SCI rats in a BBB scoring analysis. It was found in agreement with histopathological analysis of spinal cord tissue where LIN improves the neuronal architecture of spinal cord tissues, and protect neurons from degeneration. It also reduces oxidative stress via modulating endogenous antioxidants (MDA, SOD, and GSH) and inhibits the generation of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6). In western blot analysis, LIN showed dose-dependent reduction of expression of toll-like receptor (TLR-4) and nuclear factor-kappa B (NF-ĸB). Our study demonstrated that administration of Linalool alleviated spinal cord injury via anti-inflammatory and antioxidant activities in spinal cord tissues possibly due to inhibition of TLR4/NF-κB activation.

El estudio actual se realizó para determinar el papel neuroprotector y el mecanismo de acción de Linalool (LIN) en SCI. La LIN en ratas Sprague-Dawley (SD) se indujo mediante el modelo de contusión de caída de peso. Los resultados sugirieron que LIN mostró una mejora en la función locomotora de ratas SCI en un análisis de puntuación BBB. De acuerdo con el análisis histopatológico del tejido de la médula espinal se encontró que LIN mejora la arquitectura neuronal de los tejidos de la médula espinal y protege a las neuronas de la degeneración. También reduce el estrés oxidativo mediante la modulación de antioxidantes endógenos (MDA, SOD y GSH) e inhibe la generación de citocinas proinflamatorias (TNF-α, IL-1ß e IL-6). En el análisis de Western blot, LIN mostró una reducción dependiente de la dosis de la expresión del receptor tipo toll (TLR-4) y el factor nuclear kappa B (NF-ĸB). Nuestro estudio demostró que la administración de Linalool alivió la lesión de la médula espinal a través de actividades antiinflamatorias y antioxidantes en los tejidos de la médula espinal, posiblemente debido a la inhibición de la activación de TLR4/NF-κB.

Genomic landscape of Chinese patients with hepatocellular carcinoma using next-generation sequencing and its association with the prognosis.

INTRODUCTION AND OBJECTIVES: The occurrence of hepatocellular carcinoma (HCC) is not entirely clear at present. This study comprehensively described the landscape of genetic aberrations in Chinese HCC patients using next-generation sequencing (NGS) and investigated the association of genetic aberrations with clinicopathological characteristics and prognosis. MATERIALS AND METHODS: The clinicopathological data of 78 HCC patients undergoing surgery were retrospectively analyzed. The genomic DNA extracted from tumor samples was detected using a NGS-based gene panel. RESULTS: Mutations in TP53 (55%), TERT (37%), MUC16 (29%) and CTNNB1 (27%) were most common in HCC. The co-occurrences between frequently mutated genes occurring ≥10% were relatively common in HCC. Forty-eight (61.5%) cases harbored DNA damage repair gene mutations, mainly including PRKDC (11.5%), SLX4 (9.0%), ATM (7.7%), MSH6 (7.7%), and PTEN (6.4%), and 39 (50.0%) patients had at least one actionable mutation. FH amplification (odds ratio: 3.752, 95% confidence interval: 1.170-12.028, p=0.026) and RB1 mutations (odds ratio: 13.185, 95% confidence interval: 1.214-143.198, p=0.034) were identified as the independent risk factors for early postoperative recurrence in HCC. CONCLUSIONS: Our study provides a novel insight into the genomic profiling of Chinese HCC patients. FH amplification and RB1 mutations may be associated with an increased risk of early postoperative recurrence in HCC.

A causal modelling framework for short-term effects of PM2.5 on hospitalisations: A nationwide time series study in Brazil.

Accurate estimates of the causal effect of air pollution on health outcomes, are critical when calculating attributable disease burdens. Brazil has a large population exposed to fast-growing emissions of air pollutants, however no national level studies have been conducted to examine the causal effect of PM2.5 exposure on health outcomes. This study proposes a novel approach, to accurately estimate the causal relationship between daily PM2.5 exposure and hospitalisations, across 1,814 Brazilian cities during 2000-2015. A variant of the difference-in-differences (DID) approach was applied under a counterfactual framework. Daily time series data were divided into panels. Seasonality and long-term trend were controlled using indicators for the panel. Variables which do not change within a short-period were controlled using a dummy variable for the day. Controls for variables which vary day by day, were included in the model. We found the proposed model exhibited competitive power performance in detecting causal associations between short-term PM2.5 exposure and hospitalisations in Brazil. A 10 µg/m3 increase in PM2.5 concentrations over four days (lag 0-3) was associated with a 1.06 % (95 % CI: 0.94 to 1.17) increase in all-cause hospitalisations and accounted for 1.26 % (95 % CI: 1.12-1.39) of total hospitalisations. Larger effects were found for children aged 0-4 years and the elderly aged 80+ years, suggesting policies should be developed to minimise the exposure of these age groups.

Physical strength training methods in badminton teaching and training / Métodos de treinamento de força física no ensino e treinamento de badminton / Métodos de en trenamiento de fuerza física en la enseñanza y en el entrenamientodel bádminton

ABSTRACT Introduction In badminton performance, athletes need to precisely manage the movements of mastered techniques to quickly complete the swing and regroup the strength of the upper and lower limbs to hit the ball quickly. Objective Study the effect of strength exercise on the physical performance of badminton players according to training. Methods 24 badminton players were randomly divided into lower limb, upper limb, and control groups. The lower limb group and upper limb group were trained for eight weeks. The final test was conducted, and the data were properly compared and analyzed. Results After eight weeks of intense strength training, the badminton throwing ability of the upper limb group was significantly improved; In the lower limb group, the effect of improving the CVM contraction ability of bilateral knee extensors was not evidenced, and the centrifugal contraction ability of the bilateral knee extensors was significantly improved. Conclusion The experiment shows that strength training can help athletes' physical performance, positively impacting their performance. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução Na atuação de badminton, os atletas precisam gerir precisamente os movimentos das técnicas dominadas para completar rapidamente o balanço e reagrupar a força dos membros superiores e inferiores para bater a bola rapidamente. Objetivo Estudar o efeito do exercício de força no desempenho físico de jogadores de badminton de acordo com o treinamento. Métodos 24 jogadores de badminton foram divididos aleatoriamente em grupo de membros inferiores, grupo de membros superiores e grupo controle. O grupo membro inferior e o grupo membro superior foram treinados por 8 semanas. O teste final foi realizado e os dados foram devidamente comparados e analisados. Resultados Após 8 semanas de treinamento intenso de força, a habilidade de arremesso de badminton do grupo membro superior foi significativamente aprimorada. No grupo de membros inferiores, o efeito de melhorar a capacidade de contração CVM dos extensores bilaterais do joelho não ficou evidenciada e a capacidade de contração centrífuga dos extensores bilaterais do joelho foi significativamente melhorada. Conclusão O experimento mostra que o treinamento de força pode ajudar o desempenho físico dos atletas, tendo um impacto positivo no desempenho de suas atuações. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción En el rendimiento del bádminton, los atletas necesitan gestionar con precisión los movimientos de las técnicas dominadas para completar rápidamente el balanceo y reagrupar la fuerza de los miembros superiores e inferiores para golpear la pelota con rapidez. Objetivo Estudiar el efecto del ejercicio de fuerza en el rendimiento físico de los jugadores de bádminton según el entrenamiento. Métodos 24 jugadores de bádminton fueron divididos aleatoriamente en el grupo de las extremidades inferiores, el grupo de las extremidades superiores y el grupo de control. El grupo de la extremidad inferior y el grupo de la extremidad superior se entrenaron durante 8 semanas. Se llevó a cabo la prueba final y los datos se compararon y analizaron adecuadamente. Resultados Después de 8 semanas de entrenamiento de fuerza intenso, la capacidad de lanzamiento de bádminton del grupo de extremidades superiores mejoró significativamente; en el grupo de extremidades inferiores, el efecto de la mejora de la capacidad de contracción CVM de los extensores bilaterales de la rodilla no se evidenció y la capacidad de contracción centrífuga de los extensores bilaterales de la rodilla mejoró significativamente. Conclusión El experimento muestra que el entrenamiento de fuerza puede ayudar al rendimiento físico de los atletas, teniendo un impacto positivo en su desempeño. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Physical fitness training of volleyball players based on scientific theory / Treinamento de aptidão física de jogadores de voleibol baseado na teoria científica / Entrenamiento físico de jugadores de voleibol basado en la teoría científica

ABSTRACT Introduction: Athletes' physical fitness is the basis for improving their volleyball skills, and physical training can play an essential role in the whole process of training volleyball players resulting in improving the level of physical function of volleyball players and changing the structure of body conformation. Objective: Analyze the effects of physical training on the overall quality of volleyball players. Methods: Several volleyball players were randomly selected and submitted to two months of physical training based on scientific theory literature. We used mathematical statistics to analyze the fitness and performance indicators of volleyball players before and after physical training. Results: The physical fitness of volleyball players was significantly improved after two months of physical training (P<0.05). The performance of volleyball players improved after physical training (P<0.05). Conclusion: Physical agility of volleyball players is improved when submitted to systematic physical training. After physical training, the velocity quality of volleyball players can be significantly improved. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: A preparação física do atleta é a base para melhorar suas habilidades no vôlei e o treinamento físico pode ter um papel essencial em todo o processo no treino dos jogadores de voleibol resultando na melhora do nível de função física dos jogadores de vôlei e alterar a estrutura da conformação corporal. Objetivo: Analisar os efeitos do treinamento físico na qualidade geral dos jogadores de voleibol. Métodos: Vários jogadores de voleibol foram selecionados aleatoriamente e submetidos a dois meses de treinamento físico embasado na literatura da teoria científica. Foram utilizadas estatísticas matemáticas para analisar os indicadores de aptidão física e desempenho dos jogadores de voleibol antes e depois do treinamento físico. Resultados: A aptidão física dos jogadores de vôlei foi significativamente aprimorada após dois meses de treinamento físico (P<0,05). O desempenho dos jogadores de voleibol melhorou após o treinamento físico (P<0,05). Conclusão: A agilidade física dos jogadores de voleibol é aprimorada quando submetida ao treinamento físico sistemático. Após o treinamento físico, a qualidade da velocidade dos jogadores de voleibol pode ser significativamente melhorada. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: La condición física del deportista es la base para mejorar sus habilidades en el voleibol y el entrenamiento físico puede desempeñar un papel esencial en todo el proceso de formación de los jugadores de voleibol, lo que resulta en la mejora del nivel de la función física de los jugadores de voleibol y el cambio de la estructura de la conformación del cuerpo. Objetivo: Analizar los efectos del entrenamiento físico en la calidad general de los jugadores de voleibol. Métodos: Se seleccionaron aleatoriamente varios jugadores de voleibol y se los sometió a dos meses de entrenamiento físico basado en la literatura teórica científica. Se utilizó la estadística matemática para analizar la aptitud física y los indicadores de rendimiento de los jugadores de voleibol antes y después del entrenamiento físico. Resultados: La aptitud física de los jugadores de voleibol mejoró significativamente tras dos meses de entrenamiento físico (P<0,05). El rendimiento de los jugadores de voleibol mejoró tras el entrenamiento físico (P<0,05). Conclusión: La agilidad física de los jugadores de voleibol mejora cuando se los somete a un entrenamiento físico sistemático. Tras el entrenamiento físico, la calidad de la velocidad de los jugadores de voleibol puede mejorar considerablemente. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Cancer cell-derived exosomal LINC00313 induces M2 macrophage differentiation in non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the leading cause of cancer death worldwide. Tumor-associated macrophages (TAMs) are one of the main non-tumor cells in the tumor microenvironment. Here, we investigated the effect of cancer cell-derived exosomal LINC00313 on the M2 macrophage differentiation in NSCLC and clarified its underlying mechanism. METHODS: Flow cytometry, Western blotting, ELISA and immunohistochemical staining were performed to identify the macrophage phenotype by detecting the expression of M2 markers. The expression levels of LINC00313 and miR-135a-3p were measured by qRT-PCR, and luciferase reporter assay was used to validate the binding of lncRNA to miRNA, and miRNA to the target gene STAT6. The mouse-xenograft models were established by subcutaneous injection of the NCl-H1299 cells with stable overexpression or knockdown of LINC00313. GW4869 was injected intra-tumorally after tumor implantation. RESULTS: It was found that the cancer cells promoted M2 macrophage differentiation by secreting exosomes. LINC00313 was overexpressed in H1299-derived exosomes, and its knockdown abolished the effect of H1299-induced M2 macrophage differentiation. LINC00313 sponged miR-135a-3p to increase the STAT6 expression, resulting in the M2 macrophage differentiation. LINC00313 promoted tumor progression and promoted the expression of M2 markers in isolated tumor macrophages. A novel regulatory mechanism of M2 macrophage differentiation in NSCLC was revealed. It was found that cancer cell-derived exosomal LINC00313 promoted M2 macrophage differentiation in NSCLC by up-regulating STAT6 as miR-135a-3p sponge. CONCLUSIONS: This study provides a new mechanism and direction to prevent the M2 macrophage differentiation in NSCLC.

Foxa1 mediates eccrine sweat gland development through transcriptional regulation of Na-K-ATPase expression.

Eccrine sweat glands (ESGs) perform critical functions in temperature regulation in humans. Foxa1 plays an important role in ESG maturation and sweat secretion. Its molecular mechanism, however, remains unknown. This study investigated the expression of Foxa1 and Na-K-ATPase (NKA) in rat footpads at different development stages using immunofluorescence staining, qRT-PCR, and immunoblotting. Also, bioinformatics analysis and Foxa1 overexpression and silencing were employed to evaluate Foxa1 regulation of NKA. The results demonstrated that Foxa1 was consistently expressed during the late stages of ESGs and had a significant role in secretory coil maturation during sweat secretion. Furthermore, the mRNA abundance and protein expression of NKA had similar accumulation trends to those of Foxa1, confirming their underlying connections. Bioinformatics analysis revealed that Foxa1 may interact with these two proteins via binding to conserved motifs in their promoter regions. Foxa1 gain-of-function and loss-of-function experiments in Foxa1-modified cells demonstrated that the activities of NKA were dependent on the presence of Foxa1. Collectively, these data provided evidence that Foxa1 may influence ESG development through transcriptional regulation of NKA expression.

Haemophilia gene therapy-Update on new country initiatives.

INTRODUCTION: Gene therapy is emerging as a potential cure for haemophilia. Gene therapy is a one-time treatment that can elevate factor levels for many years and minimize or eliminate the need for clotting factor concentrate (CFC) replacement therapy. However, there is a paucity of reports on gene therapy efforts in countries outside of North America or Europe, especially in low-and-middle-income countries (LMIC). All indications are that gene therapy will be one of standard care treatments for haemophilia in the future. Still, it may not be accessible to many countries due to various barriers and challenges. At the same time, each country may formulate solutions that may be used globally. AIM: To summarize the approaches taken to establish haemophilia gene therapy in Japan, China, India, South Africa, and Brazil, and to describe the US-initiated multi-LMIC haemophilia gene therapy development program to include Peru, Vietnam, Thailand, Nepal, and Sri Lanka. METHODS: A review of related published information or as accessible by each country's author. RESULTS: Different starting conditions, differing input and level of support from the multitude of stakeholders, and strong leadership have led to various approaches for facilitating research and developing needed infrastructure and regulatory and financing models. Gene therapy programs are at various stages of development and include both adeno-associated viral and lentiviral vectors. CONCLUSION: Global partnerships and collaboration, exchange of knowledge and experience, and alignment of processes across borders will promote further progress towards global access to gene therapy for haemophilia.

Oxidative stress-CBP axis modulates MOB1 acetylation and activates the Hippo signaling pathway.

Reactive oxygen species (ROS) are constantly produced in cells, an excess of which causes oxidative stress. ROS has been linked to regulation of the Hippo pathway; however, the underlying detailed mechanisms remain unclear. Here, we report that MOB1, a substrate of MST1/2 and co-activator of LATS1/2 in the canonical Hippo pathway, interacts with and is acetylated at lysine 11 by acetyltransferase CBP and deacetylated by HDAC6. MOB1-K11 acetylation stabilizes itself by reducing its binding capacity with E3 ligase Praja2 and subsequent ubiquitination. MOB1-K11 acetylation increases its phosphorylation and activates LATS1. Importantly, upstream oxidative stress signals promote MOB1 acetylation by suppressing CBP degradation, independent of MST1/2 kinase activity and HDAC6 deacetylation effect, thereby linking oxidative stress to activation of the Hippo pathway. Functionally, the acetylation-deficient mutant MOB1-K11R promotes lung cancer cell proliferation, migration and invasion in vitro and accelerates tumor growth in vivo, compared to the wild-type MOB1. Clinically, acetylated MOB1 corresponds to better prediction of overall survival in patients with non-small cell lung cancer. Therefore, as demonstrated, an oxidative stress-CBP regulatory axis controls MOB1-K11 acetylation and activates LATS1, thereby activating the Hippo pathway and suppressing YAP/TAZ nuclear translocation and tumor progression.

Lysophosphatidylcholine acyltransferase 1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma via the Wnt/ß-catenin signaling pathway.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most malignant digestive tumors, and its insidious onset and rapid progression are the main reasons for the difficulty in effective treatment. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a key enzyme that regulates phospholipid metabolism of the cell membrane. However, the mechanism by which LPCAT1 regulates HCC metastasis remains unknown. This study aimed to explore its biological function and potential mechanisms concerning migration and invasion in HCC. MATERIALS AND METHODS: LPCAT1 expression in HCC tissues and its association with clinical outcomes were investigated by western blotting and bioinformatic methods, respectively. The role of LPCAT1 in migration and invasion was assessed via Transwell assays. The expression pattern of epithelial-mesenchymal transition (EMT) markers was quantified by western blotting. The biological behaviors of LPCAT1 in vivo were evaluated using xenograft tumor models and caudal vein metastatic models. Signaling pathways related to LPCAT1 were predicted using gene set enrichment analysis (GSEA) and further confirmed by western blotting. RESULTS: LPCAT1 expression was significantly upregulated in HCC tissues and indicated a poor prognosis of HCC patients. Several EMT-related markers were found to be regulated by LPCAT1. HCC cells overexpressing LPCAT1 exhibited remarkably high migration and invasion capacities, upregulated expression of mesenchymal markers and reduced E-cadherin expression. In vivo, LPCAT1 promoted HCC pulmonary metastasis. Furthermore, the Wnt/ß-catenin signaling pathway was confirmed to be activated by LPCAT1. CONCLUSIONS: LPCAT1 could serve as a promising biomarker of HCC and as a novel therapeutic target for the treatment of metastatic HCC.