A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5′′ position has been developed. The structural activity relationship (SAR) against ...aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs.
Background
Heart block is the most common and concerning complication associated with transcatheter device closure of perimembranous ventricular septal defect (pmVSD) and its occurrence remains a ...great challenge for device closure.
Methods
Between June 2002 and June 2020, 1076 pediatric patients with pmVSD, who successfully underwent transcatheter device closure in our center, were enrolled in this cohort study, with a median follow-up of 64 months (range: 1 to 19 years).
Results
Of 1076 patients, 234 (21.8%) developed postprocedural heart block, with right bundle branch block being the most common (74.8%), followed by left bundle branch block (16.2%), and atrioventricular block (5.6%). Complete atrioventricular block occurred in 5 cases, including 3 cases with permanent pacemaker implantation, 1 case with recovery to normal sinus rhythm, and 1 case with sudden cardiac death. Most patients (97.9%) developed heart block within 1 week of procedure. Finally, 138 cases returned to normal cardiac conduction. Multivariate logistic regression revealed that thin-waist occluders (odds ratio OR: 1.759; 95% confidence interval CI: 1.023 to 3.022;
P
= 0.041), and oversized devices (OR: 1.809; 95% CI: 1.322 to 2.476;
P
< 0.001) were independently associated with occurrence of postprocedural heart block. Moreover, heart block was less likely to occur when the left disk of occluder was placed within the aneurysmal tissue (OR: 0.568; 95% CI: 0.348 to 0.928;
P
= 0.024).
Conclusion
The outcome of postprocedural heart block is favorable in most cases. Oversized devices and thin-waist occluders should be avoided. Placement of the left disk of the device should into the aneurysmal tissue is highly recommended.
K-ras-mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine ...IL-1β, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1β in the lungs of mice with K-rasG12D-mutant tumors (CC-LR mice). Here, we blocked IL-1β using an anti-IL-1β mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1β blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 PD-1 expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1β blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.
The intracellular delivery of messenger (m)RNA holds great potential for the discovery and development of vaccines and therapeutics. Yet, in many applications, a major obstacle to clinical ...translation of mRNA therapy is the lack of efficient strategy to precisely deliver RNA sequence to liver tissues and cells. In this study, we synthesized virus-like mesoporous silica (V-SiO
) nanoparticles for effectively deliver the therapeutic RNA. Then, the cationic polymer polyethylenimine (PEI) was included for the further silica surface modification (V-SiO
-P). Negatively charged mRNA motifs were successfully linked on the surface of V-SiO
through electrostatic interactions with PEI (m@V-SiO
-P). Finally, the supported lipid bilayer (LB) was completely wrapped on the bionic inspired surface of the nanoparticles (m@V-SiO
-P/LB). Importantly, we found that, compared with traditional liposomes with mRNA loading (m@LNPs), the V-SiO
-P/LB bionic-like morphology effectively enhanced mRNA delivery effect to hepatocytes both
and
, and PEI modification concurrently promoted mRNA binding and intracellular lysosomal escape. Furthermore, m@V-SiO
-P increased the blood circulation time (t
= 7 h) to be much longer than that of the m@LNPs (4.2 h). Understanding intracellular delivery mediated by the V-SiO
-P/LB nanosystem will inspire the next-generation of highly efficient and effective mRNA therapies. In addition, the nanosystem can also be applied to the oral cavity, forehead, face and other orthotopic injections.
Drought and nitrogen addition are important factors influencing soil microorganisms and changes in the soil environment. In the future, droughts will become more frequent, shorter, and more severe. ...However, little is known about the soil organic carbon components, enzyme activity, and composition, structure, and functional genes of soil microbial communities under short-term drought and nitrogen application conditions. In this study, we used metagenomics sequencing technology to explore the changes in the composition and functional genes of soil microbial communities under short-term drought, nitrogen application, and their interactions in the artificial grasslands of the Loess Plateau. The results indicated that (I) short-term drought, nitrogen application, and their interactions all increased the particulate organic carbon (POC) content. (II) Short-term drought increased the contents of soil microbial biomass carbon (MBC) and microbial biomass nitrogen (MBN), as well as soil enzyme activity. (III) Short-term drought significantly increased the bacterial alpha diversity, whereas the interactions of short-term drought and nitrogen application enhanced the fungal alpha diversity. (IV) The interactions of short-term drought and nitrogen application inhibited
Fusarium
to prevent plant diseases. (V) Short-term drought enriched the relative abundance of genes related to carbon cycling and amino acid metabolism, while nitrogen application reduced genes related to carbon cycling but enriched genes related to glycan biosynthesis and metabolism. These results clearly showed that, short-term drought altered the composition and functional genes of soil microbial communities. Our research suggests that in the event of frequent short-term droughts in the future, nitrogen addition can be considered to maintain the diversity of soil microbial communities and sustain soil carbon and nitrogen cycling.
The work experimentally studies the yielding behavior of polymethyl methacrylate (PMMA) at three different loading rates through a developed combined shear–compression test technique which contains a ...universal materials testing machine, mental blocks with double beveled ends (combined shear–compression loading setup) and a column sleeve made of Teflon. The results show that the failure loci agree well with theoretical predictions involving the strain rate dependence, which indicates the validity of this test method. Additionally, the experimental data enrich the previous experimental work about polymer yielding surface in the principle stress space.
We prepared two-phase hydrogenated silicon carbide (SiC:H) intrinsic materials from silane–methane gas mixtures at a low temperature of 150°C using radio-frequency plasma enhanced chemical vapor ...deposition (RF-PECVD). We then employed Raman, HRTEM and FT-IR measurements to investigate the structural evolution of the resulting two-phase heterostructure films, and confirmed the medium range order of SiC:H materials based on the intensity of the transverse acoustic mode and microstructure factor. High concentration of medium order materials associated with nanocrystalline Si was obtained in the amorphous silicon carbide/nanocrystalline silicon hybrid layers. Under optimized deposition conditions, the intrinsic film has an optical band gap of up to ~2.0eV and photosensitivity of up to ~4×106; these qualities make it an excellent intrinsic material to use when fabricating wide band gap top cells for multi-junction thin film silicon solar cells. Using both wide band gap window layers and intrinsic layers, a high open-circuit voltage of 1.04V and short-circuit current density of 9.66mA/cm2 were achieved for a single junction n–i–p solar cell on stainless steel.
•Two-phase SiC:H intrinsic films have an E04 of up to ~2.0eV and photosensitivity of up to ~4×106.•High concentration of the medium order with nanocrystalline Si was obtained in SiC:H films.•A n–i–p type SiC:H solar cell with Voc=1.04V was deposited at a low substrate temperature of 150°C.
The in vitro osteogenic differentiation process and in vivo bone regenerative property of human amniotic epithelial cells (hAECs) were investigated. The results showed improved bone regeneration by ...direct participation and a reduced early host immune response. hAECs possess proper osteogenic differentiation potential, with a modulatory influence on early tissue remodeling, making these cells a potential source of progenitor cells for clinical restoration of the alveolar defect.
The present study investigated the detailed in vitro osteogenic differentiation process and in vivo bone regenerative property of human amniotic epithelial cells (hAECs). The in vitro osteogenic differentiation process of hAECs was evaluated by biochemical staining, real‐time polymerase chain reaction, and immunofluorescence. Next, β‐tricalcium phosphate (β‐TCP) scaffolds alone or loaded with hAECs were implanted into the alveolar defects of rats. Micro‐computed tomography evaluation and histologic studies were conducted. Our results validated the in vitro osteogenic capacity of hAECs by upregulation of Runx2, osterix, alkaline phosphatase, collagen I, and osteopontin, with positive biochemical staining for osteoblasts. An epithelial‐mesenchymal transformation process might be involved in the osteogenic differentiation of hAECs by increased expression of transforming growth factor‐β1. Our data also demonstrated that in vivo implantation of hAECs loaded on β‐TCP scaffolds, not only improved bone regeneration by direct participation, but also reduced the early host immune response to the scaffolds. The presented data indicate that hAECs possess proper osteogenic differentiation potential and a modulatory influence on the early tissue remodeling process, making these cells a potential source of progenitor cells for clinical restoration of the alveolar defect.
We aimed to assess the survival benefit of surgery for patients with stage IA-IIB small cell lung cancer (SCLC) and construct a nomogram for predicting overall survival (OS).
Patients who had been ...diagnosed with stage IA-IIB SCLC between 2004 and 2014 and who had received active treatment were selected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was OS. Cox proportional hazards models and propensity score (PS) analyses were used to compare the associations between surgery and OS. The probability of 1- and 3-year OS was predicted using a nomogram.
We reviewed 2,246 patients. The median OS of the surgery and non-surgery groups was 35 months and 19 months, respectively. Multivariable Cox proportional hazards models showed a survival benefit in the surgery group (hazards ratio HR, 0.642; 95% confidence interval CI, 0.557-0.740;
< 0.001). To balance the between-group measurable confounders, the impact of surgery on OS was assessed using PS matching. After PS matching, OS analysis still favored surgical resection. The PS-stratification, PS-weighting, and PS-adjustment models showed similar results to demonstrate a statistically significant benefit for surgery. Further, the nomogram was well calibrated and had good discriminative ability (Harrell's
-index = 0.645).
Our analysis suggests that surgery is a viable option for patients with early-stage SCLC. Our nomogram is a viable tool for quantifying treatment trade-off assumptions and may assist clinicians in decision-making. Future work is needed to validate our results and improve our tools.
Gene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease ...into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification.
Mutational status of EGFR, KRAS, and TP53 was used to define seven mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma.
The proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with co-mutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival.
The mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into seven subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.
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