Cryo-EM structures of Smc5/6 in multiple states reveal its assembly and functional mechanisms.

Smc5/6 is a member of the eukaryotic structural maintenance of chromosomes (SMC) family of complexes with important roles in genome maintenance and viral restriction. However, limited structural understanding of Smc5/6 hinders the elucidation of its diverse functions. Here, we report cryo-EM structures of the budding yeast Smc5/6 complex in eight-subunit, six-subunit and five-subunit states. Structural maps throughout the entire length of these complexes reveal modularity and key elements in complex assembly. We show that the non-SMC element (Nse)2 subunit supports the overall shape of the complex and uses a wedge motif to aid the stability and function of the complex. The Nse6 subunit features a flexible hook region for attachment to the Smc5 and Smc6 arm regions, contributing to the DNA repair roles of the complex. Our results also suggest a structural basis for the opposite effects of the Nse1-3-4 and Nse5-6 subcomplexes in regulating Smc5/6 ATPase activity. Collectively, our integrated structural and functional data provide a framework for understanding Smc5/6 assembly and function.

Anti-influenza activity of CPAVM1 protease secreted by Bacillus subtilis LjM2.

Bacillus spp. has been considered a promising source for identifying new antimicrobial substances, including anti-viral candidates. Here, we successfully isolated a number of bacteria strains from aged dry citrus peel (Chenpi). Of note, the culture supernatant of a new isolate named Bacillus subtilis LjM2 demonstrated strong inhibition of influenza A virus (IAV) infection in multiple experimental systems in vitro and in vivo. In addition, the anti-viral effect of LjM2 was attributed to its direct lysis of viral particles. Further analysis showed that a protease which we named CPAVM1 isolated from the culture supernatant of LjM2 was the key component responsible for its anti-viral function. Importantly, the therapeutic effect of CPAVM1 was still significant when applied 12 hours after IAV infection of experimental mice. Moreover, we found that the CPAVM1 protease cleaved multiple IAV proteins via targeting basic amino acid Arg or Lys. Furthermore, this study reveals the molecular structure and catalytic mechanism of CPAVM1 protease. During catalysis, Tyr75, Tyr77, and Tyr102 are important active sites. Therefore, the present work identified a special protease CPAVM1 secreted by a new strain of Bacillus subtilis LjM2 against influenza A virus infection via direct cleavage of critical viral proteins, thus facilitates future biotechnological applications of Bacillus subtilis LjM2 and the protease CPAVM1.

Foraging Behaviors of Red Imported Fire Ants (Hymenoptera Formicidae) in Response to Bait Containing Different Concentrations of Fipronil, Abamectin, or Indoxacarb.

The red imported fire ant, Solenopsis invicta Buren, is a severe pest with agricultural, ecological, and medical significance. The baiting treatment is one of the main methods to control S. invicta. However, few studies have evaluated the acceptance of fire ant bait. Here, field and laboratory studies were conducted to investigate the foraging behaviors of S. invicta responding to fire ant baits containing different concentrations of active ingredients (fipronil, abamectin, or indoxacarb). Field studies showed that S. invicta transported significantly less 0.0125% fipronil bait than control bait (without toxicant) and 0.0001% fipronil bait. The number of foraging ants significantly decreased with an increase in fipronil concentration. Our previous study showed that S. invicta usually buries the food treated with repellent chemicals, and interestingly, significantly more soil particles were transported into tubes containing 0.0001% fipronil bait than tubes containing control bait or 0.0125% fipronil bait. In addition, S. invicta transported significantly less 0.0005% abamectin bait than control bait, and significantly fewer ants were found in tubes containing 0.0125% abamectin bait than control bait. However, there was no significant difference in bait transport, number of foraging ants, and weight of soil particles relocated in tubes containing different concentrations of indoxacarb bait. In addition, laboratory studies showed that S. invicta transported significantly less 0.0125% fipronil bait than control bait and bait containing abamectin (0.0025% or 0.0125%) or indoxacarb (0.0125% or 0.0625%). In addition, the transport speed for the 0.0125% fipronil bait was the slowest. These results show that specific concentrations of some active ingredients may negatively affect bait acceptance for S. invicta, and should be avoided in fire ant bait production.

Extracellular vesicles in renal cell carcinoma: challenges and opportunities coexist.

Renal cell carcinoma (RCC) represents an extremely challenging disease in terms of both diagnosis and treatment. It poses a significant threat to human health, with incidence rates increasing at a yearly rate of roughly 2%. Extracellular vesicles (EVs) are lipid-based bilayer structures of membranes that are essential for intercellular interaction and have been linked to the advancement of RCC. This review provides an overview of recent studies on the role of EVs in RCC progression, including involvement in the interaction of tumor cells with M2 macrophages, mediating the generation of immune tolerance, and assuming the role of communication messengers in the tumor microenvironment leading to disease progression. Finally, the " troika " of EVs in RCC therapy is presented, including engineered sEVs' or EVs tumor vaccines, mesenchymal stem cell EVs therapy, and reduction of tumor-derived EVs secretion. In this context, we highlight the limitations and challenges of EV-based research and the prospects for future developments in this field. Overall, this review provides a comprehensive summary of the role of EVs in RCC and their potential as a viable pathway for the future treatment of this complex disease.

Progress of regulatory RNA in small extracellular vesicles in colorectal cancer.

Colorectal cancer (CRC) is the second most common malignant tumor of the gastrointestinal tract with the second highest mortality rate and the third highest incidence rate. Early diagnosis and treatment are important measures to reduce CRC mortality. Small extracellular vesicles (sEVs) have emerged as key mediators that facilitate communication between tumor cells and various other cells, playing a significant role in the growth, invasion, and metastasis of cancer cells. Regulatory RNAs have been identified as potential biomarkers for early diagnosis and prognosis of CRC, serving as crucial factors in promoting CRC cell proliferation, invasion and metastasis, angiogenesis, drug resistance, and immune cell differentiation. This review provides a comprehensive summary of the vital role of sEVs as biomarkers in CRC diagnosis and their potential application in CRC treatment, highlighting their importance as a promising avenue for further research and clinical translation.

Role of microRNA carried by small extracellular vesicles in urological tumors.

Small extracellular vesicles (sEVs) are minute vesicles secreted by various cells that are capable of transporting cargo, including microRNAs, between donor and recipient cells. MicroRNAs (miRNAs), small non-coding RNAs approximately 22 nucleotides in length, have been implicated in a wide array of biological processes, including those involved in tumorigenesis. Emerging evidence highlights the pivotal role of miRNAs encapsulated in sEVs in both the diagnosis and treatment of urological tumors, with potential implications in epithelial-mesenchymal transition, proliferation, metastasis, angiogenesis, tumor microenvironment and drug resistance. This review provides a brief overview of the biogenesis and functional mechanisms of sEVs and miRNAs, followed by a summarization of recent empirical findings on miRNAs encapsulated in sEVs from three archetypal urologic malignancies: prostate cancer, clear cell renal cell carcinoma, and bladder cancer. We conclude by underscoring the potential of sEV-enclosed miRNAs as both biomarkers and therapeutic targets, with a particular focus on their detection and analysis in biological fluids such as urine, plasma, and serum.

A New HIV-1 K28E32-Reverse Transcriptase Variant Associated with the Rapid Expansion of CRF07_BC among Men Who Have Sex with Men.

HIV-1 CRF07_BC originated among injection drug users (IDUs) in China. After diffusing into men who have sex with men (MSM), CRF07_BC has shown a rapid expansion in this group; however, the mechanism remains unclear. Here, we identified a new K28E32 variant of CRF07_BC that was characterized by five specific mutations (E28K, K32E, E248V, K249Q, and T338S) in reverse transcriptase. This variant was mainly prevalent among MSM, and was overrepresented in transmission clusters, suggesting that it could have driven the rapid expansion of CRF07_BC in MSM, though founder effects cannot be ruled out. It was descended from an evolutionary intermediate accumulating four specific mutations and formed an independent phylogenetic node with an estimated origin time in 2003. The K28E32 variant was demonstrated to have significantly higher in vitro HIV-1 replication ability than the wild type. Mutations E28K and K32E play a critical role in the improvement of in vitro HIV-1 replication ability, reflected by improved reverse transcription activity. The results could allow public health officials to use this marker (especially E28K and K32E mutations in the reverse transcriptase (RT) coding region) to target prevention measures prioritizing MSM population and persons infected with this variant for test and treat initiatives. IMPORTANCE HIV-1 has very high mutation rate that is correlated with the survival and adaption of the virus. The variants with higher transmissibility may be more selective advantage than the strains with higher virulence. Several HIV-1 variants were previously demonstrated to be correlated with higher viral load and lower CD4 T cell count. Here, we first identified a new variant (the K28E32 variant) of HIV-1 CRF07_BC, described its origin and evolutionary dynamics, and demonstrated its higher in vitro HIV-1 replication ability than the wild type. We demonstrated that five RT mutations (especially E28K and K32E) significantly improve in vitro HIV-1 replication ability. The appearance of the new K28E32 variant was associated with the rapidly increasing prevalence of CRF07_BC among MSM.

Effect of aerobic exercise on limb motor function in diabetic patients / Efeito do exercício aeróbico sobre a função motora dos membros em pacientes diabéticos / Efecto del ejercicio aeróbico en la función motora de las extremidades en pacientes diabéticos

ABSTRACT Introduction: Gestational Diabetes is a group of metabolic disorders that result in glucose intolerance during pregnancy. Among the range of treatments are diet, continuous use of medication, and psychological monitoring. Since it is a multidisciplinary treatment, a proper protocol is vital for a favorable outcome. In addition, there are questions about the benefits of physical activity as a complementary therapy. Objective: To verify the impact of adding exercise to the hospital protocol for patients with gestational diabetes, both on the risks of type 2 diabetes in pregnant women and on the obesity of their offspring. Methods: Sixty pregnant women diagnosed with Gestational Diabetes were randomly divided into control and intervention groups. Both groups received specific treatment and intervention, and the experimental group practiced controlled moderate-intensity physical activity (125-146bpm). Morning blood samples were collected from both groups to check fasting glucose and insulin levels, indicators of lipid metabolism, low and high-density lipoprotein cholesterol, apolipoprotein B. The Brog scale measured the fatigue level. In addition, the premature rupture of membranes, postpartum hemorrhage, neonatal asphyxia, macrosomia, and others was checked. Results: The peripheral blood total cholesterol levels were 5.93, 5. 38, low-density lipoprotein cholesterol levels were 2.95 before versus 2.64 after, and apolipoprotein B levels were 1.84 versus 1.59 in the control group, high-density lipoprotein cholesterol content increased from 1.74 to 1.88, blood cholesterol, and apolipoprotein B levels after the intervention in the experimental group were lower than those in the control group, with an elevation of high-density lipoprotein cholesterol. Conclusion: Aerobic exercise proved to be more appropriate for patients with gestational diabetes in the later stages of pregnancy and may also be adapted for bedridden patients refractory to traditional drugs. Evidence Level II; Therapeutic Studies - Investigating the result.

RESUMO Introdução: O Diabetes Gestacional é um grupo de desordens metabólicas que resultam na intolerância à glicose durante a gravidez, dentre o leque de tratamentos está a dieta, o uso continuo de medicamentos, e acompanhamento psicológico. Por ser um tratamento multidisciplinar, é importante que haja um protocolo adequado para um desfecho favorável. Há questionamentos quanto aos benefícios de atividades físicas como terapia complementar. Objetivo: Verificar o impacto da adição de exercícios ao protocolo hospitalar para pacientes com diabetes gestacional, tanto nos riscos de diabetes tipo 2 em grávidas quanto na obesidade de seus descendentes. Métodos: Sessenta mulheres grávidas que foram diagnosticadas com Diabetes Gestacional foram aleatoriamente divididas em grupos controle e intervenção. Ambos grupos receberam tratamento e intervenção específicos e o grupo experimental praticou atividade física de intensidade moderada controlada (125-146bpm). Amostras de sangue em jejum matinal foram coletados em ambos os grupos para verificar níveis de glicose e insulina em jejum, indicadores de metabolismo lipídico, colesterol lipoproteico de baixa e alta densidade, apolipoproteína B. Verificou-se também o nível de fadiga pela escala Brog, ruptura prematura de bolsa, hemorragia pós-parto, asfixia neo-natal, macrossomia entre outros. Resultados: Os níveis de colesterol total no sangue periférico foram de 5,93, 5.38, os níveis de colesterol lipoproteico de baixa densidade foram 2,95 antes contra 2,64 depois e os níveis de apolipoproteína B foram 1,84 contra 1,59 no grupo controle, o conteúdo de colesterol lipoproteico de alta densidade aumentou de 1,74 para 1,88, os níveis de colesterol, e apolipoproteína B sanguíneos depois da intervenção no grupo experimental foram menores que os do grupo controle, com elevação do colesterol lipoprotéico de alta densidade. Conclusão: O exercício aeróbico mostrou-se mais adequado para pacientes com diabetes gestacional nos estágios posteriores da gravidez, podendo ser adaptado inclusive para as pacientes acamadas refratárias aos fármacos tradicionais. Nível de evidência II; Estudos Terapêuticos - Investigação de Resultados.

Resumen Introducción: La diabetes gestacional es un grupo de trastornos metabólicos que dan lugar a una intolerancia a la glucosa durante el embarazo. Entre la gama de tratamientos se encuentra la dieta, el uso continuado de medicamentos y el seguimiento psicológico. Al tratarse de un tratamiento multidisciplinar, es importante contar con un protocolo adecuado para obtener un resultado favorable. Existen dudas sobre los beneficios de la actividad física como terapia complementaria. Objetivo: Comprobar el impacto de añadir el ejercicio al protocolo hospitalario para pacientes con diabetes gestacional, tanto en los riesgos de diabetes tipo 2 en las mujeres embarazadas como en la obesidad de su descendencia. Métodos: Sesenta mujeres embarazadas a las que se les diagnosticó diabetes gestacional fueron divididas aleatoriamente en grupos de control y de intervención. Ambos grupos recibieron un tratamiento y una intervención específicos y el grupo experimental practicó una actividad física controlada de intensidad moderada (125-146bpm). Se tomaron muestras de sangre en ayunas por la mañana de ambos grupos para comprobar los niveles de glucosa e insulina en ayunas, los indicadores del metabolismo de los lípidos, el colesterol de lipoproteínas de baja y alta densidad, la apolipoproteína B. También se comprobó el nivel de fatiga según la escala de Brog, la rotura prematura de bolsa, la hemorragia posparto, la asfixia neonatal y la macrosomía, entre otros. Resultados: Los niveles de colesterol total en sangre periférica fueron de 5,93, 5. 38, los niveles de colesterol de lipoproteínas de baja densidad eran de 2,95 antes frente a 2,64 después y los niveles de apolipoproteína B eran de 1,84 frente a 1,59 en el grupo de control, el contenido de colesterol de lipoproteínas de alta densidad aumentó de 1,74 a 1,88, el colesterol en sangre y los niveles de apolipoproteína B después de la intervención en el grupo experimental fueron inferiores a los del grupo de control, con una elevación del colesterol de lipoproteínas de alta densidad. Conclusión: El ejercicio aeróbico resultó ser más apropiado para las pacientes con diabetes gestacional en las últimas fases del embarazo, y puede adaptarse incluso a las pacientes encamadas y refractarias a los fármacos tradicionales. Nivel de evidencia II; Estudios terapéuticos - Investigación de resultados.

Mesenchymal Stem Cell-Derived Small Extracellular Vesicles: A Novel Approach for Kidney Disease Treatment.

Globally, kidney disease has become a serious health challenge, with approximately 10% of adults suffering with the disease, and increasing incidence and mortality rates every year. Small extracellular vesicles (sEVs) are 30 nm-100 nm sized nanovesicles released by cells into the extracellular matrix (ECM), which serve as mediators of intercellular communication. Depending on the cell origin, sEVs have different roles which depend on internal cargoes including, nucleic acids, proteins, and lipids. Mesenchymal stem cell (MSCs) exert anti-inflammatory, anti-aging, and wound healing functions mainly via sEVs in a stable and safe manner. MSC-derived sEVs (MSC-sEVs) exert roles in several kidney diseases by transporting renoprotective cargoes to reduce oxidative stress, inhibit renal cell apoptosis, suppress inflammation, and mediate anti-fibrosis mechanisms. Additionally, because MSC-sEVs efficiently target damaged kidneys, they have the potential to become the next generation cell-free therapies for kidney disease. Herein, we review recent research data on how MSC-sEVs could be used to treat kidney disease.

Overexpressed lncRNA FTX promotes the cell viability, proliferation, migration and invasion of renal cell carcinoma via FTX/miR­4429/UBE2C axis.

The present study aimed to explore the role of long non­coding (lnc)RNA FTX and ubiquitin­conjugating enzyme E2C (UBE2C) in promoting the progression of renal cell carcinoma (RCC) and the underlying regulatory mechanism. Relative levels of lncRNA FTX, UBE2C, AKT, CDK1 and CDK6 in RCC cell lines were detected by reverse transcription­quantitative (RT­q). Expression levels of UBE2C, phosphorylated (p)­AKT/AKT, p­CDK1/CDK1 and p­CDK6/CDK6 in RCC and paracancerous specimens and RCC cells were measured by western blot or immunohistochemistry assay. In addition, the proliferative rate, cell viability, cell cycle progression, migratory rate and invasive rate of RCC cells overexpressing lncRNA FTX by lentivirus transfection were determined by a series of functional experiments, including the colony formation assay, MTT assay, flow cytometry, Transwell assay and wound healing assay. The targeted binding relationship in the lncRNA FTX/miR­4429/UBE2C axis was validated by dual­luciferase reporter assay. By intervening microRNA (miR)­4492 and UBE2C by the transfection of miR­4429­mimics or short interfering UBE2C­2, the regulatory effect of lncRNA FTX/miR­4429/UBE2C axis on the progression of RCC was evaluated. Finally, a xenograft model of RCC in nude mice was established by subcutaneous implantation, thus evaluating the in vivo function of lncRNA FTX in the progression of RCC. The results showed that lncRNA FTX and UBE2C were upregulated in RCC specimens and cell lines. The overexpression of lncRNA FTX in RCC cells upregulated UBE2C. In addition, the overexpression of lncRNA FTX promoted the cell viability and proliferative, migratory and invasive capacities of RCC cells and accelerated the cell cycle progression. A dual­luciferase reporter assay validated that lncRNA FTX exerted the miRNA sponge effect on miR­4429, which was bound to UBE2C 3'UTR. Knockdown of UBE2C effectively reversed the regulatory effects of overexpressed lncRNA FTX on the abovementioned phenotypes of RCC cells. In the xenograft model of RCC, the mice implanted with RCC cells overexpressing lncRNA FTX showed a larger tumor size and higher tumor weight than those of controls, while the in vivo knockdown of UBE2C significantly reduced the size of RCC lesions, indicating the reversed cancer­promoting effect of lncRNA FTX. Overall, the present study showed that lncRNA FTX was upregulated in RCC and could significantly promote the proliferative, migratory and invasive capacities, enhancing the viability and accelerating the cell cycle progression of RCC cells by exerting the miRNA sponge effect on miR­4429 and thus upregulating UBE2C. lncRNA FTX and UBE2C are potential molecular biomarkers and therapeutic targets of RCC.

Observation on the Effect of Rehabilitative Physical Training on Sports Injuries under Ultrasound Image Examination.

In order to observe the effect of rehabilitative physical training on sports injuries under ultrasound examination, this study firstly carried out experiments, induction and analysis of ultrasound examination, and evaluation-related content, especially the diagnosis of ultrasound examination in muscle and tendon injuries caused by various reasons. And the clinical application of treatment (clinical research) is reviewed, in order to provide reference data for clinical stage summary. Then, by determining the fasciculation and location of the tendon rupture injury by ultrasound, the clinic can decide whether or not to proceed with surgery. Small Achilles tendon tears only require conservative treatment to avoid the development of complete Achilles tendon rupture. Finally, 26 patients and 10 healthy adults were examined by ultrasonography, and each subject was segmented to examine 11 muscles, including the tongue muscle. The bilateral trapezius, bilateral biceps brachii, bilateral abductor pollicis brevis, bilateral quadriceps femoris, and bilateral tibialis anterior muscles were evaluated by ultrasound and statistical methods. The experimental results show that if the fasciculation of the Achilles tendon injury does not reach more than 3/11, it indicates that no surgical treatment is required; for those with a complete tear of the Achilles tendon, the distance between the broken ends should be further measured in the toe flexion state to evaluate whether surgical treatment is required. It effectively solves the problem of visual diagnosis of sports injuries.

Perivascular brown adipocytes-derived kynurenic acid relaxes blood vessel via endothelium PI3K-Akt-eNOS pathway.

OBJECTIVE: Several metabolites from the kynurenine pathway of tryptophan metabolism play a critical role in vascular function and vascular wall remodeling. This study aimed to test whether metabolite kynurenic acid (KYNA) from the kynurenine pathway relaxes blood vessels. APPROACH AND RESULTS: We employed histological staining, in vitro cell culture, Western blotting, real-time PCR, and nitric oxide detection to validate kynurenine aminotransferase (KAT) localization in the vasculature as well as KYNA action on endothelial cells. We also detected vascular reactivity by organ chamber and monitored blood pressure by telemetry to investigate the regulation effect of KYNA on vascular tone. The results presented that perivascular adipose tissue (PVAT) from mice thoracic aorta had robust staining of anti-KAT1 and KYNA than PVAT from the abdominal aorta and mesenteric artery, which is consistent with the expression profile of brown adipocyte marker uncoupling protein 1. KYNA, metabolized from kynurenine by KAT, relaxed pre-contracted both aortic ring and mesenteric artery. In addition, KYNA derived from KAT in PVAT participates in the cross-talk between PVAT and vessel by mediating PVAT inhibition on agonist-induced thoracic aorta contraction. Furthermore, intraperitoneal injection of KYNA in mice reduced blood pressure. The vessel relaxation effect of KYNA was through the endothelium-dependent PI3K-Akt-eNOS pathway. Finally, the high-fat diet decreased KAT1 expression in perithoracic aortic fat and led to KYNA reduction in blood. CONCLUSIONS: Our research identified KYNA generated by KAT as a novel perivascular brown adipocyte-derived vascular relaxation factor and suggests that KYNA reduction is a critical event in vascular dysfunction under obese condition.

Research progress of extracellular vesicles in type 2 diabetes and its complications.

Type 2 diabetes is one of the most common chronic diseases in modern society. However, there is still insufficient research on the pathogenesis, diagnosis and treatment of type 2 diabetes and its complications. Extracellular vesicles are small bilayer vesicles secreted by cells. In recent years, the effect of extracellular vesicles in type 2 diabetes and its complications has aroused extensive attention. The research on the influence of protein and nucleic acids carried by extracellular vesicles secreted by stem cells and inflammatory cells on the pathogenesis of type 2 diabetes and its complications provides new ideas for its diagnosis and treatment. This review focuses on the influence of extracellular vesicles on insulin resistance by regulating inflammation and glucose transporter 4 expression. The second part mainly discusses the research progress and limitations of extracellular vesicles use in treating and diagnosing type 2 diabetes and its complications. This review introduces the current research status of type 2 diabetes and its complications, illustrates the biogenesis of extracellular vesicles, their effect on type 2 diabetes pathogenesis and its complications and their potential as therapeutic tools and diagnostic markers in type 2 diabetes and its complications.

Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance.

Despite the excellent antiviral potency of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), emergence of drug-resistant viral mutations remains a potential challenge. Sofobuvir (SOF), a nucleotide analog targeting HCV NS5B - RNA-dependent RNA polymerase (RdRp), constitutes a key component of many anti-HCV cocktail regimens and confers a high barrier for developing drug resistance. The serine to threonine mutation at the amino acid position 282 of NS5B (S282T) is the mostly documented SOF resistance-associated substitution (RAS), but severely hampers the virus fitness. In this study, we first developed new genotype 1b (GT1b) subgenomic replicon cells, denoted PR52D4 and PR52D9, directly from a GT1b clinical isolate. Next, we obtained SOF-resistant and replication-competent PR52D4 replicon by culturing the replicon cells in the presence of SOF. Sequencing analysis showed that the selected replicon harbored two mutations K74R and S282T in NS5B. Reverse genetics analysis showed that while PR52D4 consisting of either single mutation K74R or S282T could not replicate efficiently, the engineering of the both mutations led to a replication-competent and SOF-resistant PR52D4 replicon. Furthermore, we showed that the K74R mutation could also rescue the replication deficiency of the S282T mutation in Con1, another GT1b replicon as well as in JFH1, a GT2a replicon. Structural modeling analysis suggested that K74R might help maintain an active catalytic conformation of S282T by engaging with Y296. In conclusion, we identified the combination of two NS5B mutations S282T and K74R as a novel RAS that confers a substantial resistance to SOF while retains the HCV replication capacity.

Current Status of Research on Small Extracellular Vesicles for the Diagnosis and Treatment of Urological Tumors.

Extracellular vesicles (EVs) are important mediators of communication between tumor cells and normal cells. These vesicles are rich in a variety of contents such as RNA, DNA, and proteins, and can be involved in angiogenesis, epithelial-mesenchymal transition, the formation of pre-metastatic ecological niches, and the regulation of the tumor microenvironment. Small extracellular vesicles (sEVs) are a type of EVs. Currently, the main treatments for urological tumors are surgery, radiotherapy, and targeted therapy. However, urological tumors are difficult to diagnose and treat due to their high metastatic rate, tendency to develop drug resistance, and the low sensitivity of liquid biopsies. Numerous studies have shown that sEVs offer novel therapeutic options for tumor treatment, such as tumor vaccines and tumor drug carriers. sEVs have attracted a great deal of attention owing to their contribution to in intercellular communication, and as novel biomarkers, and role in the treatment of urological tumors. This article reviews the research and applications of sEVs in the diagnosis and treatment of urological tumors.

The effects of selenium supplementation on antibody titres in patients with Hashimoto's thyroiditis.

INTRODUCTION: The objective of this study was to evaluate the effect of selenium supplementation on autoantibody titres, thyroid ultrasonography, and thyroid function in patients with Hashimoto's thyroiditis (autoimmune thyroiditis) and normal thyroid reference range. MATERIAL AND METHODS: A total of 100 patients were given 200 ug/d selenium yeast orally, their thyroid function, levels of serum selenium, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), and urine iodine were measured, and thyroid ultrasonography was performed before administration and three and six months afterwards, and the data were statistically analysed. RESULTS: The subjects exhibited a selenium deficiency before the administration of selenium, and the serum levels increased to moderate levels three and six months after the selenium supplementation (p < 0.05). The titres of TGAb decreased significantly in patients after six months of selenium supplementation (p < 0.05). In the high antibody group, TgAb decreased after 6 months compared with baseline (p = p < 0.05), and TPOAb decreased after 3 and 6 months of selenium supplementation compared with baseline (p < 0.05). CONCLUSION: In patients with autoimmune thyroiditis and normal thyroid reference range, there was a general selenium deficiency, but after six months of treatment it was shown that selenium supplementation may be effective in reducing the titres of TGAb and TPOAb.

LncRNA SNHG15 modulates gastric cancer tumorigenesis by impairing miR-506-5p expression.

The gastric cancer (GC) patients commonly have a poor prognosis due to its invasiveness and distant metastasis. Growing evidence proved that aberrant long non-coding RNAs (lncRNAs) expression contributes to tumor development and progression. LncRNA SNHG15 has been reported to be involved in many different kinds of cancer, while its role in GC remains unclear. In the present study, we found that SNHG15 was up-regulated in GC tissues and cell lines. Silencing SNHG15 suppressed proliferation migration, invasion and promoted apoptosis of AGS cells. More importantly, microRNA-506-5p (miR-506-5p) was predicted as a direct target of SNHG15 by binding its 3'-UTR and further verified using luciferase reporter assay. Meanwhile, the results of rescue experiments revealed that knockdown of miR-506-5p expression reversed the functional effects of SNHG15 silenced cell proliferation, migration, invasion and apoptosis. In conclusion, our findings revealed that SNHG15 executed oncogenic properties in GC progression through targeting miR-506-5p, which might provide a novel target for the GC treatment.

MicroRNA­129 inhibits colorectal cancer cell proliferation, invasion and epithelial­to­mesenchymal transition by targeting SOX4.

Colorectal cancer (CRC) is one of the most common digestive tract cancers and ~90% of CRC­related deaths are caused by metastasis. MicroRNA (miR)­129 has been reported to be involved in the metastasis of various malignant tumors. However, the role of miR­129 in CRC metastasis remains unclear. The purpose of the present study was to identify the potential functions and mechanisms of action of miR­129 in CRC progression. The expression of miR­129 and sex­determining region Y­related high­mobility group­box 4 (SOX4) was determined in CRC tissues or cell lines by reverse transcription­quantitative PCR, western blot or immunofluorescence assays. The mechanism underlying the role of miR­129 in CRC progression was assessed by MTT, wound healing, Transwell, western blot and dual­luciferase report assays. The results revealed that miR­129 was significantly decreased, whereas SOX4 was increased, in CRC tissues and cell lines. SW620 and SW480 cells exhibited a higher proliferation, migration and invasion capacity compared with NCM460 cells. miR­129 overexpression significantly inhibited cell proliferation, migration, invasion and epithelial­to­mesenchymal transition (EMT), and it activated the nuclear factor (NF)­κB signaling pathway in CRC cells, while the inhibition of miR­129 exerted opposite effects. Additionally, SOX4 was identified as a direct target gene of miR­129. Taken together, the findings of the present study suggested that miR­129 may act as a tumor suppressor in CRC by inhibiting CRC cell proliferation, migration, invasion and EMT, in part through targeting the 3'­untranslated region of SOX4 mRNA, and the mechanism may involve activation of the NF­κB signaling pathway.

The clinical significance of UBE2C gene in progression of renal cell carcinoma.

Renal cell carcinoma (RCC), with high morbidity and mortality, is one of the top ten serious cancers. Due to limited therapies and little knowledge about the mechanism underlying RCC, overall survival of RCC patients is poor. UBE2C is a member of ubiquitin modification system and promotes carcinogenesis in cancer, but its role in RCC is unknown. Based on the TCGA (The Cancer Genome Atlas) data, UBE2C was over-expressed in a total of 525 RCC tissues and displayed higher expression in advanced tissues (stage IV vs stage I, p<0.05). RT-qPCR and IHC analysis confirmed over-expression of UBE2C in 90 of clinical RCC tissues. Further, UBE2C was associated with clinical factors including TNM stage, gender, and pathological stage. And higher UBE2C expression predicted shorter overall survival and progression-free survival. Both univariate and multivariate COX analysis suggested UBE2C as a critical gene in RCC. Then GO and KEGG analysis showed that cell cycle and DNA replication pathways were two top signaling pathways affected by UBE2C. In vitro assay showed that knockdown of UBE2C in 786-O cells inhibited proliferation and migration significantly. Therefore, this study proves that UBE2C is an important gene in RCC and is essential to proliferation and migration of RCC.