Development of CDK12 as a Cancer Therapeutic Target and Related Inhibitors.

Cyclin-dependent Kinase 12 (CDK12) is a Cyclin-dependent Kinase (CDK) that plays a crucial role in various biological processes, including transcription, translation, mRNA splicing, cell cycle regulation, and DNA damage repair. Dysregulation of CDK12 has been implicated in tumorigenesis, and genetic alterations affecting CDK12 have been identified in multiple cancer types, including breast cancer, ovarian cancer, gastric cancer, and prostate cancer. Numerous studies have demonstrated that suppression of CDK12 expression effectively inhibits tumor growth and proliferation, underscoring its significance as a cancer biomarker and a potential therapeutic target in cancer treatment. A thorough comprehension of CDK12 is expected to significantly enhance the advancement of novel approaches for the treatment and prevention of cancer. In recent times, endeavors have been undertaken to formulate targeted inhibitors for CDK12, such as PROTAC and molecular gel degraders. Concurrently, investigations have been conducted on the combined utilization of CDK12 small molecule inhibitors and immunotherapy as a potential strategy. This paper examines the diverse functions of CDK12 in the modulation of gene expression and its implications in human tumors. Specifically, it explores the recently uncovered roles of CDK12 kinases in various cellular processes, emphasizing the potential of CDK12 as a viable therapeutic target for the management of human tumors. Furthermore, this review provides an up-to-- date account of the advancements made in utilizing CDK12 in tumor therapy.

Advances in ovarian tumor stem cells and therapy.

Ovarian cancer is considered the most lethal among all gynecological malignancies due to its early metastatic dissemination, extensive spread, and malignant ascites. The current standard of care for advanced ovarian cancer involves a combination of cytoreductive surgery and chemotherapy utilizing platinum-based and taxane-based agents. Although initial treatment yields clinical remission in 70-80% of patients, the majority eventually develop treatment resistance and tumor recurrence. A growing body of evidence indicates the existence of cancer stem cells within diverse solid tumors, including ovarian cancer, which function as a subpopulation to propel tumor growth and disease advancement by means of drug resistance, recurrence, and metastasis. The presence of ovarian cancer stem cells is widely considered to be a significant contributor to the unfavorable clinical outcomes observed in patients with ovarian cancer, as they play a crucial role in mediating chemotherapy resistance, recurrence, and metastasis. Ovarian cancer stem cells possess the capacity to reassemble within the entirety of the tumor following conventional treatment, thereby instigating the recurrence of ovarian cancer and inducing resistance to treatment. Consequently, the creation of therapeutic approaches aimed at eliminating ovarian cancer stem cells holds great potential for the management of ovarian cancer. These cells are regarded as one of the most auspicious targets and mechanisms for the treatment of ovarian cancer. There is a pressing need for a comprehensive comprehension of the fundamental mechanisms of ovarian cancer's recurrence, metastasis, and drug resistance, alongside the development of effective strategies to overcome chemoresistance, metastasis, and recurrence. The implementation of cancer stem cell therapies may potentially augment the tumor cells' sensitivity to existing chemotherapy protocols, thereby mitigating the risks of tumor metastasis and recurrence, and ultimately improving the survival rates of ovarian cancer patients.

Mechanisms associated with cuproptosis and implications for ovarian cancer.

Ovarian cancer, a profoundly fatal gynecologic neoplasm, exerts a substantial economic strain on nations globally. The formidable challenge of its frequent relapse necessitates the exploration of novel cytotoxic agents, efficacious antineoplastic medications with minimal adverse effects, and strategies to surmount resistance to primary chemotherapeutic agents. These endeavors aim to supplement extant pharmacological interventions and elucidate molecular mechanisms underlying induced cytotoxicity, distinct from conventional therapeutic modalities. Recent scientific research has unveiled a novel form of cellular demise, known as copper-death, which is contingent upon the intracellular concentration of copper. Diverging from conventional mechanisms of cellular demise, copper-death exhibits a pronounced reliance on mitochondrial respiration, particularly the tricarboxylic acid (TCA) cycle. Tumor cells manifest distinctive metabolic profiles and elevated copper levels in comparison to their normal counterparts. The advent of copper-death presents alluring possibilities for targeted therapeutic interventions within the realm of cancer treatment. Hence, the primary objective of this review is to present an overview of the proteins and intricate mechanisms associated with copper-induced cell death, while providing a comprehensive summary of the knowledge acquired regarding potential therapeutic approaches for ovarian cancer. These findings will serve as valuable references to facilitate the advancement of customized therapeutic interventions for ovarian cancer.

Prospects and challenges of CAR-T in the treatment of ovarian cancer.

Ovarian cancer ranks as the seventh most prevalent cancer among women and is considered the most lethal gynecological malignancy on a global scale. The absence of reliable screening techniques, coupled with the insidious onset of nonspecific symptoms, often results in a delayed diagnosis, typically at an advanced stage characterized by peritoneal involvement. Management of advanced tumors typically involves a combination of chemotherapy and cytoreductive surgery. However, the therapeutic arsenal for ovarian cancer patients remains limited, highlighting the unmet need for precise, targeted, and sustained-release pharmacological agents. Genetically engineered T cells expressing chimeric antigen receptors (CARs) represent a promising novel therapeutic modality that selectively targets specific antigens, demonstrating robust and enduring antitumor responses in numerous patients. CAR T cell therapy has exhibited notable efficacy in hematological malignancies and is currently under investigation for its potential in treating various solid tumors, including ovarian cancer. Currently, numerous researchers are engaged in the development of novel CAR-T cells designed to target ovarian cancer, with subsequent evaluation of these candidate cells in preclinical studies. Given the ability of chimeric antigen receptor (CAR) expressing T cells to elicit potent and long-lasting anti-tumor effects, this therapeutic approach holds significant promise for the treatment of ovarian cancer. This review article examines the utilization of CAR-T cells in the context of ovarian cancer therapy.

New insights about endometriosis-associated ovarian cancer: pathogenesis, risk factors, prediction and diagnosis and treatment.

Previous studies have shown that the risk of malignant transformation of endometriosis in premenopausal women is approximately 1%, significantly impacting the overall well-being and quality of life of affected women. Presently, the diagnostic gold standard for endometriosis-associated ovarian cancer (EAOC) continues to be invasive laparoscopy followed by histological examination. However, the application of this technique is limited due to its high cost, highlighting the importance of identifying a non-invasive diagnostic approach. Therefore, there is a critical need to explore non-invasive diagnostic methods to improve diagnostic precision and optimize clinical outcomes for patients. This review presents a comprehensive survey of the current progress in comprehending the pathogenesis of malignant transformation in endometriosis. Furthermore, it examines the most recent research discoveries concerning the diagnosis of EAOC and emphasizes potential targets for therapeutic intervention. The ultimate objective is to improve prevention, early detection, precise diagnosis, and treatment approaches, thereby optimizing the clinical outcomes for patients.

Effect of HPV Oncoprotein on Carbohydrate and Lipid Metabolism in Tumor Cells.

High-risk HPV infection accounts for 99.7% of cervical cancer, over 90% of anal cancer, 50% of head and neck cancers, 40% of vulvar cancer, and some cases of vaginal and penile cancer, contributing to approximately 5% of cancers worldwide. The development of cancer is a complex, multi-step process characterized by dysregulation of signaling pathways and alterations in metabolic pathways. Extensive research has demonstrated that metabolic reprogramming plays a key role in the progression of various cancers, such as cervical, head and neck, bladder, and prostate cancers, providing the material and energy foundation for rapid proliferation and migration of cancer cells. Metabolic reprogramming of tumor cells allows for the rapid generation of ATP, aiding in meeting the high energy demands of HPV-related cancer cell proliferation. The interaction between Human Papillomavirus (HPV) and its associated cancers has become a recent focus of investigation. The impact of HPV on cellular metabolism has emerged as an emerging research topic. A significant body of research has shown that HPV influences relevant metabolic signaling pathways, leading to cellular metabolic alterations. Exploring the underlying mechanisms may facilitate the discovery of biomarkers for diagnosis and treatment of HPV-associated diseases. In this review, we introduced the molecular structure of HPV and its replication process, discussed the diseases associated with HPV infection, described the energy metabolism of normal cells, highlighted the metabolic features of tumor cells, and provided an overview of recent advances in potential therapeutic targets that act on cellular metabolism. We discussed the potential mechanisms underlying these changes. This article aims to elucidate the role of Human Papillomavirus (HPV) in reshaping cellular metabolism and the application of metabolic changes in the research of related diseases. Targeting cancer metabolism may serve as an effective strategy to support traditional cancer treatments, as metabolic reprogramming is crucial for malignant transformation in cancer.

Exploring the mechanism of Si-Ni-San against depression by UPLC-Q-TOF-MS/MS integrated with network pharmacology: experimental research.

Background: Depression is becoming an urgent mental health problem. Si-Ni-San has been widely used to treat depression, yet its underlying pharmacological mechanism is poorly understood. Thus, we aim to explore the antidepressant mechanism of Si-Ni-San by chemical analysis and in-silico methods. Methods: Compounds in Si-Ni-San were determined by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Then, bioactive compounds were obtained from Traditional Chinese Medicines for Systems Pharmacology Database and Analysis Platform and SwissADME, and the potential targets of which were acquired from SwissTargetPrediction. Depression-related targets were collected from GeneCards. The intersection between compound-related targets and depression-related targets were screened out, and the overlapped targets were further performed protein-protein interaction, biological functional and pathway enrichment analysis. Finally, networks of Si-Ni-San against depression were constructed and visualized by Cytoscape. Results: One hundred nineteen compounds in Si-Ni-San were determined, of which 24 bioactive compounds were obtained. Then, 137 overlapped targets of Si-Ni-San against depression were collected. AKT1, PIK3R1, PIK3CA, mTOR, MAPK1 and MAPK8 were the key targets. Furthermore, PI3K-Akt signalling pathway, serotonergic synapse, MAPK signalling pathway and neurotrophin signalling pathway were involved in the antidepressant mechanism of Si-Ni-San. It showed that components like sinensetin, hesperetin, liquiritigenin, naringenin, quercetin, albiflorin and paeoniflorin were the mainly key active compounds for the antidepressant effect of Si-Ni-San. Conclusions: This study demonstrated the key components, key targets and potential pharmacological mechanisms of Si-Ni-San against depression. These results indicate that Si-Ni-San is a promising therapeutic approach for treatment of depression, and may provide evidence for the research and development of drugs for treating depression.

The recent advancements of ferroptosis in the diagnosis, treatment and prognosis of ovarian cancer.

Ovarian cancer affects the female reproductive system and is the primary cause of cancer related mortality globally. The imprecise and non-specific nature of ovarian cancer symptoms often results in patients being diagnosed at an advanced stage, with metastatic lesions extending beyond the ovary. This presents a significant clinical challenge and imposes a substantial economic burden on both patients and society. Despite advancements in surgery, chemotherapy, and immunotherapy, the prognosis for most patients with ovarian cancer remains unsatisfactory. Therefore, the development of novel treatment strategies is imperative. Ferroptosis, a distinct form of regulated cell death, characterized by iron-dependent lipid peroxidation, differs from autophagy, apoptosis, and necrosis, and may hold promise as a novel cell death. Numerous studies have demonstrated the involvement of ferroptosis in various conventional signaling pathways and biological processes. Recent investigations have revealed the significant contribution of ferroptosis in the initiation, progression, and metastasis of diverse malignant tumors, including ovarian cancer. Moreover, ferroptosis exhibits a synergistic effect with chemotherapy, radiotherapy, and immunotherapy in restraining the proliferation of ovarian cancer cells. The aforementioned implies that ferroptosis holds considerable importance in the management of ovarian cancer and has the potential to serve as a novel therapeutic target. The present review provides a comprehensive overview of the salient features of ferroptosis, encompassing its underlying mechanisms and functional role in ovarian cancer, along with the associated signaling pathways and genes. Furthermore, the review highlights the prospective utility of ferroptosis in the treatment of ovarian cancer.

Advances in molecular mechanism of HPV16 E5 oncoprotein carcinogenesis.

For a considerable duration, cervical cancer has posed a significant risk to the well-being and survival of women. The emergence and progression of cervical cancer have garnered extensive attention, with prolonged chronic infection of HPV serving as a crucial etiological factor. Consequently, investigating the molecular mechanism underlying HPV-induced cervical cancer has become a prominent research area. The HPV molecule is composed of a long control region (LCR), an early coding region and a late coding region.The early coding region encompasses E1, E2, E4, E5, E6, E7, while the late coding region comprises L1 and L2 ORF.The investigation into the molecular structure and function of HPV has garnered significant attention, with the aim of elucidating the carcinogenic mechanism of HPV and identifying potential targets for the treatment of cervical cancer. Research has demonstrated that the HPV gene and its encoded protein play a crucial role in the invasion and malignant transformation of host cells. Consequently, understanding the function of HPV oncoprotein is of paramount importance in comprehending the pathogenesis of cervical cancer. E6 and E7, the primary HPV oncogenic proteins, have been the subject of extensive study. Moreover, a number of contemporary investigations have demonstrated the significant involvement of HPV16 E5 oncoprotein in the malignant conversion of healthy cells through its regulation of cell proliferation, differentiation, and apoptosis via diverse pathways, albeit the precise molecular mechanism remains unclear. This manuscript aims to provide a comprehensive account of the molecular structure and life cycle of HPV.The HPV E5 oncoprotein mechanism modulates cellular processes such as proliferation, differentiation, apoptosis, and energy metabolism through its interaction with cell growth factor receptors and other cellular proteins. This mechanism is crucial for the survival, adhesion, migration, and invasion of tumor cells in the early stages of carcinogenesis. Recent studies have identified the HPV E5 oncoprotein as a promising therapeutic target for early-stage cervical cancer, thus offering a novel approach for treatment.

[Inhibitory Effect of Cinobufotalin on Macrophage Inflammatory Factor Storm and Its Mechanism].

OBJECTIVE: To investigate the inflammatory effects of Cinobufotalin on monocytes in resting state and macrophages in activated state and its molecular mechanism. METHODS: THP-1 cells were stimulated with Phorbol 12-myristate 13-acetate to induce differentiation into macrophages. Lipopolysaccharides was added to activate macrophages in order to establish macrophage activation model. Cinobufotalin was added to the inflammatory cell model for 24 h as a treatment. CCK-8 was used to detect cell proliferation, Annexin V /PI double staining flow cytometry was used to detect cell apoptosis, flow cytometry was used to detect macrophage activation, and cytometric bead array was used to detect cytokines. Transcriptome sequencing was used to explore the gene expression profile regulated by Cinobufotalin. Changes in the significantly regulated molecules were verified by real-time quantitative polymerase chain reaction and Western blot. RESULTS: 1∶25 concentration of Cinobufotalin significantly inhibited the proliferation of resting monocytes(P<0.01), and induced apoptosis(P<0.01), especially the activated macrophages(P<0.001, P<0.001). Cinobufotalin significantly inhibited the activation of macrophages, and significantly down-regulated the inflammatory cytokines(IL-6, TNF-α, IL-1ß, IL-8) released by activated macrophages(P＜0.001). Its mechanism was achieved by inhibiting TLR4/MYD88/P-IκBa signaling pathway. CONCLUSION: Cinobufotalin can inhibit the inflammatory factors produced by the over-activation of macrophages through TLR4/MYD88/P-IκBa pathway, which is expected to be applied to the treatment and research of diseases related to the over-release of inflammatory factors.

Structural Insight Into hnRNP A2/B1 Homodimerization and DNA Recognition.

Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) has been identified as a nuclear DNA sensor. Upon viral infection, hnRNP A2/B1 recognizes pathogen-derived DNA as a homodimer, which is a prerequisite for its translocation to the cytoplasm to activate the interferon response. However, the DNA binding mechanism inducing hnRNP A2/B1 homodimerization is unknown. Here, we show the crystal structure of the RNA recognition motif (RRM) of hnRNP A2/B1 in complex with a U-shaped ssDNA, which mediates the formation of a newly observed protein dimer. Our biochemical assays and mutagenesis studies confirm that the hnRNP A2/B1 homodimer forms in solution by binding to pre-generated ssDNA or dsDNA with a U-shaped bulge. These results depict a potential functional state of hnRNP A2/B1 in antiviral immunity and other cellular processes.

Effect of Exercise Training on Serum Transaminases in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Background/Purpose: Nonalcoholic fatty liver disease (NAFLD) constitutes a spectrum of liver diseases associated with various metabolic disorders. Exercise interventions reportedly manage the clinical outcomes of NAFLD, but their efficacy depends on exercise as well as characteristics of patient. We hypothesized that exercise could alleviate the elevated transaminases level, which may be associated with the characteristics of patients (age/bodyweight/sex) or exercise variables (frequency/intensity/duration). Therefore, we examined the effect of exercise on serum transaminases, and identified the variables influencing transaminases in NAFLD patients. Methods: Article search was conducted using electronic databases (PubMed, Web of Science, EMBASE, ScienceDirect, Google Scholar) until December 2021. Studies that involved examination and comparison of the effect of an exercise intervention on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in NAFLD/nonalcoholic steatohepatitis patients were included. We calculated pooled effect upon a meta-analysis, determined correlations (between transaminases and characteristics of patients/exercise) by meta-regression, and assessed the influencing variable through subgroup analysis. Results: A total of 18 studies (22 trials) with 1098 NAFLD patients (exercise = 568; control = 530) were included. The pooled outcomes revealed that exercise intervention significantly decreased both ALT (p = 0.004) and AST (p = 0.001) levels in NAFLD patients. Meta-regression analysis showed decreased ALT (coef. = 1.138, p < 0.01) and AST (coef. = 0.459, p = 0.041) after intervention was correlated with the age of patients. Particularly, patients aged 30-39 years (MD: -25.89 U/L, 95% CI: -36.40 to -15.37, p < 0.00001) and 40-49 years (MD: -12.17 U/L, 95% CI: -20.38 to -3.96, p = 0.004) represented a substantial decrease in ALT levels. Additionally, the 50-59 years age group tended to have decreased ALT levels (MD: -3.94 U/L, 95% CI: -8.19 to 0.31, p = 0.07); however, patients above 60 years did not respond (p = 0.92) to exercise intervention. In contrast, exercise-induced AST reduction was found in only the 30-39 years age group (MD: -11.92 U/L, 95% CI: -16.78 to -7.06, p < 0.00001) and not in patients under the 40-49 (p = 0.19), and 50-59 groups (p = 0.12) and above 60 years (p = 0.15). Conclusion: Our findings suggest that the age of NAFLD patients may be an important variable in improving the levels of serum transaminases, and clinically young patients may have greater benefits from exercise than older patients.

Biomechanical Analysis of Arm Manipulation in Tai Chi.

In order to explore the kinematics and muscle force characteristics of competitive Taijiquan arm manipulation, and solve the problems of arm trajectory and control in the process of manipulation, this study puts forward the sports biomechanical analysis of arm manipulation in competitive Taijiquan. The technical characteristics and muscle force characteristics of 15 athletes from the competitive Taijiquan team of Xi'an Institute of physical education were studied. Use Excel 2007 and SPSS17.0 to statistically analyze and process the original data. According to the actual needs, the data indicators are summarized. The combined movements of competitive Taijiquan arm manipulation are captured through high-speed photography, and the kinematic data are statistically analyzed, mainly from the two aspects of action amplitude change and action braking. The results show the action track length, relative track length, and action track length of each plane of the two combined hands. The order of the two combined action tracks is: combination 1 > combination 2, in which the action track in the sagittal plane is the longest in combination 1, and it can also be considered that the motion amplitude in the sagittal plane is the largest in combination 1. The average acceleration of group A in the first beat is 0.51 m/s2 smaller than that of group B, and the value is 0.22 m/s2 smaller. Therefore, the deceleration of group A is larger than that of group B, and the braking capacity of group A is slightly stronger than that of group B. In the second beat, the average acceleration of group B is 1.5722 m/s2 larger than that of group A, and the value is 0.210 m/s2 larger. The average acceleration of group A in the third, fourth, fifth, and sixth beats is 0.9, 3.728, 0.57, and 0.837 m/s2 smaller than that of group B, and the values are 0.466, 0.174, 0.250, and 0.003 m/s2 smaller, indicating that the braking capacity of group A in the third, fourth, fifth, sixth, and eighth beats is slightly stronger than that of group B. In the braking of each beat in combination 1 and combination 2 of group AB, the braking ability of arm manipulation of group A is stronger than that of group B. In competitive Taijiquan, the movement techniques of manipulation include: bouncing technology, braking technology, and control technology. For arm manipulation, athletes should have the ability of "braking" technology. In the correlation analysis of movement track length, RMS and I EMG, the score of athletes in group A is high, and there is no correlation between movement track length and RMS. There is a significant correlation between RMS and movement track length in group B, and the correlation degree is moderate. This shows that when the movement of group B athletes is completed, the muscles are in a state of tension, the movement skills are not mastered well, and the energy saving is not achieved. During training, we should pay more attention to the proprioception of muscles and form a correct way of muscle exertion.

Characteristics of sports injuries in taekwondo athletes in physical training / Características das lesões esportivas em atletas de taekwondo durante treinamento físico / Características de las lesiones deportivas en atletas de tae kwon do durante el entrenamiento físico

ABSTRACT Introduction: Taekwondo is one of the main events of the Olympic Games. It mainly uses hands and feet for fighting or confrontation and the competition is extremely fierce. Therefore, Taekwondo is more prone to muscle, bone, and joint sports injuries. Objective: To understand the characteristics of taekwondo sports injuries. Methods: Using the literature and questionnaire survey methods, mathematical statistics is used to investigate the sports injuries of young Taekwondo athletes. Results: Among 100 young Taekwondo athletes, 93individuals had different degrees of sports injuries, accounting for 93%, and 7had no sports injuries, accounting for only 7%. The total number of injuries was 160 or 1.6injuries per capita. Conclusions: Athletes should improve their ideological understanding and training level and pay attention to the timely treatment of acute injuries, which can effectively reduce sports injuries. Level of evidence II; Therapeutic studies - investigation of treatment results.

RESUMO Introdução: O Taekwondo é um dos principais esportes dos Jogos Olímpicos. As mãos e os pés são os mais usados para lutar ou confrontar e a competição é extremamente acirrada. Portanto, os praticantes são mais sujeitos a lesões musculares, ósseas e articulares. Objetivo: Entender as características das lesões esportivas do Taekwondo. Métodos: Uso da literatura e de métodos de pesquisa por questionário. A estatística foi usada para analisar as lesões esportivas de jovens atletas de Taekwondo. Resultados: Entre 100 jovens atletas de Taekwondo, 93 indivíduos tiveram diferentes graus de lesões esportivas, representando 93%, e 7 não tiveram lesões esportivas, representando apenas 7%. O número total de lesões foi de 160 ou 1,6 lesões per capita. Conclusões: Os atletas devem ter melhor compreensão da ideologia e do nível de treinamento e estar atentos ao tratamento oportuno de lesões agudas, para que possam reduzir efetivamente as lesões esportivas. Nível de Evidência II; Estudos terapêuticos - Investigação dos resultados do tratamento.

RESUMEN Introducción: El Tae Kwon Do es uno de los principales deportes de los Juegos Olímpicos. Las manos y los pies son los más utilizados para luchar o enfrentarse y la competencia es extremadamente intensa. Por lo tanto, los practicantes son más propensos a las lesiones musculares, óseas y articulares. Objetivo: Conocer las características de las lesiones deportivas de este deporte. Métodos: Uso de la literatura y métodos de encuesta por cuestionario. Se utilizó la estadística para analizar las lesiones deportivas de jóvenes atletas de Tae Kwon Do. Resultados: Entre 100 jóvenes atletas de Tae Kwon Do, 93 individuos presentaron diferentes grados de lesiones deportivas, lo que representa el 93%, y 7 no presentaron lesiones deportivas, lo que representa sólo el 7%. El número total de lesiones fue de 160, es decir, 1,6 lesiones per cápita. Conclusiones: Los atletas deben conocer mejor la ideología y el nivel de entrenamiento y ser conscientes del tratamiento oportuno de lesiones agudas, para poder reducir eficazmente las lesiones deportivas. Nivel de Evidencia II; Estudios terapéuticos - Investigación de los resultados del tratamiento.

Meta-Analysis on the Association of Neuropeptide Y rs16139 Variant With the Risk of Alcoholism.

Introduction: The neuropeptide-Y (NPY) is involved in the development of alcoholism through NPY receptors. A T>C mutation causes substitution of leucine to proline at codon 7 (L7P; rs16139) in the signal peptide of neuropeptide Y is known to cause a 42% increase in plasma NPY levels. Studies that analyzed the association between NPY rs16139 and alcoholism risk did not demonstrate conclusive evidence for this relationship. The present study aims to evaluate the association between NPY gene rs16139 variant and alcohol dependence. Method: An electronic search of databases including PubMed and Google Scholar was performed to retrieve studies investigating the association between NPY rs16139 and alcoholism. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated in allelic and dominant genetic models. Sensitivity analyses and publication bias were assessed in our meta-analysis. The meta-analysis was conducted using the MetaGenyo web tool. Result: Significant heterogeneity was observed across studies (p < 0.001). Our results have shown that there is no significant association between NPY rs16139 variant and the risk of alcoholism in allelic (OR = 0.98, 95% CI 0.70-1.38, p = 0.921) and dominant models (OR = 0.98, 95% CI 0.69-1.40, p = 0.919). Begg's funnel plot and Egger's test have not shown publication bias (p = 0.332). Conclusion: To the best of our knowledge, this is the first meta-analysis that evaluates the relationship between the NPY rs16139 polymorphism and the risk of alcoholism. Our large-scale meta-analysis suggests that NPY rs16139 polymorphism is not associated with alcoholism. However, further studies are needed to increase our understanding of the relationship between NPY variants in alcoholism.

Depression and anxiety in patients with active ulcerative colitis: crosstalk of gut microbiota, metabolomics and proteomics.

Patients with ulcerative colitis (UC) have a high prevalence of mental disorders, such as depression and anxiety. Gut microbiota imbalance and disturbed metabolism have been suggested to play an important role in either UC or mental disorders. However, little is known about their detailed multi-omics characteristics in patients with UC and depression/anxiety. In this prospective observational study, 240 Chinese patients were enrolled, including 129 patients with active UC (69 in Phase 1 and 60 in Phase 2; divided into depression/non-depression or anxiety/non-anxiety groups), 49 patients with depression and anxiety (non-UC), and 62 healthy people. The gut microbiota of all subjects was analyzed using 16S rRNA sequencing. The serum metabolome and proteome of patients with UC in Phase 2 were analyzed using liquid chromatography/mass spectrometry. Associations between multi-omics were evaluated by correlation analysis. The prophylactic effect of candidate metabolites on the depressive-like behavior of mice with colitis was investigated. In total, 58% of patients with active UC had depression, while 50% had anxiety. Compared to patients with UC without depression/anxiety, patients with UC and depression/anxiety had lower fecal microbial community richness and diversity, with more Lactobacillales, Sellimonas, Streptococcus, and Enterococcus but less Prevotella_9 and Lachnospira. Most metabolites (e.g., glycochenodeoxycholate) were increased in the serum, while few metabolites, including 2'-deoxy-D-ribose and L-pipecolic acid, were decreased, accompanied by a general reduction in immunoglobulin proteins. These related bacteria, metabolites, and proteins were highly connected. A prophylactic administration of 2'-deoxy-D-ribose and L-pipecolic acid significantly reduced the depressive-like behaviors in mice with colitis and alleviated the inflammatory cytokine levels in their colon, blood and brain. This study has identified a comprehensive multi-omics network related to depression and anxiety in active UC. It is composed of a certain set of gut microbiota, metabolites, and proteins, which are potential targets for clinical intervention for patients with UC and depression/anxiety.

MiR-10b-5p inhibits tumorigenesis in gastric cancer xenograft mice model through down-regulating Tiam1.

The miR-10b-5p plays an important role in gastric cancer development but its exact effect on gastric cancer development in vivo has not been fully studied. We showed that miR-10b-5p inhibited the proliferation and migration of gastric cancer cells by down-regulating Tiam1 which was up-regulated in both gastric cancer cells and tissues. Gastric cancer xenograft experiment showed that lenti-miR-10b-5p treatment and agomir-10b-5p injection could significantly retard tumor growth and reduce tumor size and induced apoptosis. Therefore, our results elucidate the tumor suppressor role of miR-10b-5p in gastric cancer in which it acts as a negative regulator of Tiam1 and also provide a molecular mechanism for agomir-10b-5p to treat gastric cancer.

A genome-wide association study reveals a substantial genetic basis underlying the Ebbinghaus illusion.

The Ebbinghaus illusion (EI) is an optical illusion of relative size perception that reflects the contextual integration ability in the visual modality. The current study investigated the genetic basis of two subtypes of EI, EI overestimation, and EI underestimation in humans, using quantitative genomic analyses. A total of 2825 Chinese adults were tested on their magnitudes of EI overestimation and underestimation using the method of adjustment, a standard psychophysical protocol. Heritability estimation based on common single nucleotide polymorphisms (SNPs) revealed a moderate heritability (34.3%) of EI overestimation but a nonsignificant heritability of EI underestimation. A meta-analysis of two phases (phase 1: n = 1986, phase 2: n = 839) of genome-wide association study (GWAS) discovered 1969 and 58 SNPs reaching genome-wide significance for EI overestimation and EI underestimation, respectively. Among these SNPs, 55 linkage-disequilibrium-independent SNPs were associated with EI overestimation in phase 1 with genome-wide significance and their associations could be confirmed in phase 2 cohort. Gene-based analyses found seven genes to be associated with EI overestimation at the genome-wide level, two from meta-analysis, and five from classical two-stage analysis. Overall, this study provided consistent evidence for a substantial genetic basis of the Ebbinghaus illusion.

Predicting the local COVID-19 outbreak around the world with meteorological conditions: a model-based qualitative study.

OBJECTIVES: This study aims to investigate the relationship between daily weather and transmission rate of SARS-CoV-2, and to develop a generalised model for future prediction of the COVID-19 spreading rate for a certain area with meteorological factors. DESIGN: A retrospective, qualitative study. METHODS AND ANALYSIS: We collected 382 596 records of weather data with four meteorological factors, namely, average temperature, relative humidity, wind speed, and air visibility, and 15 192 records of epidemic data with daily new confirmed case counts (1 587 209 confirmed cases in total) in nearly 500 areas worldwide from 20 January 2020 to 9 April 2020. Epidemic data were modelled against weather data to find a model that could best predict the future outbreak. RESULTS: Significant correlation of the daily new confirmed case count with the weather 3 to 7 days ago were found. SARS-CoV-2 is easy to spread under weather conditions of average temperature at 5 to 15°C, relative humidity at 70% to 80%, wind speed at 1.5 to 4.5 m/s and air visibility less than 10 statute miles. A short-term model with these four meteorological variables was derived to predict the daily increase in COVID-19 cases; and a long-term model using temperature to predict the pandemic in the next week to month was derived. Taken China as a discovery dataset, it was well validated with worldwide data. According to this model, there are five viral transmission patterns, 'restricted', 'controlled', 'natural', 'tropical' and 'southern'. This model's prediction performance correlates with actual observations best (over 0.9 correlation coefficient) under natural spread mode of SARS-CoV-2 when there is not much human interference such as epidemic control. CONCLUSIONS: This model can be used for prediction of the future outbreak, and illustrating the effect of epidemic control for a certain area.

[Assay of 18 amino acids in Chuanmingshen violaceum roots by pre-column derivative HPLC].

The roots of Chuanmingshen violaceum is a commonly used Chinese herb and food, which contains rich amino acids. However, the kinds and amounts of amino acids are variety in this herb among the geographical location and ecological environment. Therefore, this study firstly developed a new pre-column derived HPLC method to quantify the levels of 18 amino acids in Ch. violaceum roots. Then 24 Ch. violaceum samples were harvested from its main cultivating areas in Sichuan, China. These samples were divided into 4 producing areas based on their geographical sites. The 18 kinds of amino acids were quantified in these sample by the developed method. The differences of these amino acids were further analyzed among these herbal samples and the 4 producing areas by t-test and principal component analysis(PCA). The result indicated the peaks of the 18 kinds of amino acids were separated well in 70 min.The correlation coefficients between peak areas and concentration of these amino acids were more than 0.999 1(n=6). All of their recoveries were in the range of 97.38%-101.3%(n=6).Their detection limit was in the range of 0.003-0.379 µg·mL~(-1).It demonstrates that the developed HPLC method can accurately quantify the amounts of multi-amino acids in this herb. The results of t-test analysis showed the contents of histidine, cystine, leucine, valine, tryptophan, phenylalanine and threonine were significantly different(P<0.05) among the 4 producing areas. But the differences of other amino acids were not significant.The first five factors were extracted by PCA to calculate the comprehensive score. The order of comprehensive score for the 4 producing areas was B(0.603, n=10), C(0.206, n=3), A(-0.283, n=7) and D(-1.167, n=4). The total content of amino acids in Ch. violaceum collected in B producing area was largest(12.5 mg·g~(-1)). It is concluded the Ch. violaceum contains multi-kinds of amino acids. On the basis of amino acid amount, Langzhong city and Cangxi county in Sichuan province(producing area B) is the suitable areas for cultivating Ch. violaceum.