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Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by deficient activity of iduronate-2-sulfatase (I2S), leading to pathological accumulation of glycosaminoglycans (GAGs) in tissues. We used iduronate-2-sulfatase knockout (Ids KO) mice to investigate if liver-directed recombinant adeno-associated virus vectors (rAAV8-LSP-hIDSco) encoding human I2S (hI2S) could cross-correct I2S deficiency in Ids KO mouse tissues, and we then assessed the translation of mouse data to non-human primates (NHPs). Treated mice showed sustained hepatic hI2S production, accompanied by normalized GAG levels in somatic tissues (including critical tissues such as heart and lung), indicating systemic cross-correction from liver-secreted hI2S. Brain GAG levels in Ids KO mice were lowered but not normalized; higher doses were required to see improvements in brain histology and neurobehavioral testing. rAAV8-LSP-hIDSco administration in NHPs resulted in sustained hepatic hI2S production and therapeutic hI2S levels in cross-corrected somatic tissues but no hI2S exposure in the central nervous system, perhaps owing to lower levels of liver transduction in NHPs than in mice. Overall, we demonstrate the ability of rAAV8-LSP-hIDSco to cross-correct I2S deficiency in mouse somatic tissues and highlight the importance of showing translatability of gene therapy data from rodents to NHPs, which is critical for supporting translation to clinical development.

Heavy metals are nondegradable in the natural environment and harmful to the ecological system and human beings, causing an increased environmental pollution problem. It is required to remove heavy metals from wastewater urgently. Up until now, various methods have been involved in the heavy metal removals, such as chemical precipitation, chemical reduction, electrochemical, membrane separation, ion exchange, biological, and adsorption methods. Among them, adsorption by graphene–based materials has attracted much more attentions for the removal of heavy metals from wastewater systems in recent years, arising due to their large specific surface area, high adsorption capacity, high removal efficiency, and good recyclability. Therefore, it is quite important to review the heavy metal removal with the graphene–based material. In this review, we have summarized the physicochemical property and preparation methods of graphene and their adsorption property to heavy metals. The influencing parameters for the removal of heavy metals by graphene–based materials have been discussed. In addition, the modification of graphene–based materials to enhance their adsorption capability for heavy metal removal is also reviewed. The heavy metal removal by modified graphene–based materials in the tobacco industry has been especially described in detail. Finally, the future trend for graphene–based materials in the field of heavy metal wastewater treatment is proposed. This knowledge will have great impacts on the field and facilitate the researchers to seek the new functionalization method for graphene–based materials with high adsorption capacity to heavy metals in the tobacco industry in the future.

Abstract Objective To analyze the clinical audiological characteristics of X-Linked Alport syndrome (XLAS) in males and their relationships with genotypes. Methods The clinical data of 87 male patients with AS were reviewed. Hearing levels were evaluated using pure tone audiometry (PTA) testing, acoustic immittance, and otoacoustic emissions (OAE) testing. The genotypes of COL4A5 and the pathogenic variants were analyzed. The relationships between auditory phenotypes and genotypes were analyzed. Results Among the 87 patients, the number of patients with normal hearing and hearing loss were 32 and 55, respectively. In all cases, the hearing loss was characterized as bilateral symmetrical sensorineural deafness. Majority of the patients had mild-to-moderate hearing loss. Hearing loss usually started in the middle frequency range and gradually affected high frequencies, at school age and gradually increased with increasing age. However, it maintained a relatively steady level of 50–60 dB HL during the teenage years. The audiometric curves included groove-type in 51 cases (92.73%). Patients were identified to have 60 different COL4A5 pathogenic variants. Of the 49 patients who were followed-up for more than 2 years, 28 cases presented a decreasing trend in the hearing level of about 5 dB per year. The degree of hearing loss was positively correlated with gene mutation type and renal function. Conclusions Hearing loss in males with XLAS is symmetrical sensorineural, and progressive with increasing age. There is a significant correlation between the degree of hearing loss and genotype, renal function, and age.

SUMOylation is post-translational modification implicated in several biological pathways. Here the authors describe an approach for the global profiling of SUMO attachment sites under native conditions that also allows the parallel determination of SUMO and Ub attachments.

Gaining insight into normal cellular signaling and disease biology is a critical goal of proteomic analyses. The ability to perform these studies successfully to extract the maximum value and discovery of biologically relevant candidate biomarkers is therefore of primary importance. Many successful studies in the past have focused on total proteome analysis (changes at the protein level) combined with phosphorylation analysis by metal affinity enrichment (changes at the PTM level). Here, we use the gastric carcinoma cell line MKN-45 treated with the c-Met inhibitor SU11274 and PKC inhibitor staurosporine to investigate the most efficient and most comprehensive strategies for both total protein and PTM analysis. Under the conditions used, total protein analysis yielded few changes in response to either compound, while analysis of phosphorylation identified thousands of sites that changed differentially between the two treatments. Both metal affinity and antibody-based enrichments were used to assess phosphopeptide changes, and the data generated by the two methods was largely complementary (non-overlapping). Label-free quantitation of peptide peak abundances was used to accurately determine fold-changes between control and treated samples. Protein interaction network analysis allowed the data to be placed in a biologically relevant context, and follow-up validation of selected findings confirmed the accuracy of the proteomic data. Together, this study provides a framework for start-to-finish proteomic analysis of any experimental system under investigation to maximize the value of the proteomic study and yield the best chance for uncovering actionable target candidates.

By analyzing the different phenotypes of two Chinese DFNA9 families with the same mutation located in the intervening region between the LCCL and vWFA domains of cochlin and testing the functional changes in the mutant cochlin, we investigated the different pathogeneses for mutations in LCCL and vWFA domains.Targeted next-generation sequencing for deafness-related genes was used to identify the mutation in the proband in family #208. The probands of family #208 and family #32 with the same p.C162Y mutation were followed for more than 3 years to evaluate the progression of hearing loss and vestibular dysfunction using pure-tone audiometry, caloric testing, electrocochleogram, vestibular-evoked myogenic potential, and video head-impulse test. The disruption of normal cleavage to produce secreted LCCL domain fragments and the tendency to form aggregations of mutant cochlins were tested by in vitro cell experiments.The two families showed different clinical symptoms. Family #32 was identified as having early-onset, progressive sensorineural hearing loss, similar to the symptoms in DFNA9 patients with cochlin mutations in the vWFA domain. The proband of family #208 endured late-onset recurrent paroxysmal vertigo attacks and progressively deteriorating hearing, similar to symptoms in those with cochlin mutations in the LCCL domain. We therefore suggest that the disrupted cleavage of the LCCL domain fragment is likely to cause vestibular dysfunction, and aggregation of mutant cochlin caused by mutations in the vWFA domain is responsible for early-onset hearing loss. The p.C162Y mutation causes either disruption of LCCL domain fragment cleavage or aggregation of mutant cochlin, resulting in the different phenotypes in the two families.This study demonstrates that DFNA9 families with the same genotype may have significantly different phenotypes. The mutation site in cochlin is related to the pathological mechanism underlying the different phenotypes.

We have discovered an Aleuria Aurantia Lectin (AAL)-reactive immunoglobulin G (IgG) that naturally occurs in the circulation of rabbits and mice, following immune responses induced by various foreign antigens. AAL can specifically bind to fucose moieties on glycoproteins. However, most serum IgGs are poorly bound by AAL unless they are denatured or treated with glycosidase. In this study, using an immunogen-independent AAL-antibody microarray assay that we developed, we detected AAL-reactive IgG in the sera of all animals that had been immunized 1-2 weeks previously with various immunogens with and without adjuvants and developed immunogen-specific responses. All of these animals subsequently developed immunogen-specific immune responses. The kinetics of the production of AAL-reactive IgG in mice and rabbits were distinct from those of the immunogen-specific IgGs elicited in the same animals: they rose and fell within one to two weeks, and peaked between four to seven days after exposure, while immunogen-specific IgGs continued to rise during the same period. Mass spectrometric profiling of the Fc glycoforms of purified AAL-reactive IgGs indicates that these are mainly comprised of IgGs with core-fucosylated and either mono-or non-galactosylated Fc N-glycan structures. Our results suggest that AAL-reactive IgG could be a previously unrecognized IgG subset that is selectively produced at the onset of a humoral response.

Abstract Interleukin-18, a member of the interleukin − 1 family of cytokines, is upregulated in glioma. However, its effects on glioma remain unclear. This study aimed to explore the role and underlying mechanisms of interleukin-18 expression in glioma. Here, we demonstrated that interleukin-18 enhanced resistance to temozolomide by increasing proliferation and inhibiting apoptosis in cultured glioma cells. Further in vivo studies revealed that interleukin-18 promoted temozolomide resistance in BALB/c nude mice bearing tumor. Mechanical exploration indicated that interleukin-18 stimulation could activate the PI3K/AKT signaling pathway in glioma cells, and PI3K inhibition could reduce the temozolomide resistance promoted by interleukin-18. We found that interleukin-18 upregulated CD274 expression in glioma, revealing its potential effects on the microenvironment. Furthermore, we established a tumor xenograft model and explored the therapeutic efficacy of anti-interleukin-18 monoclonal antibody. Targeting interleukin-18 prolonged survival and attenuated CD274 expression in the mice bearing tumor. Combined treatment with anti-interleukin-18 and anti-PD-1 monoclonal antibody showed better efficacy in suppressing tumor growth than either treatment alone in mice bearing tumor. Collectively, these data present that interleukin-18 promotes temozolomide chemoresistance in glioma cells via PI3K/Akt activation and establishes an immunosuppressive milieu by modulating CD274. This study highlights the therapeutic value of interleukin-18 in glioma.

Calcium–magnesium–alumina–silicate (CMAS) corrosion has attracted special attention in the thermal barrier coating (TBC) field. At high temperatures, when CMAS melts, it adheres to the coating surface and penetrates the interior, severely destroying the TBC. In this study, a promising CMAS-phobic and infiltration-inhibiting material, GdPO4, on which molten CMAS is difficult to wet and penetrate, was proposed. These desirable attributes are explained by analyzing the material characteristics of GdPO4 and its interfacial reaction with CMAS. GdPO4 is demonstrated to have low surface energy, making it difficult for molten CMAS to wet and adhere to the surface. When in contact with molten CMAS, a double-layer structured reaction layer consisting of an acicular upper sublayer and a compact lower sublayer is formed on the GdPO4 surface, which can effectively impede molten CMAS spreading and penetration. First-principles calculation results revealed that the reaction layer has low surface energy and low adhesion to CMAS, which are favorable for molten CMAS phobicity. Additionally, the formation of the reaction layer increases the viscosity of the molten CMAS, which can increase melt wetting and penetration. Hence, GdPO4, which exhibits excellent CMAS-phobicity and infiltration-inhibiting ability, is a promising protective layer material for TBCs against CMAS adhesion and attack.

Abstract Background Naïve CD4+ T cells and their differentiated counterparts play a significant regulatory role in the tumor immune microenvironment, yet their effects on lung adenocarcinoma (LUAD) are not fully understood. Methods We utilized Mendelian randomization to assess the causal association between naïve CD4+ T cells and LUAD. Employing a modified single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm with The Cancer Genome Atlas (TCGA) database, we determined the infiltration levels of naïve CD4+ T cells and their differentiation subtypes and investigated their correlation with clinical characteristics. Potential regulatory pathways of T helper cells were identified through Mantel tests and Kyoto Encyclopedia of Genes and Genomes (KEGG) database enrichment analysis. Results Mendelian randomization analysis revealed an inhibitory effect of naïve CD4+ T cells on LUAD (false discovery rate

ABSTRACT Background This study aimed to identify a specific SCLC population that would benefit from surgery. Methods This study utilized patient data retrieved from the Surveillance, Epidemiology, and End Results (SEER) database spanning 2010 to 2017. To mitigate clinical biases, the propensity score matching (PSM) technique was employed. Separate cohorts were aligned using PSM according to the AJCC 8th edition TNM classification. The Kaplan–Meier method and a competing risk model were applied to evaluate overall survival (OS) and lung cancer–specific survival (LCSS), respectively. Outcomes Among the 3394 patients with potentially resectable SCLC included in the study, 3062 underwent chemoradiotherapy and 332 underwent surgical treatment with adjuvant chemotherapy. Surgery was associated with better OS (median OS: 49 months; 95% CI: 35–63 months vs. 27 months; 95% CI: 21–33 months, p

Molten salt from the service environment leaches Y2O3 from yttria-stabilized zirconia (YSZ), threatening the security of thermal barrier coatings (TBCs). In this study, we compared the molten salt corrosion resistances of YSZ coatings prepared via plasma-spraying physical vapor deposition (PS-PVD) before and after laser remelting. At 1000 °C, the molten salt reacted with YSZ particulates in the PS-PVD YSZ coating and infiltrated the gaps between quasi-columnar crystals, resulting in phase transition of the coating and column breakage. A dense glazed layer was formed on the YSZ coating surface after remelting by the low-energy-density laser, which prohibited the penetration of molten salt and improved the hot corrosion resistance of the YSZ coating. By contrast, the failure of the high-energy-density laser-treated YSZ coating was accelerated due to the significant interfacial stress from the thick glazed layer and volume expansion caused by the corrosion products. Our investigation revealed the structural evolution of the PS-PVD YSZ coating under hot corrosion conditions, emphasized the role of laser remelting, and could serve as a guideline for TBCs modification.

Abstract Lung isolation usually refers to the isolation of the operative from the non-operative lung without isolating the non-operative lobe(s) of the operative lung. We aimed to evaluate whether protecting the non-operative lobe of the operative lung using a double-bronchial blocker (DBB) with continuous positive airway pressure (CPAP) could reduce the incidence of postoperative pneumonia. Eighty patients were randomly divided into two groups (n = 40 each): the DBB with CPAP (Group DBB) and routine bronchial blocker (Group BB) groups. In Group DBB, a 7-Fr BB was placed in the middle bronchus of the right lung for right lung surgery and in the inferior lobar bronchus of the left lung for left lung surgery. Further, a 9-Fr BB was placed in the main bronchus of the operative lung. In Group BB, routine BB placement was performed on the main bronchus on the surgical side. The primary endpoint was the postoperative pneumonia incidence. Compared with Group BB, Group DBB had a significantly lower postoperative pneumonia incidence in the operative (27.5% vs 5%, P = 0.013) and non-operative lung (40% vs 15%) on postoperative day 1. Compared with routine BB use for thoracoscopic lobectomy, using the DBB technique to isolate the operative lobe from the non-operative lobe(s) of the operative lung and providing CPAP to the non-operative lobe(s) through a BB can reduce the incidence of postoperative pneumonia in the operative and non-operative lungs.

This work aims to fully characterise the Nb-Ti-Si based alloy (Nb-26Ti-16Si-2.2Al-2Cr), processed by the electron-beam powder-bed-fusion in both as-built and heat-treated conditions, to elucidate the microstructure-property relationships. The as-built condition has [001]-oriented columnar grains of the Nb3Si phase with the Nbss phase dispersed throughout the microstructure. The microhardness is 645.2 ± 6.7 HV0.5, and the indentation fracture toughness shows distinct directionality: 7.7 MPa·m1/2 in the horizontal direction compared to 5.3 MPa·m1/2 in the vertical direction. Both properties are comparable to the cast version. The directionality is attributed to the underlying mechanisms such as crack bridging, arrest, and micro-crack formation. By contrast, in the heat-treated condition, the alloy exhibits a dual-phase microstructure (Nbss and Nb5Si3 phases) with near-equiaxed grain shape due to the Nb3Si phase decomposition. The fracture toughness increases to 12.1 MPa·m1/2, at the expense of a reduced microhardness of 564.4 ± 15.0 HV0.5.

Summary: High-sensitivity nanoflow liquid chromatography (nLC) is seldom employed in untargeted metabolomics because current sample preparation techniques are inefficient at preventing nanocapillary column performance degradation. Here, we describe an nLC-based tandem mass spectrometry workflow that enables seamless joint analysis and integration of metabolomics (including lipidomics) and proteomics from the same samples without instrument duplication. This workflow is based on a robust solid-phase micro-extraction step for routine sample cleanup and bioactive molecule enrichment. Our method, termed proteomic and nanoflow metabolomic analysis (PANAMA), improves compound resolution and detection sensitivity without compromising the depth of coverage as compared with existing widely used analytical procedures. Notably, PANAMA can be applied to a broad array of specimens, including biofluids, cell lines, and tissue samples. It generates high-quality, information-rich metabolite-protein datasets while bypassing the need for specialized instrumentation. Motivation: The ability to routinely, sensitively, and reproducibly analyze both cellular proteins and metabolite mixtures from the same biospecimens can enhance the discovery of biomolecules associated with basic biochemical processes and pathobiological states. Yet existing mass spectrometry-based profiling methods rely on specialized protocols and duplicated instrumentation platforms, resulting in increased time, sample consumption, and costs. We sought to generate an effective platform for both metabolomics and proteomics studies on the same samples by enabling nanoflow liquid chromatography for small molecules. The resulting approach was extensively optimized and benchmarked to provide in-depth molecular coverage, along with improved chromatographic separation, sensitivity, and reliability as compared with existing methods. The cost-benefit ratio of PANAMA is substantial because the platform bypasses the need for specialized instrumentation stemming from incompatible procedures.

BackgroundThis study aimed to assess the role and effect of neoadjuvant targeted therapy (TT) versus targeted combined with chemotherapy (TC) for resectable EGFR-mutant non–small cell lung cancer (NSCLC).MethodsBetween March 2021 and June 2023, 20 patients with stage IA3-IIIB NSCLC were enrolled in the study. Eleven patients received EGFR-TKIs in the TT group, while nine patients received EGFR-TKIs and two cycles of cisplatin-based doublet chemotherapy (TC group). We compare the differences between the two groups through the following variables, including age, sex, surgical approach, postoperative complications, neoadjuvant therapy adverse events, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), major pathologic response (MPR), and pathologic complete response (pCR).ResultsPatients were predominantly female (75%) and never-smokers (95%). The average age was 59.2 years (range 46-79 years). Fifty-five percent harbored an exon 19 EGFR mutation and 45% an exon 21 mutation. The average targeted drug dosing time was 2.91 ± 1.7 (range 1-6) months in the TT group and 3.56 ± 3.54 (range 1-12) months in the TC group (P=0.598). The most common side effects were rash and diarrhea. No grade 5 events with neoadjuvant therapy were observed. The rate of R0 resection was 100% in all patients. Among the 11 patients in the TT group, 6 achieved a PR and 5 had SD, resulting in an ORR of 54.5%. Among the 9 patients in the TC group, 6 had PR and the remaining 3 had SD, resulting in an ORR of 66.6%. one patient (11.1%) in the TC group achieved pCR, while no patients in the TT group achieved pCR (P = 0.142). Two patients (18.2%) in the TT group reached MPR, and 2 patients (22.2%) in the TC group reached MPR (P = 0.257). The overall clinical downstage rate is 60%. Only 9 (45%) cases of yield clinical TNM (ycTNM) were consistent with yield pathologic TNM (ypTNM).ConclusionResults from this retrospective controlled research indicate that the neoadjuvant TT group is likely to be more effective outcomes and has safer profile in patients with EGFR-positive NSCLC than the neoadjuvant TC group. However, our results need to be validated in a multicenter, large sample prospective study.

Abstract Urban greenspaces continue to grow with global urbanization. The global distribution and stock of soil organic carbon (SOC) in urban greenspaces remain largely undescribed and missing in global carbon (C) budgets. Here, we synthesize data of 420 observations from 257 cities in 52 countries to evaluate the global pattern of surface SOC density (0–20 cm depth) in urban greenspaces. Surface SOC density in urban greenspaces increases significantly at higher latitudes and decreases significantly with higher mean annual temperature, stronger temperature and precipitation seasonality, as well as lower urban greenness index. By mapping surface SOC density using a random forest model, we estimate an average SOC density of 55.2 (51.9–58.6) Mg C ha−1 and a SOC stock of 1.46 (1.37–1.54) Pg C in global urban greenspaces. Our findings present a comprehensive assessment of SOC in global urban greenspaces and provide a baseline for future urban soil C assessment under continuing urbanization.