Pharmacological induction of autophagy reduces inflammation in macrophages by degrading immunoproteasome subunits.

Defective autophagy is linked to proinflammatory diseases. However, the mechanisms by which autophagy limits inflammation remain elusive. Here, we found that the pan-FGFR inhibitor LY2874455 efficiently activated autophagy and suppressed expression of proinflammatory factors in macrophages stimulated by lipopolysaccharide (LPS). Multiplex proteomic profiling identified the immunoproteasome, which is a specific isoform of the 20s constitutive proteasome, as a substrate that is degraded by selective autophagy. SQSTM1/p62 was found to be a selective autophagy-related receptor that mediated this degradation. Autophagy deficiency or p62 knockdown blocked the effects of LY2874455, leading to the accumulation of immunoproteasomes and increases in inflammatory reactions. Expression of proinflammatory factors in autophagy-deficient macrophages could be reversed by immunoproteasome inhibitors, confirming the pivotal role of immunoproteasome turnover in the autophagy-mediated suppression on the expression of proinflammatory factors. In mice, LY2874455 protected against LPS-induced acute lung injury and dextran sulfate sodium (DSS)-induced colitis and caused low levels of proinflammatory cytokines and immunoproteasomes. These findings suggested that selective autophagy of the immunoproteasome was a key regulator of signaling via the innate immune system.

Interleukin 28A aggravates Con A-induced acute liver injury by promoting the recruitment of M1 macrophages.

Immune-mediated acute hepatic injury is characterized by the destruction of a large number of hepatocytes and severe liver function damage. Interleukin-28A (IL-28A), a member of the IL-10 family, is notable for its antiviral properties. However, despite advances in our understanding of IL-28A, its role in immune-mediated acute injury remains unclear. The present study investigated the role of IL-28A in concanavalin A (Con A)-induced acute immune liver injury. After Con A injection in mice, IL-28A level significantly increased. IL-28A deficiency was found to protect mice from acute liver injury, prolong survival time, and reduce serum aspartate aminotransferase and alanine aminotransferase levels. In contrast, recombinant IL-28A aggravated liver injury in mice. The proportion of activated M1 macrophages was significantly lower in the IL-28A-deficiency group than in the wild-type mouse group. In adoptive transfer experiments, M1 macrophages from WT could exacerbate mice acute liver injury symptoms in the IL-28A deficiency group. Furthermore, the expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), IL-12, IL-6, and IL-1ß, by M1 macrophages decreased significantly in the IL-28A-deficiency group. Western blotting demonstrated that IL-28A deficiency could limit M1 macrophage polarization by modulating the nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK), and interferon regulatory factor (IRF) signaling pathways. In summary, IL-28A deletion plays an important protective role in the Con A-induced acute liver injury model and IL-28A deficiency inhibits the activation of M1 macrophages by inhibiting the NF-κB, MAPK, and IRF signaling pathways. These results provide a potential new target for the treatment of immune-related hepatic injury.

Trajectory patterns and cumulative burden of CEA during follow-up with non-small cell lung cancer outcomes: A retrospective longitudinal cohort study.

BACKGROUND: Previous studies of non-small cell lung cancer (NSCLC) focused on CEA measured at a single time point, ignoring serial CEA measurements. METHODS: This retrospective cohort included 2959 patients underwent surgery for stage I-III NSCLC. CEA trajectory patterns and long-term cumulative CEA burden were evaluated using the latent class growth mixture model. RESULTS: Four CEA trajectory groups were identified, named as low-stable, decreasing, early-rising and later-rising. Compared with the low-stable group, the adjusted hazard ratios associated with death were 1.27, 4.50, and 3.68 for the other groups. Cumulative CEA burden were positively associated with the risk of death in patients not belonging to the low-stable group. The 5-year overall survival (OS) rates decreased from 62.3% to 33.0% for the first and fourth quantile groups of cumulative CEA burden. Jointly, patients with decreasing CEA trajectory could be further divided into the decreasing & low and decreasing & high group, with 5-year OS rates to be 77.9% and 47.1%. Patients with rising CEA trajectory and high cumulative CEA were found to be more likely to develop bone metastasis. CONCLUSIONS: Longitudinal trajectory patterns and long-term cumulative burden of CEA were independent prognostic factors of NSCLC. We recommend CEA in postoperative surveillance of NSCLC.

NaYF4 :Yb/Er@Mn3 O4 @GOX Nanocomposite for Upconversion Fluorescence Imaging and Synergistic Cascade Cancer Therapy by Apoptosis and Ferroptosis.

The cell elimination strategy based on reactive oxygen species (ROS) is a promising method for tumor therapy. However, its efficacy is significantly limited by ROS deficiency caused by H2 O2 substrate deficiency and up-regulation of cellular antioxidant defense induced by high glutathione (GSH) content in tumor cells. To overcome these obstacles, a multifunctional self-cascaded nanocomposite: glucose oxidase (GOX) loaded NaYF4 :Yb/Er@Mn3 O4 (UC@Mn3 O4 , labeled as UCMn) is constructed. Only in tumor microenvironment, it can be specifically activated through a series of cascades to boost ROS production via a strategy of open source (H2 O2 self-supplying ability). The increased ROS can enhance lipid peroxidation and induce tumor cell apoptosis by activating the protein caspase. More importantly, the nanozyme can consume GSH to inhibit glutathione peroxidase 4 (GPX4) activity, which limits tumor cell resistance to oxidative damage and triggers the tumor cell ferroptosis. Therefore, this strategy is expected to overcome the resistance of tumor to oxidative damage and achieve efficient oxidative damage of tumor. Further, degradation of the Mn3 O4 layer induced by GSH and acidic environment can promote the fluorescence recovery of UC fluorescent nuclear for tumor imaging to complete efficient integration of diagnosis and treatment for tumor.

Arabidopsis membrane protein AMAR1 interaction with type III effector XopAM triggers a hypersensitive response.

The efficient infection of plants by the bacteria Xanthomonas campestris pv. campestris (Xcc) depends on its type III effectors (T3Es). Although the functions of AvrE family T3Es have been reported in some bacteria, the member XopAM in Xcc has not been studied. As XopAM has low sequence similarity to reported AvrE-T3Es and different reports have shown that these T3Es have different targets in hosts, we investigated the functions of XopAM in the Xcc-plant interaction. Deletion of xopAM from Xcc reduced its virulence in cruciferous crops but increased virulence in Arabidopsis (Arabidopsis thaliana) Col-0, indicating that XopAM may perform opposite functions depending on the host species. We further found that XopAM is a lipase that may target the cytomembrane and that this activity might be enhanced by its membrane-targeted protein XOPAM-ACTIVATED RESISTANCE 1 (AMAR1) in Arabidopsis Col-0. The binding of XopAM to AMAR1 induced an intense hypersensitive response that restricted Xcc proliferation. Our results showed that the roles of XopAM in Xcc infection are not the same as those of other AvrE-T3Es, indicating that the functions of this type of T3E have differentiated during long-term bacterium‒host interactions.

Sapap4 deficiency leads to postsynaptic defects and abnormal behaviors relevant to hyperkinetic neuropsychiatric disorder in mice.

Postsynaptic proteins play critical roles in synaptic development, function, and plasticity. Dysfunction of postsynaptic proteins is strongly linked to neurodevelopmental and psychiatric disorders. SAP90/PSD95-associated protein 4 (SAPAP4; also known as DLGAP4) is a key component of the PSD95-SAPAP-SHANK excitatory postsynaptic scaffolding complex, which plays important roles at synapses. However, the exact function of the SAPAP4 protein in the brain is poorly understood. Here, we report that Sapap4 knockout (KO) mice have reduced spine density in the prefrontal cortex and abnormal compositions of key postsynaptic proteins in the postsynaptic density (PSD) including reduced PSD95, GluR1, and GluR2 as well as increased SHANK3. These synaptic defects are accompanied by a cluster of abnormal behaviors including hyperactivity, impulsivity, reduced despair/depression-like behavior, hypersensitivity to low dose of amphetamine, memory deficits, and decreased prepulse inhibition, which are reminiscent of mania. Furthermore, the hyperactivity of Sapap4 KO mice could be partially rescued by valproate, a mood stabilizer used for mania treatment in humans. Together, our findings provide evidence that SAPAP4 plays an important role at synapses and reinforce the view that dysfunction of the postsynaptic scaffolding protein SAPAP4 may contribute to the pathogenesis of hyperkinetic neuropsychiatric disorder.

Chemical Synthesis of Fucosylated Chondroitin Sulfate Tetrasaccharide with Fucosyl Branch at the 6-OH of GalNAc Residue.

Fucosylated chondroitin sulfate is a unique glycosaminoglycan isolated from sea cucumbers, with excellent anticoagulant activity. The fucosyl branch in FCS is generally located at the 3-OH of D-glucuronic acid but, recently, a novel structure with α-L-fucose linked to the 6-OH of N-acetyl-galactosamine has been found. Here, using functionalized monosaccharide building blocks, we prepared novel FCS tetrasaccharides with fucosyl branches both at the 6-OH of GalNAc and 3-OH of GlcA. In the synthesis, the protective group strategy of selective O-sulfation, as well as stereoselective glycosylation, was established, which enabled the efficient synthesis of the specific tetrasaccharide compounds. This research enriches knowledge on the structural types of FCS oligosaccharides and facilitates the exploration of the structure-activity relationship in the future.

Effect of administration routes of oxytocin on hemoglobin in neonates with delayed umbilical cord clamping: a multi-centre randomized controlled clinical trial.

PURPOSE: To evaluate the effect of intravenous infusion versus intramyometrial injection of oxytocin on hemoglobin levels in neonates with delayed umbilical cord clamping during cesarean section. METHODS: The multi-centre randomized controlled trial was performed at three hospitals from February to June 2023. Women with term singleton gestations scheduled for cesarean delivery were allocated to receive an intravenous infusion of 10 units of oxytocin or a myometrial injection of 10 units of oxytocin during the surgery. The primary outcome was neonatal hemoglobin at 48 to 96 h after birth. Secondary outcomes were side-effects of oxytocin, postpartum haemorrhage, phototherapy for jaundice, feeding at 1 month, maternal and neonatal morbidity and re-admissions. RESULTS: A total of 360 women were randomized (180 women in each group). The mean neonatal hemoglobin did not show a significant difference between the intravenous infusion group (194.3 ± 21.7 g/L) and the intramyometrial groups (195.2 ± 24.3 g/L) (p = 0.715). Secondary neonatal outcomes, involving phototherapy for jaundice, feeding at 1 month and neonatal intensive care unit admission were similar between the two groups. The maternal outcomes did not differ significantly between the two groups, except for a 200 mL higher intraoperative infusion volume observed in the intravenous group compared to the intramyometrial group. CONCLUSION: Among women undergoing elective cesarean delivery of term singleton pregnancies, there was no significant difference in neonatal hemoglobin at 48 to 96 h after birth between infants with delayed cord clamping, whether the oxytocin was administrated by intravenous infusion or intramyometrial injection. TRIAL REGISTRATION: Chinese Clinical trial registry: ChiCTR2300067953 (1 February 2023).

Interpreting the chemical changes and therapeutic effect of Coptidis Rhizoma against ulcerative colitis before and after processing based on mathematical statistics and network pharmacology.

INTRODUCTION: Coptidis Rhizoma (CR) is one of the most frequently used herbs to treat ulcerative colitis (UC) and is often processed before usage. However, the composition changes and therapeutic effects of CR before and after processing in the treatment of UC are still unclear. OBJECTIVE: The purpose of the study is to explore the chemical components and therapeutic effects of crude and processed CR. MATERIAL AND METHODS: CR was processed according to the 2020 version of the Chinese Pharmacopoeia. The liquid chromatography-mass spectrometry (LC-MS) and multivariate statistical analysis were used to screen the different compounds before and after processing. The network pharmacological prediction was carried out. The mechanism and therapeutic effects between crude and processed CR were verified by using dextran sulphate sodium-induced UC mice assay. RESULTS: Ten compounds distinguish crude and processed CR based on multivariate statistical analysis. Network pharmacology predicts that the 10 compounds mainly play a role through TNF-α and IL-6 targets and PI3K/Akt and HIF-1 signalling pathways, and these results are verified by molecular biology experiments. For IL-6, IL-10 and TNF-α inflammatory factors, CR is not effective, while CR stir-fried with Evodiae Fructus (CRFE) and ginger juice (CRGJ) are. For PI3K/p-Akt, Cleaved caspase3, NF- κBp65 and HIF-1α signalling pathways, CR has therapeutic effects, while CRFE and CRGJ are significant. CONCLUSION: Overall, CRFE and CRGJ show better effects in treating UC. The chemical changes of processing and the efficacy of processed CR are correlated, which provides a scientific basis for the clinical use of crude and processed CR.

Polyunsaturated fatty acids promote the rapid fusion of lipid droplets in Caenorhabditis elegans.

Lipid droplets (LDs) are intracellular organelles that dynamically regulate lipids and energy homeostasis in the cell. LDs can grow through either local lipid synthesis or LD fusion. However, how lipids involving in LD fusion for LD growth is largely unknown. Here, we show that genetic mutation of acox-3 (acyl-CoA oxidase), maoc-1 (enoyl-CoA hydratase), dhs-28 (3-hydroxylacyl-CoA dehydrogenase), and daf-22 (3-ketoacyl-CoA thiolase), all involved in the peroxisomal ß-oxidation pathway in Caenorhabditis elegans, led to rapid fusion of adjacent LDs to form giant LDs (gLDs). Mechanistically, we show that dysfunction of peroxisomal ß-oxidation results in the accumulation of long-chain fatty acid-CoA and phosphocholine, which may activate the sterol-binding protein 1/sterol regulatory element-binding protein to promote gLD formation. Furthermore, we found that inactivation of either FAT-2 (delta-12 desaturase) or FAT-3 and FAT-1 (delta-15 desaturase and delta-6 desaturase, respectively) to block the biosynthesis of polyunsaturated fatty acids (PUFAs) with three or more double bonds (n≥3-PUFAs) fully repressed the formation of gLDs; in contrast, dietary supplementation of n≥3-PUFAs or phosphocholine bearing these PUFAs led to recovery of the formation of gLDs in peroxisomal ß-oxidation-defective worms lacking PUFA biosynthesis. Thus, we conclude that n≥3-PUFAs, distinct from other well-known lipids and proteins, promote rapid LD fusion leading to LD growth.

Prediction models of colorectal cancer prognosis incorporating perioperative longitudinal serum tumor markers: a retrospective longitudinal cohort study.

BACKGROUND: Current prognostic prediction models of colorectal cancer (CRC) include only the preoperative measurement of tumor markers, with their available repeated postoperative measurements underutilized. CRC prognostic prediction models were constructed in this study to clarify whether and to what extent the inclusion of perioperative longitudinal measurements of CEA, CA19-9, and CA125 can improve the model performance, and perform a dynamic prediction. METHODS: The training and validating cohort included 1453 and 444 CRC patients who underwent curative resection, with preoperative measurement and two or more measurements within 12 months after surgery, respectively. Prediction models to predict CRC overall survival were constructed with demographic and clinicopathological variables, by incorporating preoperative CEA, CA19-9, and CA125, as well as their perioperative longitudinal measurements. RESULTS: In internal validation, the model with preoperative CEA, CA19-9, and CA125 outperformed the model including CEA only, with the better area under the receiver operating characteristic curves (AUCs: 0.774 vs 0.716), brier scores (BSs: 0.057 vs 0.058), and net reclassification improvement (NRI = 33.5%, 95% CI: 12.3 ~ 54.8%) at 36 months after surgery. Furthermore, the prediction models, by incorporating longitudinal measurements of CEA, CA19-9, and CA125 within 12 months after surgery, had improved prediction accuracy, with higher AUC (0.849) and lower BS (0.049). Compared with preoperative models, the model incorporating longitudinal measurements of the three markers had significant NRI (40.8%, 95% CI: 19.6 to 62.1%) at 36 months after surgery. External validation showed similar results to internal validation. The proposed longitudinal prediction model can provide a personalized dynamic prediction for a new patient, with estimated survival probability updated when a new measurement is collected during 12 months after surgery. CONCLUSIONS: Prediction models including longitudinal measurements of CEA, CA19-9, and CA125 have improved accuracy in predicting the prognosis of CRC patients. We recommend repeated measurements of CEA, CA19-9, and CA125 in the surveillance of CRC prognosis.

Usnea Acid-Incorporated Ca2+ /Mn2+ Ions Reservoirs for Elevated Ion-Interference Therapy through Synergetic Biocatalysis and Osmolarity Imbalance.

Ion-interference therapy (IIT) utilizes ions to disturb intracellular biological processes and has been received increasing attention in tumor treatments recently. However, the low therapeutic efficiency still hinders its further biological applications. Herein, via a simple and one-pot gas diffusion process, polyethylene glycol (PEG)-modified Mn2+ ions and usnic acid (UA)-incorporated CaCO3 nanomaterials (PEG CaMnUA) as Ca2+ /Mn2+ ions reservoirs are prepared for magnetic resonance imaging (MRI)-guided UA-elevated IIT. Among PEG CaMnUA, UA not only increases cytoplasmic Ca2+ ions to amplify Ca2+ overload caused by CaCO3 decomposition, but also enhances Mn2+ ions-participated Fenton-like biocatalysis by intracellular H2 O2 generation and glutathione consumption. Then increasing the intracellular oxidative stress and decreasing the triphosadenine supply induce apoptosis together, resulting in UA-boosted IIT. The simple and efficient design of the dual ions reservoirs will contribute to improve the antitumor activity of IIT and further development of calcium-based nanomaterials in the future.

Novel PdPtCu Nanozymes for Reprogramming Tumor Microenvironment to Boost Immunotherapy Through Endoplasmic Reticulum Stress and Blocking IDO-Mediated Immune Escape.

Breaking immunosuppressive tumor microenvironment (TME) has unique effects on inhibiting tumor growth and recurrence. Here, an endoplasmic reticulum (ER) targeted PdPtCu nanozyme (PNBCTER ) is prepared to boost immunotherapy. First, PNBCTER has three kinds of enzyme activities, including catalase (CAT), glutathione oxidase (GSHOx), and peroxidase (POD)-like activities, which can reshape the TME. Second, PNBCTER kills tumor cells by photodynamic therapy (PDT) and photothermal therapy (PTT). Third, guided by TER , PNBCTER not only realizes the combination therapy of PDT, PTT and chemodynamic therapy (CDT), but also damages the ER of tumor cells and actives antitumor immune response, which breaks through the immune blockade of TME. Finally, the NLG919 blocks the tryptophan/kynurenine immune escape pathway and reverses the immunosuppressive TME. The strategy that reshaping the TME by enzyme catalysis and breaking immunosuppression provides a novel way for the application of combination therapy in tumor.

Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: A large multicenter study.

BACKGROUND AND AIMS: To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. APPROACH AND RESULTS: Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. CONCLUSIONS: Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.

Untargeted serum metabolomics reveals potential biomarkers and metabolic pathways associated with the progression of gastroesophageal cancer.

BACKGROUND: Previous metabolic studies in upper digestive cancer have mostly been limited to cross-sectional study designs, which hinders the ability to effectively predict outcomes in the early stage of cancer. This study aims to identify key metabolites and metabolic pathways associated with the multistage progression of epithelial cancer and to explore their predictive value for gastroesophageal cancer (GEC) formation and for the early screening of esophageal squamous cell carcinoma (ESCC). METHODS: A case-cohort study within the 7-year prospective Esophageal Cancer Screening Cohort of Shandong Province included 77 GEC cases and 77 sub-cohort individuals. Untargeted metabolic analysis was performed in serum samples. Metabolites, with FDR q value < 0.05 and variable importance in projection (VIP) > 1, were selected as differential metabolites to predict GEC formation using Random Forest (RF) models. Subsequently, we evaluated the predictive performance of these differential metabolites for the early screening of ESCC. RESULTS: We found a distinct metabolic profile alteration in GEC cases compared to the sub-cohort, and identified eight differential metabolites. Pathway analyses showed dysregulation in D-glutamine and D-glutamate metabolism, nitrogen metabolism, primary bile acid biosynthesis, and steroid hormone biosynthesis in GEC patients. A panel of eight differential metabolites showed good predictive performance for GEC formation, with an area under the receiver operating characteristic curve (AUC) of 0.893 (95% CI = 0.816-0.951). Furthermore, four of the GEC pathological progression-related metabolites were validated in the early screening of ESCC, with an AUC of 0.761 (95% CI = 0.716-0.805). CONCLUSIONS: These findings indicated a panel of metabolites might be an alternative approach to predict GEC formation, and therefore have the potential to mitigate the risk of cancer progression at the early stage of GEC.

Holographic 3D renal segments reconstruction protects renal function by promote choice of selective renal artery clamping during robot-assisted partial nephrectomy.

OBJECTIVE: To investigate the impact of selective artery clamping (SAC) and main artery clamping (MAC) during robot-assisted partial nephrectomy (RAPN) on renal function and the influence of holographic three-dimensional (3D) reconstruction of renal segments on the selection between SAC and MAC. METHODS: This retrospective observational study included patients who underwent RAPN at First Hospital Affiliated to the Army Medical University between December 2016 and July 2022. According to the clamping methods, the patients were divided into the SAC group and the MAC group. The primary outcome was renal function. RESULTS: A total of 422 patients (194 in the SAC group and 228 in the MAC group) were included. The RAPN procedures were all completed successfully. The patients in SAC group had less glomerular filtration rate (GFR) decline in the affected kidney (8.6 ± 7.0 ml/min vs. 18.7 ± 10.9 ml/min, P < 0.001) and minor estimated glomerular filtration rate (eGFR) decrease (4.3 ± 10.5 ml/min vs. 12.6 ± 12.1 ml/min, P < 0.001) than those in MAC group. Among 37 patients with baseline renal insufficiency, the GFR decline of the affected kidney in the SAC subgroup was significantly lower than in the MAC subgroup (5.5 ± 6.5 ml/min vs. 14.3 ± 9.2 ml/min, P = 0.002). The proportion of patients who underwent 3D reconstruction was significant higher in the SAC group than in the MAC group. (65.46% vs. 28.07%, P < 0.001). CONCLUSION: The SAC technique during RAPN may serve as a protective measure for renal function, while the implementation of holographic 3D renal segment reconstruction technique may facilitate optimal selection of SAC.

Comparative genome analyses uncovered the cadmium resistance mechanism of enterobacter cloacae.

Cadmium (Cd) can be transported into plants from polluted soils and may cause animal and human diseases through food chains, which requires the development of highly efficient methods for soil Cd remediation. Although we isolated an Enterobacter cloacae strain Cu6 with Cd resistance, this strain cannot be used for soil Cd remediation due to its lower resistance. Here, we domesticated Cu6 and obtained a highly Cd-resistant strain, LPY6, and found that this strain can attenuate the toxic effects of Cd on wheat seedling growth. We deciphered the high Cd-resistance mechanism of LPY6 by genome comparative and genetic analysis. Compared with Cu6, 75 genes were mutated in LPY6. Thirty-four of these genes were deleted, and 41 had single nucleotide polymorphisms (SNPs). Most of these mutated proteins are involved in basic metabolism, substrate transport, stress response and formate and hydrogen metabolism. RNA quantitative analysis and promoter activity assays showed that the transcription or mRNA levels of two operons (cadA and norVW) in these mutated genes were regulated by Cd, zinc (Zn) or lead (Pb) ions, suggesting that these two operons might be required for Cd, Zn or Pb resistance. Expression of cadA and norVW operons in LPY6 partially recovered Cd susceptibility, demonstrating that CadA and NorVW are involved in Cd resistance in E. cloacae. Our findings illustrate that E. cloacae acquires Cd resistance through different pathways and lay a foundation for developing highly efficient methods for soil Cd remediation.

Laparoscopic antireflux surgery or PPIs in the management of reflux-related esophageal stricture.

BACKGROUND: Gastroesophageal reflux disease (GERD) is often associated with esophageal stricture, particularly benign esophageal stricture. We aimed to evaluate the effects of balloon catheter dilation (BD) combined with laparoscopic fundoplication (LF) surgery and proton pump inhibitors (PPIs) in patients with reflux-induced esophageal strictures. METHODS: We retrospectively analyzed 116 patients with reflux-induced benign esophageal strictures who underwent balloon dilatation therapy combined with PPIs (BD-PPIs group, n = 58) and balloon dilatation combined with LF (BD-LF group, n = 58). Patients were followed up for 24 months. The outcomes of the patients were monitored, including clinical success, symptom improvement, adverse events, and the frequency of esophagitis. RESULTS: At the latest follow-up, the rate of clinical success was higher in BD-LF group than in BD-PPIs group (80.4% vs. 57.7%, P = 0.011). The patients in the BD-PPIs group required more dilation sessions to achieve successful dilation, as compared to those in the BD-LF group (2.1 ± 1.2 vs. 0.7 ± 0.8, P < 0.001). The DeMeester score, number of reflux episodes for which pH was < 4, and lower esophageal sphincter pressure were significantly better in the BD-LF group than in the BD-PPIs group (all P < 0.001). The incidence of reflux esophagitis was higher in the BD-PPIs group than in the BD-LF group, at 24 months (58.8% vs. 18.2%, P = 0.003). CONCLUSIONS: Balloon dilatation with concomitant LF is effective and safe for esophageal stricture secondary to GERD. Moreover, antireflux surgery techniques, such as Nissen or Toupet procedure, should be added for reflux-induced benign esophageal stricture.

Exome and genome sequencing to unravel the precise breakpoints of partial trisomy 6q and partial Monosomy 2q.

BACKGROUND: Patients with complex phenotypes and a chromosomal translocation are particularly challenging, since several potentially pathogenic mechanisms need to be investigated. CASE PRESENTATION: Here, we combined exome and genome sequencing techniques to identify the precise breakpoints of heterozygous microduplications in the 6q25.3-q27 region and microdeletions in the 2q37.1-q37.3 region in a proband. The 5-year-old girl exhibited a severe form of congenital cranial dysinnervation disorder (CCDD) in addition to skeletal dysmorphism anomalies and severe intellectual disability. This is the second case affecting chromosomes 2q and 6q. The individual's karyotype showed an unbalanced translocation 46,XX,del(2)t(2;6)(q37.1;q25.3), which was inherited from her unaffected father [46,XY,t(2;6)(q37.1;q25.3)]. We also obtained the precise breakpoints of a de novo heterozygous copy number deletion [del(2)(q37.1q37.3)chr2:g.232963568_24305260del] and a copy number duplication [dup(6)(q25.3q27)chr6:g.158730978_170930050dup]. The parental origin of the observed balanced translocation was not clear because the parents declined genetic testing. CONCLUSION: Patients with a 2q37 deletion and 6q25.3 duplication may exhibit severe significant neurological and skeletal dysmorphisms, and the utilization of exome and genome sequencing techniques has the potential to unveil the entire translocation of the CNV and the precise breakpoint.

Chitooligosaccharides Derivatives Protect ARPE-19 Cells against Acrolein-Induced Oxidative Injury.

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly. The progression of AMD is closely related to oxidative stress in the retinal pigment epithelium (RPE). Here, a series of chitosan oligosaccharides (COSs) and N-acetylated derivatives (NACOSs) were prepared, and their protective effects on an acrolein-induced oxidative stress model of ARPE-19 were explored using the MTT assay. The results showed that COSs and NACOs alleviated APRE-19 cell damage induced by acrolein in a concentration-dependent manner. Among these, chitopentaose (COS-5) and its N-acetylated derivative (N-5) showed the best protective activity. Pretreatment with COS-5 or N-5 could reduce intracellular and mitochondrial reactive oxygen species (ROS) production induced by acrolein, increase mitochondrial membrane potential, GSH level, and the enzymatic activity of SOD and GSH-Px. Further study indicated that N-5 increased the level of nuclear Nrf2 and the expression of downstream antioxidant enzymes. This study revealed that COSs and NACOSs reduced the degeneration and apoptosis of retinal pigment epithelial cells by enhancing antioxidant capacity, suggesting that they have the potential to be developed into novel protective agents for AMD treatment and prevention.