Identification of a risk model for prognostic and therapeutic prediction in renal cell carcinoma based on infiltrating M0 cells.

The tumor microenvironment (TME) comprises immune-infiltrating cells that are closely linked to tumor development. By screening and analyzing genes associated with tumor-infiltrating M0 cells, we developed a risk model to provide therapeutic and prognostic guidance in clear cell renal cell carcinoma (ccRCC). First, the infiltration abundance of each immune cell type and its correlation with patient prognosis were analyzed. After assessing the potential link between the depth of immune cell infiltration and prognosis, we screened the infiltrating M0 cells to establish a risk model centered on three key genes (TMEN174, LRRC19, and SAA1). The correlation analysis indicated a positive correlation between the risk score and various stages of the tumor immune cycle, including B-cell recruitment. Furthermore, the risk score was positively correlated with CD8 expression and several popular immune checkpoints (ICs) (TIGIT, CTLA4, CD274, LAG3, and PDCD1). Additionally, the high-risk group (HRG) had higher scores for tumor immune dysfunction and exclusion (TIDE) and exclusion than the low-risk group (LRG). Importantly, the risk score was negatively correlated with the immunotherapy-related pathway enrichment scores, and the LRG showed a greater therapeutic benefit than the HRG. Differences in sensitivity to targeted drugs between the HRG and LRG were analyzed. For commonly used targeted drugs in RCC, including axitinib, pazopanib, temsirolimus, and sunitinib, LRG had lower IC50 values, indicating increased sensitivity. Finally, immunohistochemistry results of 66 paraffin-embedded specimens indicated that SAA1 was strongly expressed in the tumor samples and was associated with tumor metastasis, stage, and grade. SAA1 was found to have a significant pro-tumorigenic effect by experimental validation. In summary, these data confirmed that tumor-infiltrating M0 cells play a key role in the prognosis and treatment of patients with ccRCC. This discovery offers new insights and directions for the prognostic prediction and treatment of ccRCC.

Prognostic and therapeutic model based on disulfidptosis-related genes for patients with clear cell renal cell carcinoma.

Disulfidptosis, a newly discovered mode of cell death caused by excessive accumulation of intracellular disulfide compounds, is closely associated with tumor development. This study focused on the relationship between disulfidptosis and clear cell renal cell carcinoma (ccRCC). Firstly, the characterizations of disulfidptosis-related genes (DRGs) in ccRCC were showed, which included number variation (CNV), single nucleotide variation (SNV), DNA methylation, mRNA expression and gene mutation. Then, the ccRCC samples were classified into three clusters through unsupervised clustering based on DRGs. Survival and pathway enrichment differences were evaluated among the three clusters. Subsequently, the differentially expressed genes (DEGs) among the three clusters were screened by univariate Cox, LASSO, and multivariate Cox analysis, and five key DEGs were obtained. Based on the five key DEGs, the ccRCC samples were reclassified into two geneclusters and the survival differences and immune cell infiltration between two geneclusters was investigated. In next step, ccRCC samples were divided into two groups according to PCA scores of five key DEGs, namely high PCA score group (HPSG) and low PCA score group (LPSG). On this basis, differences in survival prognosis, immune cell infiltration and correlation with immune checkpoint, as well as differences in sensitivity to targeted drugs were compared between HPSG and LPSG. The expression levels of four immune checkpoints were higher in HPSG than in LPSG, whereas the LPSG was more sensitive to targeted drug therapy than the HPSG. Finally, validation experiments on HDAC4 indicated that HDAC4 could increase the proliferation and colony formation ability of ccRCC cells.

The Use of Spiral Cement Injector for Percutaneous Vertebroplasty to Treat Kümmell Disease: A Retrospective Study.

BACKGROUND: Percutaneous vertebroplasty (PVP) is a common method used to treat Kümmell disease. In patients without neurologic symptoms, we sought to evaluate whether using the new spiral injectors instead of the traditional push-rod injectors in PVP can result in improved clinical efficacy for the treatment of Kümmell disease. METHODS: A clinical retrospective study was conducted between August 2018 and December 2020. The study included patients diagnosed with single-level thoracolumbar Kümmell disease who underwent PVP surgery. The patients were divided into 2 groups: an observation group consisting of 53 patients treated with spiral injectors and a control group consisting of 68 patients treated with push-rod injectors. RESULTS: A 2-year follow-up period was adopted. The bone cement injection volume and occurrence of bone cement leakage were significantly greater in the observation group compared with the control group (P < 0.05). The observation group had significantly shorter operation time and intraoperative fluoroscopy times compared with the control group (P < 0.05). The scores for the visual analog scale and Oswestry Disability Index in both groups were significantly lower at 3 days or 3 months and 2 years after surgery compared with before surgery, with the scores at 2 years after surgery being significantly lower than those at 3 days or 3 months for both groups (P < 0.05). The relative anterior ledge height and Cobb angle showed significant improvement at 3 days and 2 years after surgery compared with before surgery in both groups (P < 0.05), but patients in the observation group experienced substantial improvement at 3 days and 2 years after surgery compared with those in the control group (P < 0.05). In both groups, the relative anterior ledge height was noticeably lower 2 years after surgery compared with 3 days after surgery (P < 0.05). Concurrently, there was a significant increase in the local Cobb angle over time in both groups (P < 0.05). CONCLUSIONS: The implementation of both spiral injectors and traditional push-rod injectors in PVP surgery yields effective pain relief, improved function, partially restored vertebral height, and corrected kyphosis in treating Kümmell disease. Compared with the push-rod injector, the spiral injector is highly efficient in restoring vertebral height, correcting kyphosis, and minimizing fluoroscopy use and operation time, but it carries a greater risk of bone cement leakage.

A bacterial toxin co-opts caspase-3 to disable active gasdermin D and limit macrophage pyroptosis.

During infections, host cells are exposed to pathogen-associated molecular patterns (PAMPs) and virulence factors that stimulate multiple signaling pathways that interact additively, synergistically, or antagonistically. The net effect of such higher-order interactions is a vital determinant of the outcome of host-pathogen interactions. Here, we demonstrate one such complex interplay between bacterial exotoxin- and PAMP-induced innate immune pathways. We show that two caspases activated during enterohemorrhagic Escherichia coli (EHEC) infection by lipopolysaccharide (LPS) and Shiga toxin (Stx) interact in a functionally antagonistic manner; cytosolic LPS-activated caspase-11 cleaves full-length gasdermin D (GSDMD), generating an active pore-forming N-terminal fragment (NT-GSDMD); subsequently, caspase-3 activated by EHEC Stx cleaves the caspase-11-generated NT-GSDMD to render it nonfunctional, thereby inhibiting pyroptosis and interleukin-1ß maturation. Bacteria typically subvert inflammasomes by targeting upstream components such as NLR sensors or full-length GSDMD but not active NT-GSDMD. Thus, our findings uncover a distinct immune evasion strategy where a bacterial toxin disables active NT-GSDMD by co-opting caspase-3.

A novel model based on disulfidptosis-related genes to predict prognosis and therapy of bladder urothelial carcinoma.

PURPOSE: Disulfidptosis is a novel type of cell death induced by disulphide stress that depends on the accumulation of cystine disulphide, causing cytotoxicity and triggering cell death. However, the direct prognostic effect and regulatory mechanism of disulfidptosis-related genes in bladder urothelial carcinoma (BLCA) remain unclear. METHODS: To explore the role of 10 disulfidptosis-related genes, the multiomic data of 10 genes were comprehensively analysed. Next, based on seven disulfidptosis-related differentially expressed genes, a novel disulfidptosis-related gene score was developed to help predict the prognosis of BLCA. Immunohistochemistry, EDU, Real-time PCR and western blot were used to verify the model. RESULTS: Significant functional differences were found between the high- and low-risk score groups, and samples with a higher risk score were more malignant. Furthermore, the tumour exclusion and Tumour Immune Dysfunction and Exclusion scores of the high-risk score group were higher than those of the low-risk score group. The risk score was positively correlated with the expression of immune checkpoints. Drug sensitivity analyses revealed that the low-risk score group had a higher sensitivity to cisplatin, doxorubicin, docetaxel and gemcitabine than the high-risk score group. Moreover, the expression of the TM4SF1 was positively correlated with the malignancy degree of BLCA, and the proliferation ability of BLCA cells was reduced after knockdown TM4SF1. CONCLUSION: The present study results suggest that disulfidptosis-related genes influence the prognosis of BLCA through their involvement in immune cell infiltration. Thus, these findings indicate the role of disulfidptosis in BLCA and its potential regulatory mechanisms.

An ancient defense mechanism: Conservation of gasdermin-mediated pyroptosis.

The gasdermins are a family of pore-forming proteins involved in various cellular processes such as cell death and inflammation. A new study in PLOS Biology explores the evolutionary history of gasdermins across metazoans, highlighting the conservation and divergence of gasdermin E.

Structural basis for GSDMB pore formation and its targeting by IpaH7.8.

Gasdermins (GSDMs) are pore-forming proteins that play critical roles in host defence through pyroptosis1,2. Among GSDMs, GSDMB is unique owing to its distinct lipid-binding profile and a lack of consensus on its pyroptotic potential3-7. Recently, GSDMB was shown to exhibit direct bactericidal activity through its pore-forming activity4. Shigella, an intracellular, human-adapted enteropathogen, evades this GSDMB-mediated host defence by secreting IpaH7.8, a virulence effector that triggers ubiquitination-dependent proteasomal degradation of GSDMB4. Here, we report the cryogenic electron microscopy structures of human GSDMB in complex with Shigella IpaH7.8 and the GSDMB pore. The structure of the GSDMB-IpaH7.8 complex identifies a motif of three negatively charged residues in GSDMB as the structural determinant recognized by IpaH7.8. Human, but not mouse, GSDMD contains this conserved motif, explaining the species specificity of IpaH7.8. The GSDMB pore structure shows the alternative splicing-regulated interdomain linker in GSDMB as a regulator of GSDMB pore formation. GSDMB isoforms with a canonical interdomain linker exhibit normal pyroptotic activity whereas other isoforms exhibit attenuated or no pyroptotic activity. Overall, this work sheds light on the molecular mechanisms of Shigella IpaH7.8 recognition and targeting of GSDMs and shows a structural determinant in GSDMB critical for its pyroptotic activity.

Nexinhib20 Inhibits Neutrophil Adhesion and ß2 Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction.

Neutrophils are critical for mediating inflammatory responses. Inhibiting neutrophil recruitment is an attractive approach for preventing inflammatory injuries, including myocardial ischemia-reperfusion (I/R) injury, which exacerbates cardiomyocyte death after primary percutaneous coronary intervention in acute myocardial infarction. In this study, we found out that a neutrophil exocytosis inhibitor Nexinhib20 inhibits not only exocytosis but also neutrophil adhesion by limiting ß2 integrin activation. Using a microfluidic chamber, we found that Nexinhib20 inhibited IL-8-induced ß2 integrin-dependent human neutrophil adhesion under flow. Using a dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and ß2 integrin activation after IL-8 stimulation. Western blots of Ras-related C3 botulinum toxin substrate 1 (Rac-1)-GTP pull-down assays confirmed that Nexinhib20 inhibited Rac-1 activation in leukocytes. An in vitro competition assay showed that Nexinhib20 antagonized the binding of Rac-1 and GTP. Using a mouse model of myocardial I/R injury, Nexinhib20 administration after ischemia and before reperfusion significantly decreased neutrophil recruitment and infarct size. Our results highlight the translational potential of Nexinhib20 as a dual-functional neutrophil inhibitory drug to prevent myocardial I/R injury.

Staphylococcal superantigen-like protein 10 induces necroptosis through TNFR1 activation of RIPK3-dependent signal pathways.

Staphylococcal aureus (S. aureus) infection can lead to a wide range of diseases such as sepsis and pneumonia. Staphylococcal superantigen-like (SSL) proteins, expressed by all known S. aureus strains, are shown to be involved in immune evasion during S. aureus infection. Here, we show that SSL10, an SSL family protein, exhibits potent cytotoxicity against human cells (HEK293T and HUVEC) by inducing necroptosis upon binding to its receptor TNFR1 on the cell membrane. After binding, two distinct signaling pathways are activated downstream of TNFR1 in a RIPK3-dependent manner, i.e., the RIPK1-RIPK3-MLKL and RIPK3-CaMKII-mitochondrial permeability transition pore (mPTP) pathways. Knockout of ssl10 in S. aureus significantly reduces cytotoxicity of the culture supernatants of S. aureus, indicating that SSL10 is involved in extracellular cytotoxicity during infection. We determined the crystal structure of SSL10 at 1.9 Å resolution and identified a positively charged surface of SSL10 responsible for TNFR1 binding and cytotoxic activity. This study thus provides the description of cytotoxicity through induction of necroptosis by the SSL10 protein, and a potential target for clinical treatment of S. aureus-associated diseases.

Aluminum stress signaling, response, and adaptive mechanisms in plants.

Over 40% of arable land in the world is acidic. Al stress has become a global agricultural problem affecting plant growth and limiting crop production in acidic soils. Plants have evolved different regulatory mechanisms of adaptation to exogenous environmental challenges, such as Al stress, by altering their growth patterns. In the past decades, several key genes involved in plant response to Al stress and the mechanism of Al detoxification have been revealed. However, the signaling pathways of plant response to Al stress and the regulatory mechanism of plant Al tolerance remain poorly understood. In this review, we summarized the findings of recent studies on the plant Al tolerance mechanism and the molecular regulation mechanism of phytohormones in response to Al stress. This review improves our understanding of the regulatory mechanisms of plants in response to Al stress and provides a reference for the breeding of Al-tolerant crops.

Longdan Xiegan Tang attenuates liver injury and hepatic insulin resistance by regulating the angiotensin-converting enzyme 2/Ang (1-7)/Mas axis-mediated anti-inflammatory pathway in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The ancient Chinese herbal formula Longdan Xiegan Tang (LXT, also called Gentiana Longdancao Decoction to Drain the Liver) treats insulin resistance- and inflammation-associated liver injuries in clinical practice. AIM OF THE STUDY: To investigate the molecular mechanisms underlying LXT-elicited improvement of the liver injuries. MATERIALS AND METHODS: Male rats were co-treated with olanzapine (5 mg/kg) and LXT extract (50 and 500 mg/kg) for eight weeks. Blood parameters were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry. RESULTS: LXT attenuated olanzapine-induced liver injury manifested by hyperactivities of plasma alanine aminotransferase and aspartate aminostransferase, hyperbilirubinemia and hypoalbuminemia. Furthermore, LXT improved hepatic insulin resistance that was indicated by hyperinsulinemia, the increased HOMA-IR index, and hepatic over-phosphorylation of Ser307 in insulin receptor substrate (IRS)1, Ser731 in IRS2, Tyr607 in phosphoinositide 3-kinase p85α and Ser473 in AKT at baseline. Mechanistically, LXT inhibited olanzapine-triggered hepatic over-phosphorylation of both IκB kinase (IKK)α/ß and nuclear factor (NF)κB p65 proteins, and mRNA overexpression of tumor necrosis factor α, interleukin 6, interleukin 1ß and CD68. More importantly, LXT restored the decreases in angiotensin-converting enzyme 2 (ACE2) protein level, and its downstream targets Ang (1-7) content and Mas receptor expression. CONCLUSIONS: The present results demonstrate that LXT attenuates liver injury and hepatic insulin resistance by regulating the ACE2/Ang (1-7)/Mas axis-mediated anti-inflammatory pathway in rats. Our findings provide a better understanding of LXT for treatment of insulin resistance- and inflammation-associated liver injuries.

The protein kinase D1-mediated inflammatory pathway is involved in olanzapine-induced impairment of skeletal muscle insulin signaling in rats.

AIMS: Skeletal muscle insulin resistance (SMIR) contributes to the metabolic syndrome. Mounting evidence has demonstrated that the second generation antipsychotic olanzapine causes SMIR. The present study sought to investigate the molecular mechanisms underlying olanzapine-induced SMIR. MAIN METHODS: Male rats were given olanzapine (5 mg/kg, by a gavage method) for consecutive eight weeks. Plasma glucose and insulin concentrations were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry. KEY FINDINGS: Olanzapine increased fasting plasma insulin concentration, and decreased glucose clearance during insulin tolerance test in rats. In skeletal muscle, it decreased protein expression of membrane glucose transporter (GLUT) 4, the ratio of membrane to total GLUT4, and total insulin receptor substrate 1 (IRS1). However, it increased protein phosphorylation of Ser307 in IRS1, Y607 in phosphoinositide 3-kinase p85α and Ser307 in AKT. These results indicate olanzapine-induced impairment of skeletal muscle insulin signaling. Mechanistically, olanzapine upregulated mRNA expression of TNFα, IL6 and IL1ß, and protein phosphorylation of both IκB kinase (IKK)α/ß and nuclear factor (NF)κB p65. Furthermore, it increased protein phosphorylation of Ser485/491 in AMPKα2, whereas it decreased AMPKα2 activity. More importantly, both Western blot and immunohistochemical analyses revealed that olanzapine increased protein phosphorylation of Ser744/748 in protein kinase D1 (PKD1). SIGNIFICANCE: The present results suggest that the PKD1-mediated inflammatory pathway is involved in olanzapine-induced impairment of skeletal muscle insulin signaling in rats. Our findings may go new insight into the mechanisms underlying olanzapine-induced SMIR.

Outcome and experience of arthroscopic lateral retinacular release combined with lateral patelloplasty in the management of excessive lateral pressure syndrome.

BACKGROUND: Only a few studies have described the effect of full arthroscopic surgery in treatment of excessive lateral pressure syndrome (ELPS). Therefore, the purpose of this study was to assess the clinical efficacy and experience of total arthroscopic lateral retinacular (LR) release and lateral patelloplasty for the treatment of ELPS. METHODS: A total of 73 patients (88 knees) with ELPS underwent arthroscopic LR release and lateral patelloplasty. The visual analogue scale (VAS), Kujala score, Lysholm scores, patella medial pushing distance, patellar tilt angle (PTA), and lateral patellofemoral angle (LPFA) were measured and evaluated before and after surgery. RESULTS: Follow-up ranged from 12 to 36 months with an average of 24 ± 5.8 months. The VAS was significantly lower at the last follow-up than before surgery (P < 0.01). The patella medial pushing distance, Kujala score, Lysholm score, PTA, and LPFA were significantly higher at the last follow-up than before surgery (P < 0.01, respectively). Years and lateral patella Outerbridge classification at the last follow-up have negative correlation with Kujala score, Lysholm score, Patella medial pushing distance, PTA, and LPFA (P < 0.01, respectively) and have positive correlation with VAS (P < 0.01, respectively). Related complications were not reported. CONCLUSIONS: Full arthroscopic LR release combined with lateral patelloplasty in the treatment of ELPS is an effective minimally invasive method, which can effectively correct anomalies of force line and skeleton of patella, relieve pain, and restore knee joint motor function with less complications.

Intracellular immune sensing promotes inflammation via gasdermin D-driven release of a lectin alarmin.

Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a ß-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.

Paeoniflorin ameliorates antipsychotic-induced hyperprolactinemia in rats by attenuating impairment of the dopamine D2 receptor and TGF-ß1 signaling pathways in the hypothalamus and pituitary.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniflorin, a prominent component in some Chinese formulas for hyperprolactinemia-associated disorders, has been found to inhibit prolactin secretion in prolactinoma cells. AIM: To examine the efficacy of paeoniflorin on hyperprolactinemia and the underlying mechanisms of action. MATERIALS AND METHODS: Hyperprolactinemia in female rats was generated by administration of olanzapine (5 mg/kg, by a gavage method, once daily, × 13 weeks). The rats were co-treated with paeoniflorin (10 and 50 mg/kg). Prolactin and TGF-ß1 concentrations were detected by ELISA. Protein expression was determined by Western blot. The effect in MMQ cells was also examined. RESULTS: Paeoniflorin inhibited olanzapine-induced increases in plasma prolactin concentration and prolactin protein overexpression in the pituitary and hypothalamus of rats. Further, paeoniflorin restored olanzapine-induced downregulation of pituitary and hypothalamic dopamine D2 receptor (D2R) protein expression. More importantly, paeoniflorin attenuated olanzapine-suppressed protein expression of transforming growth factor (TGF)-ß1 and its downstream genes, type II TGF-ß receptor, type I TGF-ß receptor and phosphorylated SMAD3 in the tissues. However, paeoniflorin did not affect plasma TGF-ß1 concentration and hepatic TGF-ß1 protein expression. In accord, olanzapine-induced increase in prolactin concentration, upregulation of prolactin protein expression, and downregulation of protein expression of the D2R and TGF-ß1 signals in MMQ cells were attenuated. CONCLUSIONS: This study demonstrates that paeoniflorin ameliorates olanzapine-induced hyperprolactinemia in rats by attenuating impairment of the D2R and TGF-ß1 signaling pathways in the hypothalamus and pituitary. Our findings may provide evidence to support the use of paeoniflorin-contained Chinese herbs and formulas for hyperprolactinemia and its associated disorders.

The ancient Chinese formula Longdan Xiegan Tang improves antipsychotic-induced hyperprolactinemia by repairing the hypothalamic and pituitary TGF-ß1 signaling in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Antipsychotics often induce hyperprolactinemia. The transforming growth factor (TGF)-beta1 signaling in the pituitary and hypothalamus inhibits prolactin synthesis and secretion, and its impairment is implicated in neuropsychiatric disorders. Longdan Xiegan Tang (LXT) alone or together with antipsychotics have been used to treat various neuropsychiatric diseases and hyperprolactinemia-associated disorders. AIM OF THE STUDY: To investigate the effect of LXT on hyperprolactinemia and involvement of the TGF-beta1 signaling. MATERIALS AND METHODS: Male rats were co-administered with olanzapine (5 mg/kg) and LXT extract (50 and 500 mg/kg) (p.o., × 8 weeks). Plasma concentrations of prolactin and TGF-beta1 were determined by ELISA. Protein expression was analyzed by Western blot. RESULTS: Treatment of rats with LXT extract suppressed olanzapine-induced increase in plasma prolactin concentration and overexpression of pituitary and hypothalamic prolactin protein. Importantly, LXT restored olanzapine-induced decrease in protein expression of the key components of the TGF-beta1 signaling, TGF-beta1, type II TGF-beta receptor, type I TGF-beta receptor and phosphorylated SMAD3 in the pituitary and hypothalamus. Further, it antagonized downregulation of pituitary and hypothalamic dopamine D2 receptor (D2R) protein level, and inhibited pituitary estrogen receptor (ER) alpha and ERbeta protein expression. CONCLUSIONS: The present results suggest that LXT ameliorates antipsychotic-induced hyperprolactinemia in rats by repairing the pituitary and hypothalamic TGF-beta1 signaling possibly via D2R, ERs or/and other pathways. Our findings may also provide scientific elucidation for use of the ancient Chinese formula to treat the impaired TGF-beta1 signaling-associated neuropsychiatric disorders.

Structural insights into the molecular mechanism underlying Sirt5-catalyzed desuccinylation of histone peptides.

Histone modification is a ubiquitous regulatory mechanism involved in a variety of biological processes, including gene expression, DNA damage repair, cell differentiation, and ontogenesis. Succinylation sites on histones have been identified and may have functional consequences. Here, we demonstrate that human sirtuin 5 (Sirt5) catalyzes the sequence-selective desuccinylation of numerous histone succinyl sites. Structural studies of Sirt5 in complex with four succinyl peptides indicate an essential role for the conserved main chain hydrogen bonds formed by the succinyl lysine (0), +1, and +3 sites for substrate-enzyme recognition. Furthermore, biochemical assays reveal that the proline residue at the +1 site of the histone succinylation substrate is unfavorable for Sirt5 interaction. Our findings illustrate the molecular mechanism underlying the sequence-selective desuccinylase activity of Sirt5 and provide insights for further studies of the biological functions associated with histone succinylation and Sirt5.

Crystal structures of the N-terminal domain of the Staphylococcus aureus DEAD-box RNA helicase CshA and its complex with AMP.

CshA is a DEAD-box RNA helicase that belongs to the DExD/H-box family of proteins, which generally have an RNA-dependent ATPase activity. In Staphylococcus aureus, CshA was identified as a component of the RNA degradosome and plays important roles in RNA turnover. In this study, the crystal structures of the N-terminal RecA-like domain 1 of S. aureus CshA (SaCshAR1) and of its complex with AMP (SaCshAR1-AMP) are reported at resolutions of 1.5 and 1.8 Å, respectively. SaCshAR1 adopts a conserved α/ß RecA-like structure with seven parallel strands surrounded by nine α-helices. The Q motif and motif I are responsible for the binding of the adenine group and phosphate group of AMP, respectively. Structure comparison of SaCshAR1-AMP and SaCshAR1 reveals that motif I undergoes a conformational change upon AMP binding. Isothermal titration calorimetry assays further conformed the essential roles of Phe22 in the Q motif and Lys52 in motif I for binding ATP, indicating a conserved substrate-binding mechanism in SaCshA compared with other DEAD-box RNA helicases.

MIL-100(Al) Gels as an Excellent Platform Loaded with Doxorubicin Hydrochloride for pH-Triggered Drug Release and Anticancer Effect.

Slow and controlled release systems for drugs have attracted increasing interest recently. A highly efficient metal-organic gel (MOGs) drug delivery carrier, i.e., MIL-100(Al) gel, has been fabricated by a facile, low cost, and environmentally friendly one-pot process. The unique structure of MIL-100(Al) gels has led to a high loading efficiency (620 mg/g) towards doxorubicin hydrochloride (DOX) as a kind of anticancer drug. DOX-loaded MOGs exhibited high stability under physiological conditions and sustained release capacity of DOX for up to three days (under acidic environments). They further showed sustained drug release behavior and excellent antitumor effects in in vitro experiments on HeLa cells, in contrast with the extremely low biotoxicity of MOGs. Our work provides a promising way for anticancer therapy by utilizing this MOGs-based drug delivery system as an efficient and safe vehicle.

Hue-texture-embedded region-based model for magnifying endoscopy with narrow-band imaging image segmentation based on visual features.

BACKGROUND AND OBJECTIVE: Magnification endoscopy with narrow-band imaging (ME-NBI) has become a feasible tool for detecting diseases within the human gastrointestinal tract, and is more applied by physicians to search for pathological abnormalities with gastric cancer such as precancerous lesions, early gastric cancer and advanced cancer. In order to improve the reliability of diseases detection, there is a need for applying or proposing computer-assisted methodologies to efficiently analyze and process ME-NBI images. However, traditional computer vision methodologies, mainly segmentation, do not express well to the specific visual characteristics of NBI scenario. METHODS: In this paper, two energy functional items based on specific visual characteristics of ME-NBI images have been integrated in the framework of Chan-Vese model to construct the Hue-texture-embedded model. On the one hand, a global hue energy functional was proposed representing a global color information extracted in H channel (HSI color space). On the other hand, a texture energy was put forward presenting local microvascular textures extracted by the PIF of adaptive threshold in S channel. RESULTS: The results of our model have been compared with Chan-Vese model and manual annotations marked by physicians using F-measure and false positive rate. The value of average F-measure and FPR was 0.61 and 0.16 achieved through the Hue-texture-embedded region-based model. And the C-V model achieved the average F-measure and FPR value of 0.52 and 0.32, respectively. Experiments showed that the Hue-texture-embedded region-based outperforms Chan-Vese model in terms of efficiency, universality and lesion detection. CONCLUSIONS: Better segmentation results are acquired by the Hue-texture-embedded region-based model compared with the traditional region-based active contour in these five cases: chronic gastritis, intestinal metaplasia and atrophy, low grade neoplasia, high grade neoplasia and early gastric cancer. In the future, we are planning to expand the universality of our proposed methodology to segment other lesions such as intramucosal cancer etc. As long as these issues are solved, we can proceed with the classification of clinically relevant diseases in ME-NBI images to implement a fully automatic computer-assisted diagnosis system.