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Accumulating pieces of evidence suggested that immunotypes may indicate the overall immune landscape in the tumor microenvironment, which were closely related to therapeutic response. The purpose of this study was to classify and define the immune subtypes of clear cell renal cell carcinoma (ccRCC), so as to authenticate the potential immune subtypes that respond to immunotherapy. Transcriptome expression profile and mutation profile data of ccRCC, as well as clinical characteristics used in this study were obtained from TCGA database. There were significant differences in the infiltration of immune cells, immune checkpoints, and antigens between ccRCC and para-cancerous tissues. According to immune components, patients with ccRCC were divided into three immune subtypes, with different clinical and molecular characteristics. Compared with other subtypes, IS2 showed cold immune phenotype, and was associated with better survival. IS1 represented complex immune populations and was associated with poor overall survival (OS) and progression free survival (PFS). Further analysis indicated that expression of immune checkpoints also differed among the three subtypes, and was abnormally up-regulated in IS3. Pathway enrichment analysis indicated that the mTOR signaling pathway was abnormally enriched in IS3, while the TGF_BETA, ANGIOGENESIS and receptor tyrosine kinase signaling pathways were abnormally enriched in IS2. Furthermore, there was an abnormal enrichment of the epithelial-to-mesenchymal transition (EMT) signaling pathway in IS1, which may be associated with a higher rate of metastasis. Finally, SCG2 was screened as a specific antigen of ccRCC, which was not only related to poor prognosis, but also significantly associated with immune cells and immune checkpoints. In conclusion, the immune subtypes of ccRCC may provide new insights into the tumor biology and the precise clinical management of this disease.

The podocyte is an important component of the glomerular filtration barrier, and maintenance of the integrity of its highly specified structure and function is critical for normal kidney function. Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are two crucial effectors of the Hippo signaling pathway, and recent studies have shown that podocyte-specific YAP deletion causes podocyte apoptosis and the development of focal segmental glomerulosclerosis followed by progressive renal failure. In the present study, we investigated a potential role of the YAP paralog TAZ in podocytes. TAZ was found to be constitutively active in podocytes, and mice with podocyte-specific deletion of TAZ (Taz(podKO)) developed proteinuria starting at 4 wk of age and had increased podocyte apoptosis. Using primary cultured podocytes or immortalized mouse podocytes from Taz(flox/flox) mice, we found that TAZ is a transcriptional activator for TEAD-dependent expression of synaptopodin, zonula occludens-1, and zonula occludens-2. This is the first study to determine that TAZ plays an important role in the maintenance of the structure and function of podocytes. NEW & NOTEWORTHY Podocytes play an important role in maintaining the integrity of the structure and function of the kidney. We observed that mice with selective deletion of transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes developed proteinuria. TAZ is constitutively active and critical for expression of synaptopodin, zonula occludens-1, and zonula occludens-2 in podocytes. The findings of this study implicate TAZ as an important mediator of podocyte structural integrity and provide further insights into the role of Hippo-Yes-associated protein/TAZ in podocyte biology.

The treatment of bone metastases is a thorny issue. Immunotherapy may be one of the few hopes for patients with unresectable bone metastases. Immune checkpoint inhibitors are the most commonly used immunotherapy drugs currently. In this review, the characteristics and interaction of bone metastases and their immune microenvironment were systematically discussed, and the relevant research progress of the immunological mechanism of tumor bone metastasis was reviewed. On this basis, we expounded the clinical application of immune checkpoint inhibitors for bone metastasis of common tumors, including non-small-cell lung cancer, renal cell carcinoma, prostate cancer, melanoma, and breast cancer. Then, the deficiencies and limitations in current researches were summarized. In-depth basic research on bone metastases and optimization of clinical treatment is needed.

In the present work, a double-pass continuous expansion extrusion forming (CEEF) process was proposed for an Al-Mg-Si alloy, in which the diameter of rods was gradually expanded. The microstructural evolution, mechanical properties and deformation characteristics were investigated by utilizing microstructural observations, mechanical testing and a finite element method coupled with a cellular automata model. The results showed that the strength and ductility of the double-pass CEEF processed Al-Mg-Si alloys were improved synchronously, especially in artificially aged alloys. The grain size of the processed Al-Mg-Si alloy rods was refined remarkably by continuous dynamic recrystallization (CDRX) and geometric dynamic recrystallization (GDRX), and the homogeneity of microstructure was gradually improved with increasing number of processing passes. The artificially aged alloy processed with double-pass CEEF and water quenching contained fine (sub)grains and high-density dislocations, which resulted in more needle-shaped β” precipitates and a larger precipitate aspect ratio than the as-received and air-cooled CEEF alloys owing to the different precipitation kinetics. The severe cumulate strain and microshear bands were found to accelerate CDRX and GDRX for grain refinement between adjacent positions of the parabolic metal flow due to the special temperature characteristics and large shear straining during the CEEF process.

Calcium oxalate (CaOx) is a major contributor to urolithiasis, one of the most common urological diseases. Our previous study has shown that Klotho rs3752472 polymorphism correlates with an increased risk of CaOx-related urolithiasis in human cohorts. This study aims to identify the effect of Klotho rs3752472 polymorphism on the renal epithelium injury caused by CaOx. A rat urolithiasis model was established and validated. Renal function was assessed, and histological examination was performed. The distribution and expression of Klotho in the rat model were detected by immunohistochemical staining and western blotting analysis. A renal epithelial cell line (HK2) was used and intervened by COM crystals with several concentrations and time points. Expression of Klotho and key mediators in Wnt/β-catenin pathway were assessed by Western blotting analysis. Wide-type and mutated plasmids of Klotho rs3752472 were added in the cell culture, and the activation of Wnt/β-catenin signaling was tested. Finally, Wide-type and mutated plasmids of Klotho rs3752472 were adoptively transferred to the rat model, and the expression of Klotho was verified. In the rat model, Klotho was mainly distributed in the renal tubular area, which significantly declined in the urolithiasis group. In vitro, COM crystals significantly inhibited the expression of Klotho and induced remarkable renal epithelial cell injury. The mutation of Klotho rs3752472 can notably enhance the expression of Klotho, as well as the protection from renal epithelial cell injury and the inhibition of Wnt/β-catenin signaling pathway. After adoptively transferred to the rat urolithiasis model, similar results were observed for the mutation of Klotho rs3752472. Klotho was significantly correlated with the renal epithelial cell injury induced by CaOx crystals. Furthermore, the mutation of Klotho rs3752472 can remarkably enhance the expression of Klotho in renal tissues and cells, and subsequently protect the renal epithelial cell from the formation of CaOx crystals through the inhibition of Wnt/β-catenin signaling pathway.

The primary treatment of tophaceous gout is to control the disease by pharmacological therapy. Additional surgical intervention is used to correct cosmetic deformation in joints or disabling functional disorder; however, one of its reported complications is hyperuricemia and recurrent attacks of pain. Objectives: to access the effectiveness of Low Intensity Laser therapy as addition to urate lowering treatment in patients with tophaceous gout, who underwent joints surgery in the Chengdu Rheumatism Hospital, in comparison to those patients who received only nonsurgical treatment. Subjects and methods. The effectiveness of Low Intensity Laser therapy (LILT) and urate lowering treatment in patients with tophaceous gout was investigated in 63 male patients of Chengdu Rheumatism hospital with tophaceous gout who underwent joints surgery. Control group was formed of 63 gout patients comparable in age and pre-treatment uric acid, who received non-surgical treatment.Results. Patients underwent surgery in one or two sessions, the most common lesion site being foot joints: toes (49.41%), ankle (39.68%) and knee (34.92%), with restricted mobility in the mentioned joints. Levels of CRP before the treatment were elevated in almost all patients (median 3.74 (0.2, 48.75) mg/L), regardless of the other comorbidities. Urate lowering therapy notably reduced the levels of CRP to 2.44 (0, 33.27) mg/L in study group and to 1.3 (0.13, 31.72) mg/L in controls. After surgery and following urate lowering therapy all patients noted functional improvement and reduction of pain. Decrease in serum urate levels were reported in 96.83% of patients in study group and in 93.65% of controls. There was no significant difference in serum UA between patients who underwent joint surgery and who didn’t. Patients, who in addition to surgery received Low-Level Laser Therapy therapy, had a lowest mean serum UA after treatment (280.93 ± 97.05 μmol/L), but due to wide range of variation, difference to other groups wasn’t statistically significant. Addition of laser therapy also helped to reduce the pain almost twice (0.56±0.56 compared to 1.04 ± 0.91). However, we haven’t registered notable anti-inflammatory influence of LILT. There was a weak direct link established between levels of serum UA and CRP after treatment, but in patients receiving laser therapy, CRP was elevated more often, compared to those who weren’t prescribed with LILT or controls. Conclusion. Arthroscopic shaving and other surgical approaches focused on joints often doesn’t affect system hyperuricemia in any way and can’t be viewed as a substitute to urate lowering therapy. However, our experience confirms that timely performed surgery contribute to functional improvement and reduction of pain in gout patients. Low Intensity Laser therapy doesn’t affect hyperuricemia or guarantee long-term systemic anti-inflammatory effect, but help to additionally relieve pain in joints and thus enhance treatment effect and quality of patients’ life.

The mechanical properties and castability of Al-Si-based alloys can be remarkably improved by adding Al-Sr master alloy, which modifies the structure and morphology of eutectic silicon. The size of Al4Sr phases in Al-Sr master alloy has been found to take key effect in Sr-modification. To obtain optimized processing parameters and understand the refinement mechanisms of Al4Sr phases during plastic deformation, the hot compression and industrial extrusion characteristics of an as-cast Al-10Sr master alloy were systematically investigated in this work. The results showed that the flow behavior of the Al-10Sr master alloy can be well described by a constitutive equation with the hot deformation activation energy of 222.23 kJ/mol. The obtained optimum processing region was located at temperature of 460–530 °C and strain rate of 0.2–1 s−1 from the established processing maps. During hot compression testing, plastic deformation mainly occurred in soft Al matrix and the Al4Sr phases were slightly broken. During industrial extrusion process, the Al4Sr phases were refined effectively based on the above optimum processing conditions. Comparing to conventional extrusion process, repetitive Conform process showed better ability in refining Al4Sr phases. After three repetitive Conform passes, the length of Al4Sr phases decreased from 80 to 11 μm and the width decreased from 25.6 to 8.3 μm, and the Al4Sr phases were also distributed homogeneously. The in-depth refinement mechanisms of Al4Sr phases during plastic forming were also discussed based on microstructural examinations and finite element analysis.

An increasing number of studies suggest that the renal proximal tubule is a site of injury in diabetic nephropathy (DN), and progressive renal tubulointerstitial fibrosis is an important mediator of progressive kidney dysfunction in DN. In this study, we observed increased expression and activation of YAP (yes-associated protein) in renal proximal tubule epithelial cells (RPTC) in patients with diabetes and in mouse kidneys. Inducible deletion of Yap specifically in RPTC or administration of the YAP inhibitor verteporfin significantly attenuated diabetic tubulointerstitial fibrosis. EGFR-dependent activation of RhoA/Rock and PI3K-Akt signals and their reciprocal interaction were upstream of proximal tubule YAP activation in diabetic kidneys. Production and release of CTGF in culture medium were significantly augmented in human embryonic kidney (HEK)-293 cells transfected with a constitutively active YAP mutant, and the conditioned medium collected from these cells activated and transduced fibroblasts into myofibroblasts. This study demonstrates that proximal tubule YAP-dependent paracrine mechanisms play an important role in diabetic interstitial fibrogenesis; therefore, targeting Hippo signaling may be a therapeutic strategy to prevent the development and progression of diabetic interstitial fibrogenesis.

Avian paramyxovirus 13 (APMV-13), formerly known as Avian orthoavulavirus 13, is found scatteredly in wild birds around the world. Although four complete genome sequences of APMV-13 had been identified since the first discovery in Japan in 2003, the information available on the genetic variation and biological characteristics of APMV-13 is still limited. In the present study, we isolated six APMV-13 strians from fecal samples of wild migratory waterfowls during annual (2013-2018) viral surveillance of wild bird populations from wetland in China. The phylogenetic analyses showed that they had very close relationship in HN and F genes. The molecular clock estimations also showed a low evolutionary rate of APMV-13. However, there are obvious sequence differences among these strains. Bean goose/Hubei/V97-1/2015 is 1,953 nt in size (ORF, 1, 776 nt), which is a unique size and longer than other reported APMV-13 strians. Additionally, Swan goose/Hubei/VI49-1/2016 has four repeats of conserved sequences “AAAAAT” in the 5’-end trailer, which is unprecedented in the APMV-13. These findings reveal the existence of novel variants within APMV-13, which highlights the importance of continuous monitoring the specific species of APMVs.

In the period from 2011 to 2020, 4 large-scale population-based studies were conducted to identify gout in patients with obstructive sleep apnea (OSA), as well as one study to detect the frequency of sleep apnea in patients with gout.All recently published studies confirm connection between the development of OSA and an increase in the level of uric acid in blood serum, both against the background of clinically significant gout arthritis and without it. However, only one big population-based study during 2010 — 2020 assessed the development of OSA against the background of gout. According to this study, incidence of OSA was 14.3 per 1.000 person-years in patients with gout, compared with 3.9 per 1.000 person-years without gout, with HR = 2.07 (95 % CI 2.00 — 2.15 %), which is significantly higher than the incidence of gout in patients with OSA, even taking into account hypertension and hyperlipidemia.The data from these studies showed an undoubted relationship between the two diseases, but to date it is not completely known how much it is due to common risk factors and how interlinked the development mechanisms are. Older age and restricted mobility put patients with gout at a significant risk during OSA episodes. In cases where the treatment of both diseases is conducted independently, the volume of drug therapy and the likelihood of developing negative side effects increase. In this regard, it is necessary to monitor patients with gout who develop sleep apnea differently to gout only patients, as well as to prescribe adequate treatment for both diseases.In our review, we aimed to show the most recent information on the mechanisms of gout-OSA development, shared pathways, targets and biomarkers, emphasizing the likely ways that cause the progression of OSA in patients with gout. In addition, analysis of the latest publications to date showed nonuniformity in study subjects, allowing to identify different subtypes of gout-OSA patients: combined with metabolic syndrome (most common), combined with renal dysfunction without obesity, and others (dietary violations, genetic diseases, acidosis)., У період з 2011 до 2020 р. проведено чотири масштабних демографічних дослідження для виявлення подагри у пацієнтів з обструктивним апное сну (ОАС), а також одне дослідження для виявлення захворюваності апное сну у пацієнтів з подагрою. Всі нещодавно опубліковані роботи підтверджують зв’язок між розвитком ОАС і збільшенням рівня сечової кислоти в сироватці крові як на тлі клінічно значущого подагричного артриту, так і без нього. Однак лише в одному великому дослідженні за останні 10 років оцінено розвиток ОАС на тлі подагри. Згідно з отриманими даними захворюваність на ОАС становила 14,3 на 1000 людино-років у пацієнтів з подагрою порівняно із 3,9 на 1000 людино-років без подагри (відношення ризиків — 2,07, 95 % довірчий інтервал — 2,00 — 2,15), що значно вище, ніж захворюваність на подагру у пацієнтів з ОАС, навіть з урахуванням гіпертонії та гіперліпідемії.Ці дослідження підтверджують зв’язок між двома захворюваннями, але не відомо, наскільки це зумовлено спільними чинниками ризику і як взаємопов’язані механізми розвитку. Старший вік та обмежена мобільність у пацієнтів з подагрою значно підвищують ризик для життя під час епізодів ОАС. У випадках, коли лікування обох захворювань проводиться паралельно, збільшуються обсяг медикаментозної терапії та ризик негативних побічних ефектів. Це зумовлює необхідність застосування диференційованого підходу до спостереження за пацієнтами з комбінацією подагра-ОАС, яке відрізняється від спостереження за пацієнтами з ізольованою подагрою, а також адекватного лікування обох захворювань.В огляді наведено нову інформацію щодо механізмів розвитку комбінації подагра-ОАС, зокрема щодо спільних шляхів, мішеней та біомаркерів, а також імовірні умови, за яких ОАС прогресує у пацієнтів з подагрою. В останніх публікаціях існує деяка суперечливість клінічних даних, що дає змогу виділити різні підтипи комбінації пацієнтів з подагрою-ОАС: в поєднанні з метаболічним синдромом (найпоширеніший підтип), з дисфункцією нирок без ожиріння та інші (дієтичні розлади, генетичні захворювання, ацидоз)., В период с 2011 по 2020 г. проведено 4 масштабных демографических исследования в целях выявления подагры у пациентов с обструктивным апноэ сна (ОАС), а также одно исследование для выявления частоты сонного апноэ у пациентов с подагрой. Все недавно опубликованные работы подтверждают связь между развитием ОАС и повышением уровня мочевой кислоты в сыворотке крови как на фоне клинически значимого подагрического артрита, так и без него. Однако только в одном большом исследовании за последние 10 лет оценено развитие ОАС на фоне подагры. Согласно полученным данным, заболеваемость ОАС составила 14,3 на 1000 человеко-лет у пациентов с подагрой по сравнению с 3,9 на 1000 человеко-лет без подагры (отношение рисков — 2,07, 95 % доверительный интервал — 2,00 — 2,15), что значительно выше, чем заболеваемость подагрой у пациентов с ОАС, даже с учетом гипертонии и гиперлипидемии.Данные исследований подтверждают связь между двумя заболеваниями, но не известно, насколько это обусловлено общими факторами риска и насколько взаимосвязаны механизмы развития. Пожилой возраст и ограниченная подвижность у пациентов с подагрой значительно повышают риск для жизни во время эпизодов ОАС. В тех случаях, когда лечение обоих заболеваний проводится параллельно, увеличиваются объем медикаментозной терапии и риск развития негативных побочных эффектов. Это обуславливает необходимость применения дифференцированного подхода к наблюдению за пациентами с комбинацией подагра-ОАС, которое отличается от наблюдения за пациентами с изолированной подагрой, а также адекватного лечения обоих заболеваний.В обзоре приведена новая информация о механизмах развития комбинации подагры-ОАС, включая общие пути, мишени и биомаркеры, и вероятных условиях, которые вызывают прогрессирование ОАС у пациентов с подагрой. В последних публикациях имеется противоречивость клинических данных, позволяющая выявить разные подтипы комбинации пациентов с подагрой-ОАС: в сочетании с метаболическим синдромом (наиболее распространенный тип), с дисфункцией почек без ожирения и другие (диетические нарушения, генетические заболевания, ацидоз).

The epidermal growth factor receptor (EGFR) is the prototypical member of a family of membrane-associated intrinsic tyrosine kinase receptors, the ErbB family. EGFR is activated by multiple ligands, including EGF, transforming growth factor (TGF)-α, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen. EGFR is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation in both development and normal physiology, as well as in pathophysiological conditions. In addition, EGFR transactivation underlies some important biologic consequences in response to many G protein-coupled receptor (GPCR) agonists. Aberrant EGFR activation is a significant factor in development and progression of multiple cancers, which has led to development of mechanism-based therapies with specific receptor antibodies and tyrosine kinase inhibitors. This review highlights the current knowledge about mechanisms and roles of EGFR in physiology and disease.

Increasing studies have suggested that the renal proximal tubule is a site of injury in diabetic nephropathy (DN), and progressive renal tubulointerstitial fibrosis is an important mediator of progressive kidney dysfunction in DN. In this study, we observed increased expression and activation of YAP (Yes-associated protein) in renal proximal tubule epithelial cells (RPTC) in diabetic patient and mouse kidneys. Inducible deletion of Yap specifically in RPTC or administration of the YAP inhibitor verteporfin significantly attenuated diabetic tubulointerstitial fibrosis. EGFR-dependent activation of RhoA/Rock and PI3K-Akt signals and their reciprocal interaction were upstream of proximal tubule YAP activation in diabetic kidneys. Production and release of CTGF in culture medium were significantly augmented in HEK293 transfected with a constitutively active YAP mutant, and the conditioned medium collected from these cells activated and transduced fibroblasts into myofibroblasts. This study demonstrates that proximal tubule YAP dependent paracrine mechanisms play an important role in diabetic interstitial fibrogenesis; therefore, targeting Hippo signaling may be a therapeutic strategy to prevent the development and progression of diabetic interstitial fibrogenesis.

BACKGROUND The purpose of this study was to use kinematic gait analysis, to evaluate the clinically curative effects of minimally invasive needle-knife scope therapy in the treatment of rheumatoid arthritis (RA) of the knee joint. METHODS A total of 32 patients with RA of the knee joint were treated with minimally invasive needle-knife scope therapy. All patients were assessed with a kinematic gait analysis system, and then analyzed and compared the measurements with the kinematic gait performances of 28 healthy middle-aged and elderly participants. RESULTS Before receiving the therapy, the ranges of motion (ROMs) of the patients' tibial inward and outward rotation, flexion and extension, anterior and posterior displacement of the tibia, and tibial upward and downward movement were all smaller than those of the healthy middle-aged and elderly group (P

BACKGROUND Patients with primary Sjogren's syndrome (pSS) often suffer from sleep disturbance. Studies suggest it may be related to symptoms, including xerostomia and dry eyes. Clinical studies have confirmed that hydroxychloroquine (HCQ) has a definite effect on pSS, but there is no clear report about its effect on sleep disorders in pSS patients. METHODS A total of 383 pSS patients were enrolled and followed up. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of the patients, and the World Health Organization Quality of Life Brief Version (WHOQOL-BREF) scale was used to evaluate the quality of life (QoL) of patients. The European League assessed the patient's condition against Rheumatism Sjogren's syndrome patients reported index (ESSPRI). According to PSQI, patients were divided into two groups: good sleep group (GSG) and poor sleep group (PSG). The risk factors of sleep disorder are analyzed by univariate and multivariate analysis. The patients were further divided into HCQ-administered group and non-administered group, and the differences of baseline characteristics and outcome in follow-up between the two groups were compared. RESULTS There were 208 patients with PSG (54.3%) and 175 patients with GSG (45.7%). Further, there is no statistical difference between the two groups in baseline data. Also, there were 112 cases (53.8%) and 118 cases (67.4%) taking HCQ in the two groups, respectively, P=0.007. Univariate and multivariate analysis showed that long-term use of HCQ, menopause, and income were related to sleep quality. The patients were divided into the HCQ-administered group (n=230) and non-administered group (n=153) according to whether they took HCQ. One hundred eighteen patients (51.3%) in the HCQ-administered group had a good sleep, and 58 patients in the non- administered group had a good sleep (37.9%), P

To investigate the influence of castration on insulin resistance, quality of life and immune function of prostate cancer (PCa) patients.A total of 57 PCa patients definitely diagnosed via prostate biopsy underwent bilateral orchiectomy. No patient had history of diabetes mellitus before operation. The hemoglobin, leukocyte count, platelet count, albumin and alkaline phosphatase in the blood before operation and at 1 year after operation were analyzed using a full-automatic biochemistry analyzer, and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in the peripheral blood were calculated.The levels of serum testosterone (T) and free testosterone (FT) in PCa patients declined remarkably at 1 month after castration. Compared with those before operation, the levels of serum T and FT were decreased significantly at 1, 2, 4 and 8 months as well as 1 year after castration. The levels of triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were elevated gradually with the prolongation of time after operation. The level of high-density lipoprotein cholesterol (HDL-C) displayed an apparent rising trend from 2 months after surgical castration. The results of flow cytometry indicated that the levels of cluster of differentiation (CD) 4+ and CD4+/CD8+ were lowered markedly, while that of CD8+ was raised significantly in comparison with those before castration (p0.05) After castration, both fasting blood glucose and fasting insulin were increased obviously in the patients (p0.05). The 2 h postprandial blood glucose and insulin were raised distinctly at 1 month after castration (p0.05). The insulin resistance index was increased persistently and prominently (p0.05).The treatment of PCa through castration can aggravate the insulin resistance, reduce the immune function and improve the patient quality of life.

Objective. To explore the optimal time points for deep brain stimulation (DBS) on the treatment of morphine addiction and its possible mechanisms by investigating how high-frequency stimulation (HFS) in bilateral nucleus accumbens (NAc) at different time points influences the addictive behaviors of rats with drug addiction. Methods. The rats were randomly divided into extinction stimulation group (n = 20) and postextinction stimulation group (n = 20). Ten rats in the extinction stimulation group were treated using 120 Hz HFS during extinction stage while another 10 rats with pseudostimulation were served as control group. The CPP scores were evaluated at the second day after intervention, with total 9 sections accomplished. The CPP scores were evaluated at the second day of the intervention. In the postextinction stimulation group, 120 Hz HFS was intervened during the postextinction stage in 10 experimental rats and pseudostimulation was performed in 10 control rats. Stimulation was performed for 7 days continuously, and a small dose of morphine was administrated to induce relapse after the postextinction period. Results. During the extinction phase, CPP scores after HFS were significantly higher. During the postextinction phase, relapse CPP scores after HFS were dramatically lower. Conclusion. HFS of bilateral NAc inhibits the extinction of addictive behavior during the extinction phase, and HFS during the postextinction period suppresses relapse of drug seeking behavior.

Glioma causes great harm to people worldwide. Systemic coexpression analysis of this disease could be beneficial for the identification and development of new prognostic and predictive markers in the clinical management of glioma. In this study, we extracted data sets from the Gene Expression Omnibus data set by using "glioma" as the keyword. Then, a coexpression module was constructed with the help of Weighted Gene Coexpression Network Analysis software. Besides, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the genes in these modules. As a result, the critical modules and target genes were identified. Eight coexpression modules were constructed using the 4,000 genes with a high expression value of the total 141 glioma samples. The result of the analysis of the interaction among these modules showed that there was a high scale independence degree among them. The GO and KEGG enrichment analyses showed that there was a significant difference in the enriched terms and degree among these eight modules, and module 5 was identified as the most important module. Besides, the pathways it was enriched in, hsa04510: Focal adhesion and hsa04610: Complement and coagulation cascades, were determined as the most important pathways. In summary, module 5 and the pathways it was enriched in, hsa04510: Focal adhesion and has 04610: Complement and coagulation cascades, have the potential to serve as biomarkers for patients with glioma.

SUMMERY Shunt thrombosis remains a major cause of morbidity and mortality, especially during the initial palliation for single-ventricle physiology. The authors present evidence that the P2Y12 inhibitor cangrelor may fill a therapeutic void in thromboprophylaxis. They base this theory on results showing that platelets from neonatal patients with cyanotic congenital heart disease have a robust response to adenosine diphosphate and are amenable to P2Y12 inhibition with cangrelor. Unique to this study was their ability to establish drug efficacy in an avatar mouse model that permits the in vivo evaluation of human platelet–mediated thrombus formation illustrating that this P2Y12 inhibitor yields the intended biological response., Graphical abstract

Background. Stimulation-induced transient nonmotor psychiatric symptoms (STPSs) are side effects following bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients. We designed algorithms which (1) determine the electrode contacts that induce STPSs and (2) provide a programming protocol to eliminate STPS and maintain the optimal motor functions. Our objective is to test the effectiveness of these algorithms. Materials and Methods. 454 PD patients who underwent programming sessions after STN-DBS implantations were retrospectively analyzed. Only STPS patients were enrolled. In these patients, the contacts inducing STPS were found and the programming protocol algorithms used. Results. Eleven patients were diagnosed with STPS. Of these patients, two had four episodes of crying, and two had four episodes of mirthful laughter. In one patient, two episodes of abnormal sense of spatial orientation were observed. Hallucination episodes were observed twice in one patient, while five patients recorded eight episodes of hypomania. There were no statistical differences between the UPDRS-III under the final stimulation parameter (without STPS) and previous optimum UPDRS-III under the STPSs (p=1.000). Conclusion. The flow diagram used for determining electrode contacts that induce STPS and the programming protocol employed in the treatment of these symptoms are effective.

Introduction Poor cell uptake and incomplete intracellular drug release are the two major challenges for polymeric prodrug-based drug delivery systems (PPDDSs) in cancer treatment. Methods Herein, a PPDDS with pH-induced surface charge-reversal and reactive oxygen species (ROS) amplification for ROS-triggered self-accelerating drug release was developed, which was formed by encapsulating a ROS generation agent (vitamin K3 (VK3)) in pH/ROS dual-sensitive polymetric prodrug (PEG-b-P(LL-g-TK-PTX)-(LL-g-DMA)) based micelle nanoparticles (denoted as PVD-NPs). Results The surface charge of the PVD-NPs can change from negative to positive for enhanced cell uptake in response to tumor extracellular acidity pH. After internalization by cancer cells, PVD-NPs demonstrate dual drug release in response to intracellular ROS-rich conditions. In addition, the released VK3 can produce ROS under the catalysis by NAD(P)H:quinone oxidoreductase-1, which facilitates tumor-specific ROS amplification and drug release selectively in cancer cells to enhance chemotherapy. Conclusion Both in vitro and in vivo experiments demonstrated that the PVD-NPs showed significant antitumor activity in human prostate cancer.

Due to the complicated structure and control difficulties of the HTS-SMES equipment, it is necessary to design a real-time monitoring system which has perfect function, friendly interface and simple operation, so as to realize monitoring various electrical and non-electrical quantity. This paper mainly designed the monitoring interface and communication program based on LabVIEW. Among them, the monitoring system includes data acquisition, waveform display, control strategy and data storage. Finally, a set of HTS-SMES monitoring systems and equipment were developed and functional tests were carried out, the results show that the monitoring system can effectively detect the data of each channel, monitor and control two SMES device, implement multi-target control strategy, also meet the predetermined system functions.

As the user load continues to increase, the safety accidents caused by the overload of the transformer frequently occur. In order to improve the safety and stability of the transformer operation, this paper conducts an in-depth study on the overload capability of the transformer based on the hot spot temperature model. When the oil-immersed distribution transformer is overloaded, the internal temperature of the transformer rises, causing insulation aging and reducing the service life. This paper first introduces the characteristics of distribution transformers in different types of loads, and analyzes the changes occurring inside the transformers during overload operation, and then based on the hot water temperature calculation model in GB/T 1094. 7-2008 standard, from the perspective of operating temperature and heat aging, The research and analysis of the overload capacity of the distribution transformer is carried out, and the relationship between the allowable overload time of the transformer and the allowable overload multiple is obtained, and the theoretical analysis of the life loss is made.

A novel unified power quality controller based on magnetic flux compensation is proposed in this paper. The principle of the novel unified power quality controller is addressed, where it is based on controllable harmonic and fundamental impedance of linear transformer. The primary winding of series transformer can exhibit variable impedance to fundamental current and large magnetic impedance to harmonic current. The equivalent fundamental impedance of shunt transformer is nearly zero to harmonic current and continuously adjustable reactance to fundamental current which can compensate reactive power. Thus, the harmonic current is lead to flow into shunt transformer circuit. Besides, the variable impedance to fundamental current of series transformer can limit fault current. The simulation results built on MATLAB/Simulink verify the effectiveness of the proposed novel unified power quality controller.

Background Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. Methods To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. Results In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. Conclusions These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.

Chen Xu,1,* Ri-jin Song,2,* Pei Lu,2,* Jian-chun Chen,1 Yong-qiang Zhou,1 Gang Shen,1 Min-jun Jiang,1 Wei Zhang2 1Department of Urology, The First People’s Hospital of Wujiang City, Suzhou, China; 2Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China *These authors contributed equally to this work Aim: To significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study. Materials and methods: The nanocarrier was constructed by conjugating 3,3'-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment. Results: Compared to the control group, the invitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group. Conclusion: These findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy. Keywords: combination therapy, charge reversal, redox-responsive, pH-responsive

The mandarin orange canning industry consumes a large quantity of fresh water, and discharges a similarly high volume of wastewater. If insufficiently treated, this effluent can seriously impact the environment. Water conservation and wastewater minimization can facilitate wastewater treatment. In this study, four filtration treatments were investigated to improve effluent quality from the sorting/grading operation at two mandarin canning factories for the purpose of water reclamation. The combined treatment consisting of a bag filter, activated carbon filter and precision filter yielded the best water quality improvement. The resulting elimination ratios for Chroma, turbidity, total sugars, pectin, and chemical oxygen demand were individually 27.64%, 55.56%, 22.55%, 21.35% and 42.22%. The treated water was clear and free of odor, and the pH was 6.7 ± 0.2. When the residual chlorine concentration was greater than 0.5 mg/L, the total bacterial count in the treated effluent was less than 10 CFU/mL and the coliform group was not detected. Further, the physicochemical and microbial parameters of the treated water conformed to the Chinese Standard of Drinking Water Quality except for chemical oxygen demand (38.60 ± 7.00 mg/L), which was mainly due to the saccharides in oranges. The results for the combined treatment of chlorination, bag filter and activated carbon filter at pilot scale indicated the feasibility of water reclamation during the sorting/grading step of full scale mandarin orange processing. At an average usage of 3500 t/d fresh water for a mandarin canning production line having a daily output of 100 metric tons, the water saving efficiency achieved with this combined treatment could reach 34.28%. A factory of this capacity can pay back the required investment for the treatment technology in the third production season, and will simultaneously save 373,840 Yuan. The cost-effective approach to water reclamation identified in this study minimized wastewater generation and facilitated clean production in a mandarin orange canning factory. The results indicate that a recycling process to enable water re-use can be implemented in food processing industries if it will not affect food safety. Such an approach to water management is beneficial to the coordinated and sustained development of economy, society, resources and environment.

The development of distributed new energy and electric car and the characteristic of open-loop design closed-loop operation both increase power imbalance between feeders in distribution networks. SNOP(Soft Normally Open Points) do great job in solving power imbalance problems. The parameters of main circuit have huge influence on performance and stability of SNOP. This paper researches selection principles of important elements in main circuit, and combines with typical scenarios to optimally design circuit parameters. Considering optimization goals and restrictions, we use optimization calculation to get optimal parameters.

In this paper, a principle of microgrid variable reactor with filtering function using transformer and inverter is proposed to solve the problems of control deviation caused by harmonic pollution in microgrid and the variable reactor's discontinuous adjustment. Firstly, it introduces the principle of variable reactor. A transformer with air gap is chosen and the voltage of the transformer's primary winding is detected and functioned as the reference signal after filtering, phase shift and superposition. A voltage source PWM inverter is applied to produce a voltage source, which follows the reference signal and energizes the secondary winding of the transformer so that the equivalent impedance of primary winding can present a four-quadrant continuously variable impedance to fundamental and infinite impedance to harmonic. The stability condition is also analyzed. The simulation results show the effectiveness and excellent filtering characteristic of the proposed microgrid variable reactor with filtering function.