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The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+forkhead box A1 (FOXA1)+prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1and MYConcogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

Cardiomyopathy is a genetic disorder of heart muscle; 2/3 of cases are gene-elusive on panel testing. Cryptic splice site variants disrupt the normal pattern of mRNA splicing through the creation of novel exon boundaries, resulting in abnormal protein isoforms. These variants are not routinely evaluated during genetic testing in cardiomyopathy. Our objective was to identify the contribution of cryptic splice site variants in childhood cardiomyopathy.

Idiopathic restrictive cardiomyopathy (RCM) is a rare cardiomyopathy in children notable for severe diastolic dysfunction and progressive elevation of pulmonary vascular resistance (PVR). Traditionally, those with pulmonary vascular resistance indices (PVRI) >6 W.U. × m2have been precluded from heart transplantation (HTX). The clinical course of all patients transplanted for RCM between 1986 and 2006 were reviewed. Preoperative, intraoperative and postoperative variables were evaluated. A total of 23 patients underwent HTX for RCM, with a mean age of 8.8 ± 5.6 years and a mean time from listing to HTX of 43 ± 60 days. Preoperative and postoperative (114 ± 40 days) PVRI were 5.9 ± 4.4 and 2.9 ± 1.5 W.U. × m2, respectively. At time of most recent follow-up (mean 5.7 ± 4.6 years), the mean PVRI was 2.0 ± 1.0 W.U. × m2. Increasing preoperative mean pulmonary artery pressure (PA) pressure (p 0.04) and PVRI > 6 W.U. × m2(?2 7.4, p < 0.01) were associated with the requirement of ECMO postoperatively. Neither PVRI nor mean PA pressure was associated with posttransplant mortality; 30-day and 1-year actuarial survivals were 96 and 86, respectively. Five of the seven patients with preoperative PVRI > 6 W.U. × m2survived the first postoperative year. We report excellent survival for patients undergoing HTX for RCM despite the high proportion of high-risk patients.

Idiopathic restrictive cardiomyopathy (RCM) is a rare cardiomyopathy in children notable for severe diastolic dysfunction and progressive elevation of pulmonary vascular resistance (PVR). Traditionally, those with pulmonary vascular resistance indices (PVRI) >6 W.U. × m2have been precluded from heart transplantation (HTX). The clinical course of all patients transplanted for RCM between 1986 and 2006 were reviewed. Preoperative, intraoperative and postoperative variables were evaluated. A total of 23 patients underwent HTX for RCM, with a mean age of 8.8 ± 5.6 years and a mean time from listing to HTX of 43 ± 60 days. Preoperative and postoperative (114 ± 40 days) PVRI were 5.9 ± 4.4 and 2.9 ± 1.5 W.U. × m2, respectively. At time of most recent follow-up (mean = 5.7 ± 4.6 years), the mean PVRI was 2.0 ± 1.0 W.U. × m2. Increasing preoperative mean pulmonary artery pressure (PA) pressure (p = 0.04) and PVRI > 6 W.U. × m2(χ2= 7.4, p < 0.01) were associated with the requirement of ECMO postoperatively. Neither PVRI nor mean PA pressure was associated with posttransplant mortality; 30-day and 1-year actuarial survivals were 96% and 86%, respectively. Five of the seven patients with preoperative PVRI > 6 W.U. × m2survived the first postoperative year. We report excellent survival for patients undergoing HTX for RCM despite the high proportion of high-risk patients.

Cardiomyopathy (CMP) is a genetic disease of the heart muscle that causes heart failure and sudden cardiac death in children. Our goal was to define the missing genetic etiology of childhood onset CMP by identifying the role of functionally active genomic variants in regulatory elements of CMP genes.

Liver involvement is commonly observed in patients with typhoid fever. However, a hepatitis-like picture with fever and jaundice is unusual and infrequently reported in the paediatric literature. Our aim was to characterize the clinical picture, biochemical features, and prognosis of typhoid hepatitis. One hundred cases of typhoid fever (age 0 to 12 years), proven by positive blood cultures to Salmonella typhi, were found to have hepatitis during the course of their illness. All had high fever, tender hepatomegaly, elevated serum bilirubin (in the range of 2.5-5.8 mg/dl), and elevated serum alanine transaminase levels (in the range 100-620 IU/I). All the eight patients showed complete clinical and biochemical recovery in response to appropriate antibiotics. The clinical picture of typhoid hepatitis frequently mimics acute viral hepatitis. In tropical areas, the differential diagnosis of a child presenting with fever and jaundice should include typhoid hepatitis.

Liver involvement is commonly observed in patients with typhoid fever. However, a hepatitis-like picture with fever and jaundice is unusual and infrequently reported in the paediatric literature. Our aim was to characterize the clinical picture, biochemical features, and prognosis of typhoid hepatitis. One hundred cases of typhoid fever (age 0 to 12 years), proven by positive blood cultures to Salmonella typhi, were studied with special reference to hepatic dysfunction. Of these, eight patients were found to have hepatitis during the course of their illness. All had high fever, tender hepatomegaly, elevated serum bilirubin (in the range of 2.5-5.8 mg/dl), and elevated serum alanine transaminase levels (in the range 100-620 IU/l). All the eight patients showed complete clinical and biochemical recovery in response to appropriate antibiotics. The clinical picture of typhoid hepatitis frequently mimics acute viral hepatitis. In tropical areas, the differential diagnosis of a child presenting with fever and jaundice should include typhoid hepatitis.

A generic unit cell model which includes a unique fiber substructuring concept is proposed for the development of micromechanics equations for continuous fiber reinforced ceramic composites. The unit cell consists of three constituents: fiber, matrix and an interphase. In the present approach, the unit cell is further subdivided into several slices and the equations of micromechanics are derived for each slice. These are subsequently integrated to obtain ply level properties. A stand-alone computer code containing the micromechanics model as a module is currently being developed specifically for the analysis of ceramic matrix composites. Towards this development, equivalent ply property results for a SiC (silicon carbide fiber) /Ti-15-3 (titanium matrix) composite with a 0.5 fiber volume ratio are presented and compared with those obtained from customary micromechanics models to illustrate the concept. Also, comparisons with limited experimental data for the ceramic matrix composite, SiC/RBSN (Reaction Bonded Silicon Nitride) with a 0.3 fiber volume ratio are given to validate the concepts.

Computational simulation procedures are used to identify the key deformation mechanisms for a [0]8and a [90]8SiC/Ti-15 metal matrix composite. The computational simulation procedures employed consist of a three-dimensional finite-element analysis and a micromechanics-based computer code METCAN. The interphase properties used in the analysis have been calibrated using the METCAN computer code with the [90]8experimental stress-strain curve. Results of the simulation show that although shear stresses are sufficiently high to cause the formation of some slip bands in the matrix concentrated mostly near the fibers, the nonlinearity in the composite stress-strain curve in the case of the [9018composite is dominated by interfacial damage, such as microcracks and debonding rather than microplasticity. The stress-strain curve for the [0]8composite is largely controlled by the fibers and shows only slight nonlinearity at higher strain levels that could be the result of matrix microplasticity.

Rauvolfia serpentina (L.) Benth. ex Kurtz genetic resources from several regions of India were evaluated at New Delhi in the period 1970–76 to understand the variation pattern for root yield and associated polygenic traits. The Uttar Pradesh populations represented the wides range of diversity for most of the traits; the populations from Assam possessed high root yield potential. In other states, too, variation was evident. On the basis of variation pattern, areas in the Indian subcontinent were identified for collection and conservation of Rauvolfia germplasm.

Synthesis and characterization of different types of lanthanum(III) and samarium(III) ketazinate complexes are reported. These derivatives of the type, (RO)Ln(AZ), Ln2(AZ)3 and (AZ)Ln(AZH) [where Ln = La(III) or Sm(III); R = C3H7i or C4H9t; AZ-2 = anion of the 2-hydroxyacetophenone azine] are obtained as yellow solids by the different molar reactions of tris(isopropoxy)lanthanon and ketazine, which behaves as a tridentate ligand. On the basis of analyses, molecular weight determinations and conductance and magnetic measurements, along with ir, electronic and pmr spectral studies, the tentative structures have been assigned for the resulting complexes.

Meso-mechanics and meso-structures are described in terms of the scales at which they are observed and formulated. Select composite examples are presented to illustrate that meso-mechanics and/or meso-structures are meaningful only when they refer to a specific scale in a hierarchical scale observation/simulation. These examples include different types of composite unit cells, woven fabric unit cells, and progressive fracture as a composite enhanced infrastructure made from reinforced concrete. The results from the select examples indicate that meso-mechanics and meso-structures are elusive terms and depend mainly on the investigators' knowledge and available information.

Synthesis and characterization of lanthanum(III) and samarium(III) semicarbazonato complexes are reported. These derivatives of the type (OR)Ln(SCZ), Ln2(SCZ)3 and Ln(SCZ)(SCZH) [where Ln = La(III) or Sm(III), R = isopropyl or tertiary butyl and SCZ-2 = anion of the aldimine or ketimine semicarbazones viz. salicylidinesemicarbazone, 2-hydroxy-1-naphthalidinesemicarbazone and 2-hydroxy-1-acetophenoneiminesemicarbazone] are obtained in the form of coloured solids by the reactions of tris(isopropoxy) lanthanon with the ligands in different molar ratios. The infrared and ultraviolet spectra alongwith magnetic measurements are interpreted in relation to the proposed structures. The crystal symmetry of these structures has been determined by X-ray studies. The thermolytic decomposition of the representative complexes have also been carried out by evaluating their relative thermal stability, activation energy and the order of thermal decomposition.

Ln(OPr1)(TYC), Ln2(TSC)3 and Ln(TSC)(TSCH) [where Ln = Pr(III) or Nd(III) and TSCH2 = bifunctional trident ate thiosemicarbazones e.g., H2N[image omitted]; R1 = H, R2 = c6H4OH or C10H6OH and R1=CH3, R2-C6H4OH] type s of lanthnnan thiosemicarbazone derivatives have been ryntherized by 1:1, 2:3 and 1:2 (M:L) moler reectiona of tris (isopropoxy)lanthanon with thioremioarbazones derived by the condensation of salicylaldehyde, 2-hydroxy-l-naphthaldehyde or O-hydroxyacetophenone with thiosemioarbszide. There are obtained as coloulrd solids and behave as non-electrolytes in anhydrous IMF. Suitable struc structures based on elemental analysis, molecular weight detemlnations, conductance measurements and infrared and proton magnetic reaonanoe spectral studies together with magnetic mearurements are indicated for these compounds. The pyrolytic behaviour of a few derivatives has also been studied and the data have been used for evaluating the klnetic parameters along with thermal rtabilities. Further, the X-ray powder diffraction patterns have been uaed for detennining the orystal system.