BCKDK Modification Enhances the Anticancer Efficacy of CAR-T Cells by Reprogramming Branched Chain Amino Acid Metabolism.

Altered Branched Chain Amino Acids (BCAA), including leucine, isoleucine and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of Chimeric Antigen Receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and deceasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cells treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and the increasing proportion of CAR-T cells in peripheral circulation. BCKDK-KO CAR-T cells treatment resulted in shorter survival and decreasing percentage of CAR-T cells in peripheral circulation. In conclusion, BCKDK engineered CAR-T cells exert distinct phenotype for the superior anticancer efficiency.

hnRNPU is required for spermatogonial stem cell pool establishment in mice.

The continuous regeneration of spermatogonial stem cells (SSCs) underpins spermatogenesis and lifelong male fertility, but the developmental origins of the SSC pool remain unclear. Here, we document that hnRNPU is essential for establishing the SSC pool. In male mice, conditional loss of hnRNPU in prospermatogonia (ProSG) arrests spermatogenesis and results in sterility. hnRNPU-deficient ProSG fails to differentiate and migrate to the basement membrane to establish SSC pool in infancy. Moreover, hnRNPU deletion leads to the accumulation of ProSG and disrupts the process of T1-ProSG to T2-ProSG transition. Single-cell transcriptional analyses reveal that germ cells are in a mitotically quiescent state and lose their unique identity upon hnRNPU depletion. We further show that hnRNPU could bind to Vrk1, Slx4, and Dazl transcripts that have been identified to suffer aberrant alternative splicing in hnRNPU-deficient testes. These observations offer important insights into SSC pool establishment and may have translational implications for male fertility.

BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly.

Teratozoospermia is a significant cause of male infertility, but the pathogenic mechanism of acephalic spermatozoa syndrome (ASS), one of the most severe teratozoospermia, remains elusive. We previously reported Spermatogenesis Associated 6 (SPATA6) as the component of the sperm head-tail coupling apparatus (HTCA) required for normal assembly of the sperm head-tail conjunction, but the underlying molecular mechanism has not been explored. Here, we find that the co-chaperone protein BAG5, expressed in step 9-16 spermatids, is essential for sperm HTCA assembly. BAG5-deficient male mice show abnormal assembly of HTCA, leading to ASS and male infertility, phenocopying SPATA6-deficient mice. In vivo and in vitro experiments demonstrate that SPATA6, cargo transport-related myosin proteins (MYO5A and MYL6) and dynein proteins (DYNLT1, DCTN1, and DNAL1) are misfolded upon BAG5 depletion. Mechanistically, we find that BAG5 forms a complex with HSPA8 and promotes the folding of SPATA6 by enhancing HSPA8's affinity for substrate proteins. Collectively, our findings reveal a novel protein-regulated network in sperm formation in which BAG5 governs the assembly of the HTCA by activating the protein-folding function of HSPA8.

Ferritin-nanocaged aggregation-induced emission nanoaggregates for NIR-II fluorescence-guided noninvasive, controllable male contraception.

Controllable contraception in male animals was demonstrated through the utilization of gold nanorods' photothermal effect to accomplish mild testicular hyperthermia. However, the challenges arising from testicular administration and the non-biodegradability of nanoparticles hinder further clinical implementation. Therefore, a straightforward, non-invasive, and enhanced contraception approach is required. This study explores the utilization of human heavy chain ferritin (HFn) nanocarriers loaded with aggregation-induced emission luminogens (AIEgens) for noninvasive, controllable male contraception guided by Near-Infrared-II (NIR-II) fluorescence imaging. The HFn-caged AIEgens (HFn@BBT) are delivered via intravenous injection and activated by near-infrared irradiation. Lower hyperthermia treatment induces partial damage to the testes and seminiferous tubules, reducing fertility indices by approximately 100% on the 7th day, which gradually recovers to 80% on the 60th day. Conversely, implementation of elevated hyperthermia therapy causes total destruction of both testes and seminiferous tubules, leading to a complete loss of fertility on the 60th day. Additionally, the use of AIEgens in NIR-II imaging offers improved fluorescence efficiency and penetration depth. The findings of this study hold significant promise for the advancement of safe and effective male contraceptive methods, addressing the need for noninvasive and controllable approaches to reproductive health and population control.

Crucial computed tomography and magnetic resonance imaging findings of fallopian tubal tuberculosis for diagnosis: a retrospective study of 26 cases.

Background: Fallopian tubal tuberculosis (FTTB), which typically presents with non-specific clinical symptoms and mimics ovarian malignancies clinically and radiologically, often affects young reproductive females and can lead to infertility if not promptly managed. Early diagnosis by imaging modalities is crucial for initiating timely anti-tuberculosis (anti-TB) treatment. Currently, comprehensive radiological descriptions of this relatively rare disease are limited. We aimed to comprehensively investigate the computed tomography (CT) and magnetic resonance imaging (MRI) characteristics of FTTB in patients from the Kashi area, which has the highest incidence of TB in China, to extend radiologists' understanding of this disease. Methods: We conducted a retrospective cross-sectional study of 26 patients diagnosed with FTTB at the First People's Hospital of Kashi Area. All the patients underwent abdominal and pelvic contrast-enhanced CT examinations and/or pelvic contrast-enhanced MRI from January 2017 to June 2022. The imaging findings were evaluated in consensus by two experienced radiologists specialized in abdominal and pelvic imaging. The evaluated sites included the fallopian tubes, ovaries, peritoneum, mesentery, retroperitoneal nodes, and parailiac nodes. The patient characteristics are reported using descriptive statistics. The patient imaging results are presented as percentages. The normally distributed continuous variables are reported as the mean ± standard deviation (SD), and otherwise as the median with the interquartile range (IQR). Results: The median age of the patients was 27 years (IQR: 25-34 years). Bilateral involvement of the fallopian tubes was observed in all patients. The tubal wall appeared coarse with tiny intraductal nodules in 96% (25 of 26) of the patients. The mean CT value of the tubal contents was 34 Hounsfield units (HUs; SD: 3.3 HUs). Ascites was present in 92% (24 of 26) of the patients, with 20 patients showing encapsulated effusion. Among these patients, 20 exhibited the highest CT values of ascites (>20 HUs). Linear enhancement of the parietal peritoneum was observed in 88% (23 of 26) of the patients, of whom 22 had peritoneal nodules measuring a median diameter of 0.4 cm (IQR: 0.3-0.6 cm). Eight patients had retroperitoneal and parailiac nodal enlargement, of whom two showed nodal necrosis, and none displayed nodal calcification. Conclusions: FTTB is consistently accompanied by tuberculous peritonitis. FTTB typically presents with tubal dilation, and coarseness and nodules in the lumen, as well as intraductal caseous material and calcification. Tuberculous peritonitis exhibits high-density ascites, peritoneal adhesion, linear enhancement of the parietal peritoneum, and tiny peritoneal nodules. The co-occurrence of these features strongly suggests a diagnosis of FTTB.

Glycan-Lectin interactions between platelets and tumor cells drive hematogenous metastasis.

Glycosylation is a ubiquitous cellular or microenvironment-specific post-translational modification that occurs on the surface of normal cells and tumor cells. Tumor cell-associated glycosylation is involved in hematogenous metastasis. A wide variety of tumors undergo aberrant glycosylation to interact with platelets. As platelets have many opportunities to engage circulating tumor cells, they represent an important avenue into understanding the role glycosylation plays in tumor metastasis. Platelet involvement in tumor metastasis is evidenced by observations that platelets protect tumor cells from damaging shear forces and immune system attack, aid metastasis through the endothelium at specific sites, and facilitate tumor survival and colonization. During platelet-tumor-cell interactions, many opportunities for glycan-ligand binding emerge. This review integrates the latest information about glycans, their ligands, and how they mediate platelet-tumor interactions. We also discuss adaptive changes that tumors undergo upon glycan-lectin binding and the impact glycans have on targeted therapeutic strategies for treating tumors in clinical settings.

Tumor hematogenous metastasis is a serious threat to the survival and prognosis of patients, and a variety of factors help this process to occur, and platelets are also involved. During tumor cell metastasis, platelets can adhere to each other and tumor cells, a phenomenon that leads to the immunity of tumor cells from various threats in metastasis, including immune attacks, shearing forces, etc. Scientists have shown that the adhesion effect between platelets and tumor cells is often dependent on various types of sugars, which are not the sugars we ingest. These sugars often appear as glycosylation modifications on the proteins of the cells, including normal glycosylation modifications and some abnormal structures that only appear on tumor cells, and their ligands, lectins, are also present on the surface of the tumor cells or platelets. Their combination results in the better adaptation of tumor cells to the metastatic process, where proteins such as P-selectin, CLEC-2, and Galectins have been more studied. Focusing on Glycan-Lectin interactions between platelets and tumor cells, related studies help us to further understand tumor metastasis, and intervene in this binding and develop related drugs with great potential.

Optimal Size Threshold for MRI-Detected Retropharyngeal Lymph Nodes to Predict Outcomes in Nasopharyngeal Carcinoma: A Two-Center Study.

BACKGROUND. Retropharyngeal lymph node (RLN) metastases have profound prognostic implications in patients with nasopharyngeal carcinoma (NPC). However, the AJCC staging system does not specify a size threshold for determining RLN involvement, resulting in inconsistent thresholds in practice. OBJECTIVE. The purpose of this article was to determine the optimal size threshold for determining the presence of metastatic RLNs on MRI in patients with NPC, in terms of outcome predictions. METHODS. This retrospective study included 1752 patients (median age, 46 years; 1297 men, 455 women) with NPC treated by intensity-modulated radiotherapy (RT) from January 2010 to March 2014 from two hospitals; 438 patients underwent MRI 3-4 months after treatment. Two radiologists measured the minimal axial diameter (MAD) of the largest RLN for each patient using a consensus process. A third radiologist measured MAD in 260 randomly selected patients to assess interobserver agreement. Initial ROC and restricted cubic spline (RCS) analyses were used to derive an optimal MAD threshold for predicting progression-free survival (PFS). The threshold's predictive utility was assessed in multivariable Cox regression analyses, controlling for standard clinical predictors. The threshold's utility for predicting PFS and overall survival (OS) was compared with a 5-mm threshold using Kaplan-Meier curves and log-rank tests. RESULTS. The intraclass correlation coefficient for MAD was 0.943. ROC and RCS analyses yielded an optimal threshold of 6 mm. In multivariable analyses, MAD of 6 mm and greater independently predicted PFS in all patients (HR = 1.35, p = .02), patients with N0 or N1 disease (HR = 1.80, p = .008), and patients who underwent posttreatment MRI (HR = 1.68, p = .04). In patients with N1 disease without cervical lymph node involvement, 5-year PFS was worse for MAD greater than or equal to 6 mm than for MAD that was greater than or equal to 5 mm but less than 6 mm (77.2% vs 89.7%, p = .03). OS was significantly different in patients with stage I and stage II disease defined using a 6-mm threshold (p = .04), but not using a 5-mm threshold (p = .09). The 5-year PFS rate was associated with a post-RT MAD of 6 mm and greater (HR = 1.68, p = .04) but not a post-RT MAD greater than or equal to 5 mm (HR = 1.09, p = .71). CONCLUSION. The findings support a threshold MAD of 6 mm for determining RLN involvement in patients with NPC. CLINICAL IMPACT. Future AJCC staging updates should consider incorporation of the 6-mm threshold for N-category and tumor-stage determinations.

Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.

Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 µM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

Comparison of the heterogeneous reaction of NO2 on the surface of clay minerals and desert dust particles.

Mineral particles in air could provide atmospheric chemical reaction interface for gaseous substances and participate in atmospheric chemical reaction process, and affecting the status and levels of gaseous pollutants in air. However, differences of the heterogenous reaction on the surface minerals particles are not very clear. Considering main mineral composition of ambient particles was from dust emission, therefore, typical clay minerals (chlorite, illite) and desert particles (Taklimakan Desert) were selected to analysize chemical reaction of NO2, one of major gaseous pollutants, on mineral particles by using of In-situ DRIFTS (diffuse reflectance infrared Fourier transform spectroscopy) under different condition. And In situ near-ambient pressure X-ray photoelectron spectroscopy (In situ NAP-XPS) was employed to investigate iron (one of the major metals) species variation on the surface of mineral dust particles during the heterogeneous reactions. Our data show that humidity controlled by deuterium oxide (D2O) has a greater effect on chemical reactions compared to light and temperature. Under dry conditions, the amount of heterogeneous reaction products of NO2 on the particles shows Xiaotang dust > chlorite > illite > Tazhong dust regardless of dark or light conditions. In contrast, under humidity conditions, the order of nitrate product quantity under moderate conditions was chlorite > illite > Xiaotang dust > Tazhong dust. In situ NAP-XPS results demonstrate that specie variation of the Fe could promote the heterogenous reactions. These data could provide useful information for understanding the formation mechanism of nitrate aerosols and removal of nitrogen oxides in the atmosphere.

Microglia-derived TNF-α contributes to RVLM neuronal mitochondrial dysfunction via blocking the AMPK-Sirt3 pathway in stress-induced hypertension.

BACKGROUND: Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been associated with the pathogenesis of stress-induced hypertension (SIH). Neuronal mitochondrial dysfunction is involved in many pathological and physiological processes. However, the impact of neuroinflammation on neuronal mitochondrial homeostasis and the involved signaling pathway in the RVLM during SIH are largely unknown. METHODS: The morphology and phenotype of microglia and the neuronal mitochondrial injury in vivo were analyzed by immunofluorescence, Western blot, RT-qPCR, transmission electron microscopy, and kit detection. The underlying mechanisms of microglia-derived tumor necrosis factor-α (TNF-α) on neuronal mitochondrial function were investigated through in vitro and in vivo experiments such as immunofluorescence and Western blot. The effect of TNF-α on blood pressure (BP) regulation was determined in vivo via intra-RVLM microinjection of TNF-α receptor antagonist R7050. RESULTS: The results demonstrated that BP, heart rate (HR), renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE), and electroencephalogram (EEG) power increased in SIH rats. Furthermore, the branching complexity of microglia in the RVLM of SIH rats decreased and polarized into M1 phenotype, accompanied by upregulation of TNF-α. Increased neuronal mitochondria injury was observed in the RVLM of SIH rats. Mechanistically, Sirtuin 3 (Sirt3) and p-AMPK expression were markedly downregulated in both SIH rats and TNF-α-treated N2a cells. AMPK activator A769662 upregulated AMPK-Sirt3 signaling pathway and consequently reversed TNF-α-induced mitochondrial dysfunction. Microinjection of TNF-α receptor antagonist R7050 into the RVLM of SIH rats significantly inhibited the biological activities of TNF-α, increased p-AMPK and Sirt3 levels, and alleviated neuronal mitochondrial injury, thereby reducing c-FOS expression, RSNA, plasma NE, and BP. CONCLUSIONS: This study revealed that microglia-derived TNF-α in the RVLM impairs neuronal mitochondrial function in SIH possibly through inhibiting the AMPK-Sirt3 pathway. Therefore, microglia-derived TNF-α in the RVLM may be a possible therapeutic target for the intervention of SIH.

ADAD2 interacts with RNF17 in P-bodies to repress the Ping-pong cycle in pachytene piRNA biogenesis.

Pachytene piRNA biogenesis is a hallmark of the germline, distinct from another wave of pre-pachytene piRNA biogenesis with regard to the lack of a secondary amplification process known as the Ping-pong cycle. However, the underlying molecular mechanism and the venue for the suppression of the Ping-pong cycle remain elusive. Here, we showed that a testis-specific protein, ADAD2, interacts with a TDRD family member protein RNF17 and is associated with P-bodies. Importantly, ADAD2 directs RNF17 to repress Ping-pong activity in pachytene piRNA biogenesis. The P-body localization of RNF17 requires the intrinsically disordered domain of ADAD2. Deletion of Adad2 or Rnf17 causes the mislocalization of each other and subsequent Ping-pong activity derepression, secondary piRNAs overproduced, and disruption of P-body integrity at the meiotic stage, thereby leading to spermatogenesis arrested at the round spermatid stage. Collectively, by identifying the ADAD2-dependent mechanism, our study reveals a novel function of P-bodies in suppressing Ping-pong activity in pachytene piRNA biogenesis.

LncRNA INPP5F ameliorates stress-induced hypertension via the miR-335/Cttn axis in rostral ventrolateral medulla.

AIMS: The rostral ventrolateral medulla (RVLM) is an essential vasomotor center responsible for regulating the development of stress-induced hypertension (SIH). Long non-coding RNAs (lncRNAs) play critical roles in various physiopathology processes, but existing research on the functions of RVLM lncRNAs on SIH has been lacking. In this study, we investigated the roles of RVLM lncRNAs in SIH. METHODS: Genome-wide lncRNA profiles in RVLM were determined by RNA sequencing in a SIH rat model established using electric foot shocks plus noises. The hypotensive effect of lncRNA INPP5F and the underlying mechanisms of lncRNA INPP5F on SIH were explored through in vivo and in vitro experiments, such as intra-RVLM microinjection and immunofluorescence. RESULTS: We discovered 10,179 lncRNA transcripts, among which the lncRNA INPP5F expression level was significantly decreased in SIH rats. Overexpression of lncRNA INPP5F in RVLM dramatically reduced the blood pressure, sympathetic nerve activity, and neuronal excitability of SIH rats. LncRNA INPP5F overexpression markedly increased Cttn expression and reduced neural apoptosis by activating the PI3K-AKT pathway, and its inhibition had opposite effects. Mechanistically, lncRNA INPP5F acted as a sponge of miR-335, which further regulated the Cttn expression. CONCLUSION: LncRNA INPP5F was a key factor that inhibited SIH progression, and the identified lncRNA INPP5F/miR-335/Cttn/PI3K-AKT/apoptosis axis represented one of the possible mechanisms. LncRNA INPP5F could serve as a therapeutic target for SIH.

Prognostic value of MR-detected mandibular nerve involvement: potential indication for future individual induction chemotherapy in T4 nasopharyngeal carcinoma.

PURPOSE: To investigate the prognostic significance of MR-detected mandibular nerve involvement (MNI) and its value for induction chemotherapy (IC) administration in patients with nasopharyngeal carcinoma (NPC) and T4 disease. METHODS: This retrospective study enrolled 792 non-metastatic, biopsy-proven NPC patients. Univariate and multivariate analysis were used to evaluate potential prognosticators. The inter-observer agreement was assessed by the kappa values. RESULTS: MR-detected MNI was observed in 141 (72.3%) patients among 195 patients with T4 disease, with excellent agreement between the readers (kappa = 0.926). Patients with MR-detected MNI presented better 5-year overall survival (OS) (hazard ratio [HR], 0.40; P = 0.006) than those with MR-negative MNI. Of these patients, IC treatment was verified as an independent factor (HR: 0.35; P = 0.014) with preferable effect on OS. CONCLUSION: MR-detected MNI could serve as an independent favorable prognostic predictor for OS in NPC patients with stage T4, which should be considered for stratifying these patients for IC administration.

Safety and effectiveness of indocyanine green fluorescence imaging-guided laparoscopic hepatectomy for hepatic tumor: a systematic review and meta-analysis.

Introduction: Previous clinical investigations have reported inconsistent findings regarding the feasibility of utilizing indocyanine green fluorescence imaging (ICGFI) in laparoscopic liver tumor removal. This meta-analysis aims to comprehensively evaluate the safety and effectiveness of ICGFI in laparoscopic hepatectomy (LH). Methods: A systematic search of pertinent clinical studies published before January 30th, 2023 was conducted in databases including PubMed, Embase, Cochrane, and Web of Science. The search strategy encompassed key terms such as "indocyanine green fluorescence," "ICG fluorescence," "laparoscopic hepatectomy," "hepatectomies," "liver Neoplasms," "hepatic cancer," and "liver tumor." Additionally, we scrutinized the reference lists of included articles to identify supplementary studies. we assessed the quality of the incorporated studies and extracted clinical data. Meta-analysis was performed using STATA v.17.0 software. Either a fixed-effects or a random-effects model was employed to compute combined effect sizes, accompanied by 95% confidence intervals (CIs), based on varying levels of heterogeneity. Results: This meta-analysis encompassed eleven retrospective cohort studies, involving 959 patients in total. Our findings revealed that, in comparison to conventional laparoscopic hepatectomy, patients receiving ICGFI-guided LH exhibited a higher R0 resection rate (OR: 3.96, 95% CI: 1.28, 12.25, I2 = 0.00%, P = 0.778) and a diminished incidence of intraoperative blood transfusion (OR: 0.42, 95% CI: 0.22, 0.81, I 2 = 51.1%, P = 0.056). Additionally, they experienced shorter postoperative hospital stays (WMD: -1.07, 95% CI: -2.00, -0.14, I 2 = 85.1%, P = 0.000). No statistically significant differences emerged between patients receiving ICGFI-guided LH vs. those undergoing conventional LH in terms of minimal margin width and postoperative complications. Conclusion: ICGFI-guided LH demonstrates marked superiority over conventional laparoscopic liver tumor resection in achieving R0 resection and reducing intraoperative blood transfusion rates. This technique appears to hold substantial promise. Nonetheless, further studies are needed to explore potential long-term benefits associated with patients undergoing ICGFI-guided LH. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD 42023398195.

The influencing factors of infectious complications after percutaneous nephrolithotomy: a systematic review and meta-analysis.

Infection is the most common complications of percutaneous nephrolithotomy (PCNL) in treating urinary calculi. However, the risk factors for developing infectious complications after surgery have not been clarified, and the predictive value of some factors is controversial. This study aimed to assess the risk factors for postoperative infectious complications of PCNL. We performed a systematic search of PubMed, Web of Science, Cochrane Library, and EMBASE to obtain studies reporting risk factors for postoperative infection complications after PCNL. In this review, demographic factors, laboratory test factors, and perioperative factors were evaluated. The odds ratio (OR) or mean difference (MD) with a 95% confidence interval (CI) was calculated to assess the risk factors. A total of 18 studies were included, with a total of 7161 study patients with a mean age of 46.4 to 55.5 years and an incidence of infectious complications after PCNL ranging from 2.4% to 40.4%. Twelve factors were identified as independent risk factors for post-PCNL infection complications (P < 0.05), female (OR = 1.60, 95% CI 1.23-2.07), positive urine culture (UC) (OR = 3.16, 95% CI 2.11-4.74), positive renal pelvis urine culture (RPUC) (OR = 5.81, 95% CI 1.75-19.32), positive stone culture (SC) (OR = 5.11, 95% CI 1.46-17.89), positive urine leukocyte (OR = 3.61, 95% CI 2.45-5.34), infected stones (OR = 7.00, 95% CI 1.27-38.55), elevated blood leukocyte (MD = 0.71, 95% CI 0.31-1.10), elevated neutrophil-to-lymphocyte ratio (NLR) (MD = 0.55, 95% CI 0.43-0.66), preoperative stenting (OR = 1.55, 95% CI 1.10-2.20), multiple puncture access (OR = 2.58, 95% CI 1.75-3.82), prolonged operative time (MD = 10 20, 95% CI 4.80-15.60), and postoperative residual stone (OR = 1.56, 95% CI 1.24-1.98). Female, UC positivity, RPUC positivity, SC positivity, urine leukocyte positivity, infected stones, elevated peripheral blood leukocytes, elevated NLR, preoperative stent implantation, multiple puncture channels, prolonged operation time, and postoperative residual stones were identified as independent risk factors for infection complications after PCNL.

Novel Approaches for Inhibiting the Indoor Allergen Der f 2 Excreted from House Dust Mites by Todomatsu Oil Produced from Woodland Residues.

House dust mite (HDM) is a globally ubiquitous domestic cause of allergic diseases. There is a pressing demand to discover efficient, harmless, and eco-friendly natural extracts to inhibit HDM allergens that are more likely to trigger allergies and challenging to be prevented entirely. This study, therefore, is aimed at assessing the inhibition of the allergenicity of major HDM allergen Der f 2 by todomatsu oil extracted from residues of Abies Sachalinensis. The inhibition was investigated experimentally (using enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)) and in silico using molecular docking. The results showed that todomatsu oil inhibits the allergenicity of Der f 2 by reducing its amount instead of the IgG binding capacity of a single protein. Moreover, the compounds in todomatsu oil bind to Der f 2 via alkyl hydrophobic interactions. Notably, most compounds interact with the hydrophobic amino acids of Der f 2, and seven substances interact with CYS27. Contrarily, the principal compounds fail to attach to the amino acids forming the IgG epitope in Der f 2. Interestingly, chemical components with the lowest relative percentages in todomatsu oil show high-affinity values on Der f 2, especially ß-maaliene (-8.0 kcal/mol). In conclusion, todomatsu oil has been proven in vitro as a potential effective public health strategy to inhibit the allergenicity of Der f 2.

UHRF1 interacts with snRNAs and regulates alternative splicing in mouse spermatogonial stem cells.

Life-long male fertility relies on exquisite homeostasis and the development of spermatogonial stem cells (SSCs); however, the underlying molecular genetic and epigenetic regulation in this equilibrium process remains unclear. Here, we document that UHRF1 interacts with snRNAs to regulate pre-mRNA alternative splicing in SSCs and is required for the homeostasis of SSCs in mice. Genetic deficiency of UHRF1 in mouse prospermatogonia results in gradual loss of spermatogonial stem cells, eventually leading to Sertoli-cell-only syndrome (SCOS) and male infertility. Comparative RNA-seq data provide evidence that Uhrf1 ablation dysregulates previously reported SSC maintenance- and differentiation-related genes. We further found that UHRF1 could act as an alternative RNA splicing regulator and interact with Tle3 transcripts to regulate its splicing event in spermatogonia. Collectively, our data reveal a multifunctional role for UHRF1 in regulating gene expression programs and alternative splicing during SSC homeostasis, which may provide clues for treating human male infertility.

Transcription factor YY1 contributes to human melanoma cell growth through modulating the p53 signalling pathway.

Melanoma has a higher mortality rate than any other skin cancer, and its cases are increasing. The transcription factor YY1 has been proven to be involved in tumour progression; however, the role of YY1 in melanoma is not well understood. This study investigates how YY1 functions in melanoma progression, and it also elucidates the underlying mechanisms involved. We have found that in clinical human melanoma tissues, YY1 is overexpressed compared with YY1 expression in normal melanocytes and skin tissues. Cellular immunofluorescence shows that YY1 is mainly located in the nucleus. YY1 knockdown reduces proliferation, migration and invasion of melanoma cell lines. Moreover, the apoptosis rate of cells is significantly increased in low-YY1 environments. The overexpression of YY1 resulted in decreased apoptotic rates in melanoma cells. YY1 also affects the expression of EMT-related proteins. Additional experiments reveal that YY1 knockdown disrupts the interaction of MDM2-p53, and that it both stabilizes and increases p53 activity. The upregulation of p53 expression in turn stimulates p21 expression just as it suppresses CDK4 expression, which then induces cells that were arrested in the G1 phase. The effect then is to constrain cell proliferation in melanoma cells. Upon activation of the p53 pathway, Bax, a pro-apoptotic protein, is upregulated, and Bcl-2, an anti-apoptotic protein, was downregulated in A375 cells. The findings of this study provide novel insights into the pathology of melanoma as well as the role that YY1 plays in tumour progression. The findings also suggest that targeting YY1 has the potential to improve the diagnosis and treatment of melanoma.

ANGPTL4 negatively regulates the progression of osteosarcoma by remodeling branched-chain amino acid metabolism.

Angiopoietin-like-4 (ANGPTL4), a secreted glycoprotein that is mainly known as a regulator in lipid metabolism, now, is also indicated to be involved in the regulation of cancer progression and metastasis. However, little is known about not only biological functions, but also underlying mechanism of ANGPTL4 in the progression of osteosarcoma (OS). Here, we discovered that ANGPTL4 is downregulated in OS, and is associated with branched-chain amino acid (BCAA) metabolism. The BCAAs (valine, leucine, and isoleucine) are essential amino acids that play an important role in metabolic regulation. Aberrant BCAA metabolism is also found in various cancers and is associated with tumor progression, including proliferation, invasion, and metastasis. In this study, we indicated that the negative relation between the expression of ANGPTL4 and BCAA catabolism in OS samples and cell lines. The knockdown of ANGPTL4 in OS cells resulted in the accumulation of BCAAs, which in turn activated the mTOR signaling pathway, enhancing OS cell proliferation. Thus, reduced expression of ANGPTL4 is associated with the progression of OS. Taken together, our results demonstrated that the ANGPTL4/BCAA/mTOR axis is an important pathway in OS progression and may be a potential therapeutic target to slow OS progression.

UHRF1 is indispensable for meiotic sex chromosome inactivation and interacts with the DNA damage response pathway in mice†.

During male meiosis, the constitutively unsynapsed XY chromosomes undergo meiotic sex chromosome inactivation (MSCI), and the DNA damage response (DDR) pathway is critical for MSCI establishment. Our previous study showed that UHRF1 (ubiquitin-like, with PHD and ring finger domains 1) deletion led to meiotic arrest and male infertility; however, the underlying mechanisms of UHRF1 in the regulation of meiosis remain unclear. Here, we report that UHRF1 is required for MSCI and cooperates with the DDR pathway in male meiosis. UHRF1-deficient spermatocytes display aberrant pairing and synapsis of homologous chromosomes during the pachytene stage. In addition, UHRF1 deficiency leads to aberrant recruitment of ATR and FANCD2 on the sex chromosomes and disrupts the diffusion of ATR to the XY chromatin. Furthermore, we show that UHRF1 acts as a cofactor of BRCA1 to facilitate the recruitment of DDR factors onto sex chromosomes for MSCI establishment. Accordingly, deletion of UHRF1 leads to the failure of meiotic silencing on sex chromosomes, resulting in meiotic arrest. In addition to our previous findings, the present study reveals that UHRF1 participates in MSCI, ensuring the progression of male meiosis. This suggests a multifunctional role of UHRF1 in the male germline.