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Gasdermin D (GSDMD)-mediated macrophage pyroptosis plays a critical role in inflammation and host defense. Plasma membrane perforation elicited by caspase-cleaved GSDMD N-terminal domain (GSDMD-NT) triggers membrane rupture and subsequent pyroptotic cell death, resulting in release of pro-inflammatory IL-1β and IL-18. However, the biological processes leading to its membrane translocation and pore formation are not fully understood. Here, using a proteomics approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner and demonstrated that post-translational palmitoylation of GSDMD at Cys191/Cys192 (human/mouse) led to membrane translocation of GSDMD-NT but not full-length GSDMD. GSDMD lipidation, mediated by palmitoyl acyltransferases ZDHHC5/9 and facilitated by LPS-induced reactive oxygen species (ROS), was essential for GSDMD pore-forming activity and pyroptosis. Inhibition of GSDMD palmitoylation with palmitate analog 2-bromopalmitate or a cell permeable GSDMD-specific competing peptide suppressed pyroptosis and IL-1β release in macrophages, mitigated organ damage, and extended the survival of septic mice. Collectively, we establish GSDMD-NT palmitoylation as a key regulatory mechanism controlling GSDMD membrane localization and activation, providing a novel target for modulating immune activity in infectious and inflammatory diseases.One Sentence SummaryLPS-induced palmitoylation at Cys191/Cys192 is required for GSDMD membrane translocation and its pore-forming activity in macrophages.

Judicious use of antibiotics and stringent adherence to practice guidelines is the need of the hour as antibiotic resistance is a rampant problem. Despite several reports in the literature describing the optimal duration of antibiotics, there is no consensus. A "one for all" protocol may be impractical and hence the guidelines need to be tweaked to take into consideration local factors. We designed a protocol for prophylactic antibiotics in clean-contaminated head and neck cancer squamous cell carcinoma (HNSCC) surgeries to prevent unchecked abuse and evaluated its feasibility.Two hundred consecutive patients who underwent a clean-contaminated surgery for HNSCC between January 2017 and December 2019 were included. Single-dose intravenous amoxicillin-clavulanate at induction followed by three doses of amoxicillin-clavulanate, metronidazole, and amikacin in the postoperative period was used. Adherence to the antibiotic protocol was assessed from a prospectively maintained database.The mean age was 55.99 ± 11.71 years. The protocol was effective in 70% of the patients with an acceptable surgical site infection (SSI) rate of 12%. Flap-related complications (9.5%) and oro-cutaneous fistula (5%) were common causes of prolonged antibiotics. On univariate analysis, blood transfusion (P = .014), clinical stage at presentation (P = .028), patients undergoing reconstruction (P = .001), longer operative time (P = .009), and pathological T stage (P = 0.03) were at higher chance of deviating from the protocol. On multivariate analysis, age more than 50 years (OR: 2.14, 95% CI: (1.01, 4.52); P value = 0.047) and reconstruction (OR: 3.36, 95% CI: (1.21, 9.32); P value = 0.020) were found to be significant.A three-dose perioperative antibiotic prophylaxis in clean-contaminated HNSCC surgeries is feasible. Similar protocols should be developed and validated at other major centers to limit the unnecessary use of antibiotics and prevent the emergence of antibiotic resistance.

Parathyroid hormone (PTH) acts on osteoblasts and functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We previously reported that PTH stimulates the expression of matrix metalloproteinase-13 (MMP-13) in rat osteoblasts and that MMP-13 plays a key role in bone remodeling, endochondral bone formation, and bone repair. Recent evidence indicated that microRNAs (miRNAs) have regulatory functions in bone metabolism. In this study, we hypothesized that the down-regulation of miRNAs that target MMP-13 by PTH leads to the stimulation of MMP-13 expression in osteoblasts. We used various bioinformatic tools to identify miRNAs that putatively target rat MMP-13. Among these miRNAs, the expression of miR-532-5p in rat osteoblasts decreased at 4 h of PTH-treatment, whereas MMP-13 mRNA expression was maximal at the same time point. When an miR-532-5p mimic was transiently transfected into UMR-106-01 cells, MMP-13 mRNA and protein expression decreased. Using a luciferase reporter assay system, we also identified that miR-532-5p directly targeted the 3′ UTRs of MMP-13 gene. Based on these results, we suggest that PTH-induced down-regulation of miR-532-5p resulted in the stimulation of MMP-13 expression in rat osteoblasts. This study identified a significant role of miRNA in controlling bone remodeling via PTH-stimulated MMP-13 expression. This finding enhances our understanding of bone metabolism and bone-related diseases and it could provide information regarding the usage of miRNAs as therapeutic agents or biomarkers.

Bronsted acids are found to be effective and generally applicable catalysts for inducing the cationic chain-growth polymerization of a wide variety of 2-halogenated-3-substituted-thiophenes with hydrogen, alkyl, alkylthio, alkoxy, and dialkoxy substituent groups. The effectiveness of the cationic polymerization depends on the acid strength and the electron density of the 2-halothiophene monomer. For the most electron-rich monomer, like EDOT, the polymerization can be initiated essentially with any acid that is stronger than acetic acid. While for the electron-poor 2-bromothiophene, it only works with the strongest acid, e.g., trifluoromethanesulfonic acid. Using this new polymerization method, highly solution-processable and conductive poly(alkylthiothiophene)s with a conductivity greater than 180 S cm−1 can be conveniently prepared. Control experiments indicate that Lewis acid like BF3 and SnCl4 (0.5 equiv.) can also induce the polymerization of 3-alkylthio-2-bromothiophenes in a similar fashion, but their polymerization failed totally in the presence of a trace amount of acid scavenger (e.g.

Background/Objectives: The present day students, research supervisors and faculty members depend on Google search engine as a tool for collecting information on any specific topic of interest. There is a need to understand what extent the materials selected is relevant for their work under consideration. This study investigates the outcome of the use of Google search engine for the choice of material and the reading habits among the research supervisors, research scholars, faculty members and graduate students. Methods: Questionnaires were used to conduct the survey. The responses were obtained through telephonic interviews or receiving duly filled in questionnaire through E-mail. Findings: It has been identified that search engines like Google has reduced the level of lateral thinking and force the academicians to depend on Google for information. This actively reduces the thinking process and developing innovative research ideas. Applications/Improvements: The use of search engine has resulted in thinking less and searching more when it comes to academic purpose, which also drastically reduces the analytical capability.

A new class of highly fluorescent mono-substituted polyarylacetylenes (P1–P3) has been successfully prepared with good yields and high molecular weights from a series of phenylethynylene-substituted arylacetylenes (M1–M3), using W-based catalyst. These polymers are readily soluble in common organic solvents (e.g., THF, toluene, and chloroform) and thermally stable up to ∼350 °C. Both 1H NMR and IR studies confirmed that all the monomers were selectively polymerized at the terminal triple bond. The 1H NMR results showed that both P1 and P2 have essentially trans-polyene backbone structures, while P3 contains significant amounts of both cis- and trans-structures. Coincidently, the photoluminescence (PL) intensity of P3 is also much lower than both P1 and P2. Nevertheless, the PL intensity of P1–P3 are all much higher than that of PPA, suggesting that the introduction of phenylethynylene group to the phenyl rings of PPAs have made the in general nonemissive PPAs to become highly photoluminescent. Most interestingly, although P1 did not contain any substituent group on its tolane pendant group, it is already highly soluble in common organic solvent and emitting blue fluorescence (416 nm) with a reasonably good quantum yield (0.36). © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5483–5498, 2008

New highly solution-processable aniline/butylthioaniline copolymers were prepared via oxidative copolymerization (OCP) and by concurrent reduction and substitution (CRS). Butylthio-substituted polyaniline obtained via the CRS route (Pan-SBu), being in line with the expected property changes after the addition of an electron-donating substituent to an aromatic ring, displayed a lowered redox potential (E°) and a redshifted maximum wavelength (λ max ; ultraviolet-visible) in comparison with its parent unsubstituted polyaniline (Pan). However, copolymers CP1-CP4 (obtained via the OCP method) displayed opposite behaviors, showing higher E° values and blue-shifts in λ max than the unsubstituted Pan. The results suggested that CP1-CP4 had shorter conjugation lengths than the unsubstituted Pan, possibly because of their chain conjugation defects (e.g., 1,3-ring linkage structures), as evidenced by IR studies. The results of 1 H NMR studies also indicated that Pan-SBu had much higher structural homogeneity than copolymer CP4. Because the CRS synthetic route involved no backbone alternations, the resultant copolymer (Pan-SBu) should have maintained the same backbone structure and hence the high conductivity of the parent unsubstituted Pan.

Summary Strongyloides stercoralis hyperinfection poses a great challenge to physicians in the tropics due to their non-specific symptoms and signs. Early identification and initiation of treatment improves mortality rates. Reports of Strongyloides infection in Hansens disease, systemic lupus erythematosus (SLE), organ transplant recipients and malnourished individuals have been reported in the published literature. The outcomes were variable, which may be attributed to a lack of treatment protocol. Treatment has been individualized and reports available are based on individual case reports and small case series. We report a successfully treated case of hyperinfection in SLE and discuss the various treatment options available.

Keratoconus (KC) is a progressive degenerative disease of the eye which causes an irregularly shaped cornea leading to severe impairment of vision. Despite basic and clinical studies KC remains a poorly understood disease. This project was designed to investigate the levels of proteins, proteases and cytokines in the tears of people with KC. Basal tears were collected from normal controls (C); people with KC and from people who had undergone corneal collagen cross-linking (CXL) for the treatment of KC. Corneal curvature of each subject was mapped. Proteomic technologies including gel electrophoresis, ELISA, mass spectrometry, antibody arrays and activity assays were used to examine the changes in tear proteins, proteases and cytokines between the different subject groups. There was approximately 2-fold decrease in total protein levels, lactoferrin, secretory IgA between KC and C tears, but the level of albumin was not significantly reduced. The tear protein changes correlated to the severity of the disease. Increased levels of cathepsin B (2.7-fold) and decreased levels of cystatin S (2.1-fold) and cystatin SN (2-fold), polymeric immunoglobulin receptor (9.4-fold), fibrinogen alpha chain (8.2-fold) were observed in KC compared to C. Keratin type-1 cytoskelatal-14 and keratin type-2 cytoskeletal-5 was present only in the tears of KC. Tears of people with KC had 1.9 times higher levels of proteolytic activity and over-expression of several matrix metalloproteinases (MMP) -1, -3, -7, -13 and interleukins (IL) -4, -5, -6, -7, -8 and tumour necrosis factor (TNF) -α, -β compared to tears from C. No significant difference in MMPs were observed between the C and CXL groups, although the expression levels of TNF-α was 1.5 times increased in CXL compared to C. The activity of tear proteases in CXL were not significantly different compared to either KC or C subjects. The tears of people with KC appear to have an altered tear protein profile, higher levels of proteases and cytokines that might reflect the pathological events in KC corneas. The novel findings reported in this thesis might lead the way to the development of non-invasive diagnostic or prognostic tests for KC or determine the success of CXL using tear proteomics.