Synthesis of Azepinoindoles and Oxepinoindoles through Brønsted-Acid-Catalyzed Cyclization of an In Situ Generated Dihydrospiroquinoline Intermediate.

We have developed a straightforward and efficient synthetic protocol to produce 5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole and 7,12-dihydro-6H-benzo[2,3]oxepino[4,5-b]indole derivatives under mild conditions. This annulation process involves the intramolecular cyclization of the in situ generated ketimine moiety via the formation of dihydrospiroindolequinoline, which serves as a key intermediate in the reaction pathway. Several control experiments and spectroscopic studies were performed to elucidate the underlying reaction mechanism.

Characteristics, incidence, and outcomes of gastrointestinal complications post cardiac surgery in a quaternary referral centre: A retrospective study.

BACKGROUND: Gastrointestinal (GI) complications after cardiac surgery are associated with high morbidity and mortality. Early identification and treatment of GI complications could improve patient outcomes. OBJECTIVES: The objective of this study was to ascertain the incidence, risk factors, and clinical outcomes of GI complications following cardiac surgery. METHODS: A retrospective single-centre cohort study of adult patients undergoing cardiac surgery in an Australian quaternary cardiothoracic surgical referral centre was conducted from November 2012 to March 2020. Preoperative, intraoperative, and postoperative characteristics were compared between patients who did and did not develop GI complications. Data are presented as n (%). Between-group comparisons were analysed using Chi-square and Fisher's exact tests (where n < 6) for categorical variables and Wilcoxon rank-sum test for continuous variables. RESULTS: Of the 4417 patients who underwent cardiac surgery, 95 (2.2%) patients developed a total of 100 GI complications, with the most common being paralytic ileus (n = 22/100, 22%). Baseline characteristics and preoperative factors associated with GI complications included an age of >70 years (GI complication vs no GI complication: 55.8% vs 37.6%; p = 0.000), preexisting diabetes (49.5% vs 34.5%; p = 0.002), and a creatinine level >200 mcg/ml (11.6% vs 3.7%; p = 0.000). Intra-operative factors included a cardiopulmonary bypass time >120 min (28.4% vs 15.5%; p < 0.01). Postoperatively, developing a GI complication was associated with return to theatre (36.8% vs 13.9%; p < 0.01) and new stroke, pneumonia, and acute kidney injury (all p < 0.01). Patients with a GI complication had a higher intensive care unit and hospital mortality (7.4% vs 1.1%, and 13.6% vs 1.4%, respectively), and a longer intensive care unit and hospital stay (5.5 vs 2.3 days, and 24.0 vs 10.3 days). CONCLUSIONS: Multiple risk factors associated with GI complications in cardiac surgery patients were identified. These provide potential targets to support the early detection and management of GI complications to reduce morbidity and mortality in these patients.

Nondirected, Site-Selective Arylation of Quinone Imine Ketals Derived from Arylamines: One-Pot Access to meta-Substituted Anilines.

Herein, we develop a metal-free, nondirected, site-selective, one-pot approach to meta-arylation of arylamines. This Brønsted acid-catalyzed, direct C-C bond formation offers a broad substrate scope and scalability and creates the ideal conditions for overriding the conventional site-selectivity to furnish meta-substituted anilines. Additionally, the protocol applies to the meta-allylation of anilines and has been extended to afford late-stage functionalization and synthesis of medicinally privileged arylated diamines and densely functionalized anilines. The control experiments and density functional theory studies provide evidence for the proposed mechanism and selectivity.

Comparative evaluation of osteogenic cell growth on titanium surface and titanium coated with boron nitride surface: An in vitro study.

Context: To promote better biological response and osseointegration continuous research is going on to modify the titanium (Ti) implant surface for successful implant treatment modality. Aims: This study aims to evaluate the osteogenic cell growth upon the uncoated Ti discs and boron nitride (BN) coated Ti to assess osseointegration and clinical success of dental implants. Settings and Design: This is an descriptive experimental study which includes coating of uncoated titanium alloy suraface with boron nitride in the form of hexagonal boron nitride sheets. Than comparative evaluation of osteogenic cell growth upon both coated and uncoated titanium surfaces was done using specific cell growth determinants. Materials and Methods: In this descriptive experimental study, both BN-coated and uncoated Ti discs were assessed for osteogenic cell growth using 3-(4, 5-dimethyl thiazolyl-2)-2, 5-diphenyltetrazolium bromide assay, 4',6-diamidino-2-phenylindole, is a fluorescent stain assay, and cell adhesion assay. Statistical Analysis Used: As this study is a descriptive experimental analysis between two variables only so there is no need of statistical analysis or p-value. Results: Overall good cell adhesion, cell differentiation, and cell proliferation occurred in the BN-coated Ti discs as compared to uncoated Ti discs. Conclusions: To promote osseointegration of dental implants, surface coating with BN proved to be an effective approach toward better osseointegration and long-duration success of dental implants as a single unit or implant-supported prosthesis BN which is a biocompatible graphene material with advantages in chemical and thermal stability. BN promoted better osteogenic cell adhesion, differentiation, and proliferation. Hence, it can be used as a new promising Ti implant surface-coating material.

Antibacterial Efficacy and Surface Characteristics of Boron Nitride Coated Dental Implant: An In-Vitro Study.

This in vitro study evaluated bacterial cell proliferation and biofilm adhesion on titanium discs with and without antibacterial surface treatment to reduce the chances of peri-implant infections. Hexagonal boron nitride with 99.5% purity was converted to hexagonal boron nitride nanosheets via the liquid phase exfoliation process. The spin coating method was used for uniform coating of h-BNNSs over titanium alloy (Ti6Al4V) discs. Two groups of titanium discs were formed: Group I (n = 10) BN-coated titanium discs and Group II (n = 10) uncoated titanium discs. Two bacterial strains, Streptococcus mutans (initial colonizers) and Fusobacterium nucleatum (secondary colonizers), were used. A zone of inhibition test, microbial colony forming units assay, and crystal violet staining assay were used to evaluate bacterial cell viability. Surface characteristics and antimicrobial efficacy were examined by scanning electron microscopy with energy dispersion X-ray spectroscopy. SPSS (Statistical Package for Social Sciences) version 21.0 was used to analyze the results. The data were analyzed for probability distribution using the Kolmogorov-Smirnov test, and a non-parametric test of significance was applied. An inter-group comparison was done using the Mann-Whitney U test. A statistically significant increase was observed in the bactericidal action of BN-coated discs compared to uncoated discs against S. mutans, but no statistically significant difference was found against F. nucleatum.

Practical Access to meta-Substituted Anilines by Amination of Quinone Imine Ketals Derived from Anisidines: Efficient Synthesis of Anti-Psychotic Drugs.

Reversing the conventional site-selectivity of C-H activation provides efficient retrosynthetic disconnections to otherwise unreactive bonds. Described herein is the Brønsted acid-catalyzed reaction that selectively performs meta-amination of anisidines with aliphatic-, heterocyclic- and aromatic amines in a one-pot procedure. In addition to dramatically simplifying the synthesis of meta-substituted anilines, our approach has the advantage of the scalability and remarkable functional group tolerance, including late-stage functionalization of pharmaceutical compounds and natural products. The control experiments and detailed computational analysis provide insight into the reaction mechanism and the origin of meta-selectivity. The protocol extended to the synthesis of challenging tri-aminated arenes and successfully applied for the efficient synthesis of 5-HT6 receptor antagonists, the anti-psychotic drugs viz.. SB-214111, SB-258510, and specifically, anti-schizophrenic drug SB-271046.

TCR-signals downstream adversely correlate with the survival signals of memory CD8+ T cells under homeostasis.

The significance of self-peptide-MHC-I/TCR (SMT) interaction in the survival of CD8+ T cells during naïve- and developmental-stages is well documented. However, the same for the memory stage is contentious. Previous studies have attempted to address the issue using MHC-I or TCR deficient systems, but inconsistent findings with memory CD8+ T cells of different TCR specificities have complicated the interpretation. Differential presence and/or processing of TCR-signals downstream in memory CD8+ T cells of different TCR specificities could be thought of as a reason. In this study, we examined the TCR-signals downstream in memory CD8+ T cells and compared them to the presence of survival-related signals (Annexin-V, Bcl-2, and Ki-67). We categorically tracked foreign antigen-experienced memory CD8+ T (TM) cells generated after Plasmodium pre-erythrocytic-stage malaria infection in C57BL/6 mice. Interestingly, we found that memory CD8+ T cells had more TCR-signals downstream than naive cells. We reasoned and attributed the increased expression of cell adhesion molecules to the enhanced TCR-signaling. TCR-signals downstream correlate more closely with survival signals in naive CD8+ T cells than with death signals in TM cells. Further investigation using antigen-specific CD8+ T cells and diverse infection systems would aid in conceptualizing the findings.

Supplemental Pioglitazone to Patients of CML with Suboptimal TKI Response: A Pragmatic Pilot Study.

Tyrosine kinase inhibitors (TKIs) have improved outcomes of chronic myeloid leukemia (CML). However, 20-30% of patients require second-line TKIs following suboptimal response. The cost and adverse events limit their use in resource-constraint settings. We conducted a pilot study to ascertain the benefit of adding pioglitazone to TKIs with suboptimal response in real-world resource-constraint settings. In this pragmatic pilot study from 01 Jan 2017 to 31 July 2021, CML patients from a tertiary care center in North India with sub-optimal response to TKIs were additionally given pioglitazone after ruling out imatinib resistance mutation (n - 31). Pioglitazone was stopped if there was disease progression on follow-up, and second-line TKI was started. The data were analyzed with the intention-to-treat principle using JMP Ver.15.1.1. The median age of the study population was 54y (27-82), who were followed up for a median duration of 1023.5d (59-1117). Pioglitazone showed the benefit of one-log reduction in BCR-ABL in 89.7% of the study participants. 1y, 2y and 3y-PFS were 92.57%, 76.5%, and 68.3% respectively. During follow-up period, the disease progressed in 38.7%, of which two succumbed. No adverse events to Pioglitazone were documented. This study proved that adding Pioglitazone to the existing TKI regime in CML with sub-optimal response can benefit. The addition of Pioglitazone was well tolerated. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-022-01561-x.

More time to kill: A longer liver stage increases T cell-mediated protection against pre-erythrocytic malaria.

Liver stage (LS) Plasmodia mature in 2-2.5 days in rodents compared to 5-6 days in humans. Plasmodium-specific CD8+ T cell expansion differs across these varied timespans. To mimic the kinetics of CD8+ T cells of human Plasmodium infection, a two-dose challenge mouse model that achieved 4-5 days of LS antigen exposure was developed. In this model, mice were inoculated with a non-protective, low dose of late-arresting, genetically attenuated sporozoites to initiate T cell activation and then re-inoculated 2-3 days later with wild-type sporozoites. Vaccines that partially protected against traditional challenge completely protected against two-dose challenge. During the challenge period, CD8+ T cell frequencies increased in the livers of two-dose challenged mice but not in traditionally challenged mice, further suggesting that this model better recapitulates kinetics of CD8+ T cell expansion in humans during the P. falciparum LS. Vaccine development and antigen discovery efforts may be aided by using the two-dose challenge strategy.

Comparison of Tensile Bond Strength of Fixed-Fixed Versus Cantilever Single- and Double-Abutted Resin-Bonded Bridges Dental Prosthesis.

Resin-bonded fixed dental prostheses (RBFDP) are minimally invasive alternatives to traditional full-coverage fixed partial dentures as they rely on resin cements for retention. This study compared and evaluated the tensile bond strength of three different resin-bonded bridge designs, namely, three-unit fixed-fixed, two-unit cantilever single abutment, and three-unit cantilever double-abutted resin-bonded bridge. Furthermore, the study attempted to compare the tensile bond strengths of the Maryland and Rochette types of resin-bonded bridges. Based on the inclusion and exclusion criteria, a total of seventy-five extracted maxillary incisors were collected and later were mounted on the acrylic blocks. Three distinct resin-bonded metal frameworks were designed: three-unit fixed-fixed (n = 30), two-unit cantilever single abutment (n = 30), and a three-unit cantilever double abutment (n = 30). The main groups were further divided into two subgroups based on the retainer design such as Rochette and Maryland. The different prosthesis designs were cemented to the prepared teeth. Later, abutment preparations were made on all specimens keeping the preparation as minimally invasive and esthetic oriented. Impression of the preparations were made using polyvinyl siloxane impression material, followed by pouring cast using die stone. A U-shaped handle of 1.5 mm diameter sprue wax with a 3 mm hole in between was attached to the occlusal surface of each pattern. The wax patterns were sprued and cast in a cobalt-chromium alloy. The castings were cleaned by sandblasting, followed by finishing and polishing. Lastly, based on the study group, specimens for Rochette bridge were perforated to provide mechanical retention between resin cement and metal, whereas the remaining 15 specimens were sandblasted on the palatal side to provide mechanical retention (Maryland bridge). In order to evaluate the tensile bond strength, the specimens were subjected to tensile forces on a universal testing machine with a uniform crosshead speed. The fixed-fixed partial prosthesis proved superior to both cantilever designs, whereas the single abutment cantilever design showed the lowest tensile bond strength. Maryland bridges uniformly showed higher bond strengths across all framework designs. Within the limitations of this study, the three-unit fixed-fixed design and Maryland bridges had greater bond strengths, implying that they may demonstrate lower clinical failure than cantilever designs and Rochette bridges.

Silyl Cation-Initiated, Brønsted Acid-Catalyzed Strategy toward Unsymmetrical 3,3-Disubstituted 2-Oxindoles and Azonazine Cores.

Herein, a mild, metal-free, robust approach for synthesizing valuable and sterically demanding unsymmetrical 3,3-disubstituted 2-oxindoles via reductive cyclization of α-ketoamides is reported. This operationally simple protocol is initiated by a silyl cation and further catalyzed by a Brønsted acid. We have utilized a wide range of arenes, amines, and thiols as coupling partners with various α-ketoamides. The products were afforded in excellent regioselectivity and good functional group tolerance. This procedure provides easy access to the scaffolds of azonazine and its derivatives with an excellent syn-diastereoselectivity bearing all-carbon quaternary stereocenters.

Japanese encephalitis virus induces vasodilation and severe lethality in adult and aged AG129 mice lacking alpha, beta and gamma interferon receptors.

Japanese encephalitis virus (JEV) is a single-stranded positive-sense RNA virus belonging to the Flaviviridae family. The JEV is the leading cause of viral encephalitis in children and the elderly which is spread by mosquitoes. JEV infection has been established in different animal models such as mouse, hamster, guinea pig, swine, rat, monkey, rabbit by using the different routes of inoculations. Here, we have shown that the alpha/beta and gamma -receptor deficient AG129 mouse induces fatal encephalitis in both young and aged old mice, when challenged with high titer JEV Indian clinical isolate by both intraperitoneal and intradermal route. The JEV infected AG129 mouse have shown neurological symptoms, JEV-induced pathological features and supported high level viral replication. Additionally, administration of JEV in AG129 mice resulted in the induction of severe peripheral vascular permeability, which is a major hall mark of Dengue infection but not shown in JEV. Taken together, our results demonstrate interferon α/ß and γ receptors knock out AG129 mouse does not need adaptation of JEV clinical isolates and could be is a promising JEV challenge mouse model by mimicking the natural intradermal route of administration for rapid screening of novel antivirals and vaccines.

Brookhart's Acid-Catalyzed Switchable Regioselective N-Alkylation of Arylamines/Heterocyclic Amines with Cyclopropylcarbinols by Temperature Regulation.

An unprecedented, Brookhart's acid-catalyzed temperature-switchable regioselective divergent approach for N-alkylation of arylamines and heterocyclic amines by utilising cyclopropylcarbinols is presented herein. The reaction offers N-alkylated cyclopropyl derivatives and homoallyl amines by employing 2.5 mol% catalyst loading at different temperatures in excellent regioselectivity and yields. This method has shown to be relevant with a wide range of cyclopropylcarbinols, including aliphatic ones. Several control experiments and spectroscopic studies have been performed to gain insight into the reaction mechanism. Further, the synthetic utility of the protocol has also been described.

Analysis of Denture Base Displacement between Conventional Acrylic Removable Partial Dentures and Click Fit Partials for Kennedy's Class I and II Situations: An In Vitro Study.

AIM/OBJECTIVE: The aim of this study was to evaluate the displacement of the denture base of conventional acrylic dentures and Click Fit partials in Kennedy's class I and II situations in the mandibular arch. MATERIALS AND METHODS: Four removable partial dentures-two conventional clasp dentures and two attachment dentures (Click Fit)-were designed. The two conventional clasp dentures were retained by C (conventional) clasps, and the two attachment dentures were retained by rigid precision attachments. The displacement of denture bases and the movements of denture bases were investigated, and the influences of denture design were studied. RESULT: The values obtained were statistically analyzed by using independent t-tests. For all statistical purposes, a p-value of ≤0.001 was considered significant. The results showed that mean vertical displacements (mm) of the conventional acrylic removable partial denture base for Kennedy's class I mandibular arch under 50, 75, and 100 N forces were 0.0317, 0.04377, and 0.06392, respectively, and those for Kennedy's class II mandibular arch under 50, 75, and 100 N forces were 0.04922, 0.09849, and 0.1522, respectively. Vertical displacements (mm) of the Click Fit removable partial denture base for Kennedy's class I mandibular arch under 50, 75, and 100 N forces were 0.02185, 0.03436, and 0.005365, respectively, and those for Kennedy's class II mandibular arch under 50N, 75N, and 100N forces were 0.0445, 0.07851, and 0.14457, respectively. The difference between the groups was statistically significant (p ≤0.001). CONCLUSION: The vertical displacement of the denture base retained by conventional C clasps was more than that of the denture base retained by rigid precision attachment. The displacement of the denture base tended to be less when the denture was designed with a rigid connection for the retainer and with cross-arch stabilization as in Kennedy's class I case. CLINICAL IMPLICATIONS: This research evaluated the vertical denture base displacement using different designs and retention types. Hence, it helped predict the prognosis of different removable partial denture base designs in various clinical conditions.

Catalyst-Switchable Divergent Synthesis of Bis(indolyl)alkanes and 3-Alkylated Indoles from Styrene Oxides.

A novel and effective Brønsted acid-catalyzed chemoselective synthesis of bis(indolyl)alkanes and 3-alkyl indoles is reported. The selectivity of two significant indole derivatives is attained by allowing the same substrates to go through divergent reaction routes catalyzed by different catalysts. Furthermore, this mild approach is applicable to a wide range of substrates and has high efficacy in large-scale reactions. A plausible mechanism is provided based on the control experiments and spectroscopic studies.

Comparative Evaluation of Tensile Bond Strength of Poly Ether Ether Ketone (PEEK) and Zirconia Copings Using Resin Cement with or without Adhesive: An In Vitro Study.

This in vitro research aimed to evaluate the Tensile Bond Strength of Poly Ether Ether Ketone and Zirconia copings using resin cement with or without Visio.link adhesive. From commercially available Zirconia and PEEK, blocks were machined milled using (CAD)/(CAM) to obtain 20 Zirconia and 20 PEEK copings. These specimens were sandblasted using 110 µm of alumina. The two main groups (20 Zirconia and 20 PEEK copings) were divided further into 4 subgroups, GROUP 1 (n = 10) PEEK substructure with self-adhesive resin cement without pretreatment, and GROUP 2 (n = 10) PEEK substructure with self-adhesive resin cement pre-treated with Visio.link adhesive. GROUP 3 (n = 10) Zirconia copings with self-adhesive resin cement without pretreatment. GROUP 4 (n = 10) Zirconia copings with self-adhesive resin cement pre-treated with Visio.link adhesive. Universal testing machine was used to evaluate the tensile bond strength of these copings. The results were analyzed using SPSS software Version 25.0 (SPSS Inc., Chicago, IL, USA). One-way ANOVA and independent t-test were used to compare the mean scores. Statistically significant increase was observed in Tensile Bond Strength of samples when Visio.link adhesive was used. Tensile Bond Strength of PEEK copings and Zirconia copings with Visio.link adhesive is considerably greater than PEEK copings and Zirconia copings without adhesive. The mean Tensile Bond Strength of Zirconia (with or without adhesive) is less as compared to Tensile Bond Strength of PEEK (with or without adhesive), but the difference is not statistically significant.

Rapid Access to Arylated and Allylated Cyclopropanes via Brønsted Acid-Catalyzed Dehydrative Coupling of Cyclopropylcarbinols.

A regioselective protocol for the synthesis of cyclopropyl derivatives that relies on Brookhart acid-catalyzed dehydrative coupling over substituted cyclopropylcarbinols without rearrangement is reported herein. The reactions proceed promptly at 25 °C with only 2.0 mol % catalyst loading and produce the cyclopropyl derivatives in excellent yields. This method is well tolerated with a vast range of cyclopropylcarbinols including aliphatic cyclopropylcarbinols, where no elimination product was obtained, demonstrating the protocol's utility. Further, the Hammett correlation suggested the formation of a cyclopropylcarbinyl cation followed by a coupling reaction. An extremely effective gram-scale reaction has also been demonstrated with a high turnover number.

Brønsted Acid-Catalysed Epoxide Ring-Opening Using Amine Nucleophiles: A Facile Access to ß-Amino Alcohols.

A mild, efficient, and metal-free synthetic protocol for the synthesis of ß-amino alcohols is reported. The reaction proceeds at room temperature with only 0.5 mol % catalyst loading and affords ß-amino alcohol derivatives in excellent yield. This protocol is well-tolerated by a wide range of styrene oxide and aniline derivatives. A notably efficacious gram-scale synthesis is also reported with a high TON=842. Further, the Hammett correlation study was also performed to identify the rate-determining step.