Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma.

Schwannoma tumours typically arise on the eighth cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the eighth or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a preclinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.

Indole-based aryl sulfides target the cell wall of Staphylococcus aureus without detectable resistance.

Sulfur-containing classes of the scaffold "Arylthioindoles" have been evaluated for antibacterial activity; they demonstrated excellent potency against methicillin-resistant Staphylococcus aureus (MRSA) as well as against vancomycin-resistant strains and a panel of clinical isolates of resistant strains. In this study, we have elucidated the mechanism of action of lead compounds, wherein they target the cell wall of S. aureus. Further, S. aureus failed to develop resistance against two lead compounds tested in a serial passage experiment in the presence of the compounds over a period of 40 days. Both the compounds demonstrated comparable in vivo efficacy with vancomycin in a neutropenic mice thigh infection model. The results of these antibacterial activities emphasize the excellent potential of thioethers for developing novel antibiotics and may fill in as a target for the adjustment of accessible molecules to develop new powerful antibacterial agents with fewer side effects.

The interplay between chromophore and protein determines the extended excited state dynamics in a single-domain phytochrome.

Phytochromes are a diverse family of bilin-binding photoreceptors that regulate a wide range of physiological processes. Their photochemical properties make them attractive for applications in optogenetics and superresolution microscopy. Phytochromes undergo reversible photoconversion triggered by the Z ⇄ E photoisomerization about the double bond in the bilin chromophore. However, it is not fully understood at the molecular level how the protein framework facilitates the complex photoisomerization dynamics. We have studied a single-domain bilin-binding photoreceptor All2699g1 (Nostoc sp. PCC 7120) that exhibits photoconversion between the red light-absorbing (Pr) and far red-absorbing (Pfr) states just like canonical phytochromes. We present the crystal structure and examine the photoisomerization mechanism of the Pr form as well as the formation of the primary photoproduct Lumi-R using time-resolved spectroscopy and hybrid quantum mechanics/molecular mechanics simulations. We show that the unusually long excited state lifetime (broad lifetime distribution centered at ∼300 picoseconds) is due to the interactions between the isomerizing pyrrole ring D and an adjacent conserved Tyr142. The decay kinetics shows a strongly distributed character which is imposed by the nonexponential protein dynamics. Our findings offer a mechanistic insight into how the quantum efficiency of the bilin photoisomerization is tuned by the protein environment, thereby providing a structural framework for engineering bilin-based optical agents for imaging and optogenetics applications.

Photoisomerization of phytochrome chromophore models: an XMS-CASPT2 study.

Phytochromes are a superfamily of photoreceptors that harbor linear tetrapyrroles as chromophores. Upon light illumination, the linear tetrapyrrole chromophore undergoes a double bond isomerization which starts a photocycle. In this work, we studied the photoisomerization of chromophore models designed based on the C- and D-rings of the phycocyanobilin (PCB) chromophore. In total, five different models with varying substitutions were investigated. Firstly, the vertical excitation energies were benchmarked using different computational methods to establish the relative order of the excited states. Based on these calculations, we computed the photoisomerization profiles using the extended multi-state (XMS) version of the CASPT2 method. The profiles were obtained for both the clockwise and counterclockwise rotations of the C15C16 bond in the Z and E isomers using a linear interpolation of internal coordinates between the Franck-Condon and MECI geometries. In the minimal chromophore model that lacks the substitutions at the pyrrole rings, the isomerization involves both C14-C15 and C15C16 bonds of the methine bridge between the C- and D-rings, resembling the hula-twist motion. The MECIs are characterized by a partial charge transfer between the two pyrrole rings pointing towards a twisted intramolecular charge transfer. Systematic introduction of substituents leads to an increase in the steric repulsion between the two pyrrole rings causing a pretwist of the dihedral around the C15C16 bond, which creates a preference for the counterclockwise isomerization. An introduction of the carbonyl group at the D-ring increases the extent of charge transfer which changes the isomerization mechanism from hula-twist to one-bond flip.

Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2.

Cyanobacteriochromes are compact and spectrally diverse photoreceptor proteins that bind a linear tetrapyrrole as a chromophore. They show photochromicity by having two stable states that can be interconverted by the photoisomerization of the chromophore. These photochemical properties make them an attractive target for biotechnological applications. However, their application is impeded by structural heterogeneity that reduces the yield of the photoconversion. The heterogeneity can originate either from the chromophore structure or the protein environment. Here, we study the origin of the heterogeneity in AnPixJg2, a representative member of the red/green cyanobacteriochrome family, that has a red absorbing parental state and a green absorbing photoproduct state. Using molecular dynamics simulations and umbrella sampling we have identified the protonation state of a conserved histidine residue as a trigger for structural heterogeneity. When the histidine is in a neutral form, the chromophore structure is homogenous, while in a positively charged form, the chromophore is heterogeneous with two different conformations. We have identified a correlation between the protonation of the histidine and the structural heterogeneity of the chromophore by detailed characterization of the interactions in the protein binding site. Our findings reconcile seemingly contradicting spectroscopic studies that attribute the heterogeneity to different sources. Furthermore, we predict that circular dichroism can be used as a diagnostic tool to distinguish different substates.

Correction: Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2.

Correction for 'Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2' by Aditya G. Rao et al., Phys. Chem. Chem. Phys., 2021, DOI: 10.1039/d0cp05314g.

Synergistic Dual Role of [hmim]Br-ArSO2Cl in Cascade Sulfenylation-Halogenation of Indole: Mechanistic Insight into Regioselective C-S and C-S/C-X (X = Cl and Br) Bond Formation in One Pot.

Bifunctionalized indoles are an important class of biologically active heterocyclic compounds and potential drug candidates. Because of the lack of efficient synthetic methods, one pot cascade synthesis of these compounds is rare and remains a challenge. To expand this field, we herein disclose a step-economical and temperature tunable strategy wherein the synergistic effect between [hmim]Br-ArSO2Cl leads exclusively to the formation of 3-arylthio indole via sulfenylation of indole at room temperature, while heating the reaction mixture at 50 °C provided an unexpected 2-halo-3-arylthio indole with construction of C-S and C-S/C-X (X = Cl and Br) bonds without addition of any external halogenating agent via cascade sulfenylation-halogenation reactions under metal-oxidant-base-free conditions. Further, insight into the reaction mechanism provides an unprecedented observation wherein the synergistic interaction between [hmim]Br-ArSO2X in the presence of a catalytic amount of water generates arylsulfonic anhydride (ArSO2)2O in situ as a new sulfur source along with the formation of [hmim]PTS as probed by NMR, ESI-MS, DART-MS, and HPLC studies. Notably, the mixture of bifunctionalized 2-halo(Br/Cl)-3-arylthio indole was smoothly diversified with privileged heterocycle triazole to provide 2-(1 H-triazole-1-yl)-3-arylthio indole, which is an analogue of the potent indole-based anticancer agent.

Hetero-bimetallic cooperative catalysis for the synthesis of heteroarenes.

Multi-metallic cooperative catalysis has gained a lot of interest in organic synthesis over the past few years exploring various organic transformations. Of all the myriad chemical transformations, multi-metallic cooperative catalysis offers exceptional chemo-, stereo- and regio-selectivities. In recent years, hetero-multi-metallic catalysis has not only been used to synthesise only simpler organic molecules but rather more complex molecules like heteroarenes which include a variety of commercially important molecules. The current review, in this context, emphasises the synthesis of 5- and 6-membered as well as condensed heteroarenes, covering the literature over the last decade. The discussion focusses on the combinations in cooperative catalytic systems in strategies used to achieve selectivity and also highlights the mode of action for the cooperative catalysis leading to the synthesis of a few commercially and biologically relevant heteroarenes. Finally, the review concludes with a brief outlook on the future scope and opportunities in the field of cooperative catalyses and their prospects for providing state-of-the-art solutions for synthetically challenging organic transformations.

Biocatalytic synthesis of diaryl disulphides and their bio-evaluation as potent inhibitors of drug-resistant Staphylococcus aureus.

Staphylococcus aureus is a WHO Priority II pathogen for its capability to cause acute to chronic infections and to resist antibiotics, thus severely impacting healthcare systems worldwide. In this context, it is urgently desired to discover novel molecules to thwart the continuing emergence of antimicrobial resistance. Disulphide containing small molecules has gained prominence as antibacterials. As their conventional synthesis requires tedious synthetic procedure and sometimes toxic reagents, a green and environmentally benign protocol for their synthesis has been developed through which a series of molecules were obtained and evaluated for antibacterial activity against ESKAPE pathogen panel. The hit compound was tested for cytotoxicity against Vero cells to determine its selectivity index and time-kill kinetics was determined. The activity of hit was determined against a panel of S. aureus multi-drug resistant clinical isolates. Also, its ability to synergize with FDA approved drugs was tested as was its ability to reduce biofilm. We identified bis(2-bromophenyl) disulphide (2t) as possessing equipotent antimicrobial activity against S. aureus including MRSA and VRSA strains. Further, 2t exhibited a selectivity index of 25 with concentration-dependent bactericidal activity, synergized with all drugs tested and significantly reduced preformed biofilm. Taken together, 2t exhibits all properties to be positioned as novel scaffold for anti-staphylococcal therapy.

The Effective Conjugation Length Is Responsible for the Red/Green Spectral Tuning in the Cyanobacteriochrome Slr1393g3.

The origin of the spectral shift from a red- to a green-absorbing form in a cyanobacteriochrome, Slr1393g3, was identified by combined quantum mechanics/molecular mechanics simulations. This protein, related to classical phytochromes, carries the open-chain tetrapyrrole chromophore phycocyanobilin. Our calculations reveal that the effective conjugation length in the chromophore becomes shorter upon conversion from the red to the green form. This is related to the planarity of the entire chromophore. A large distortion was found for the terminal pyrrole rings A and D; however, the D ring contributes more strongly to the photoproduct tuning, despite a larger change in the twist of the A ring. Our findings implicate that the D ring twist can be exploited to regulate the absorption of the photoproduct. Hence, mutations that affect the D ring twist can lead to rational tuning of the photoproduct absorption, allowing the tailoring of cyanobacteriochromes for biotechnological applications such as optogenetics and bioimaging.

Collection-limited theory interprets the extraordinary response of single semiconductor organic solar cells.

The bulk heterojunction (BHJ) organic photovoltaic (OPV) architecture has dominated the literature due to its ability to be implemented in devices with relatively high efficiency values. However, a simpler device architecture based on a single organic semiconductor (SS-OPV) offers several advantages: it obviates the need to control the highly system-dependent nanoscale BHJ morphology, and therefore, would allow the use of broader range of organic semiconductors. Unfortunately, the photocurrent in standard SS-OPV devices is typically very low, which generally is attributed to inefficient charge separation of the photogenerated excitons. Here we show that the short-circuit current density from SS-OPV devices can be enhanced significantly (∼100-fold) through the use of inverted device configurations, relative to a standard OPV device architecture. This result suggests that charge generation may not be the performance bottleneck in OPV device operation. Instead, poor charge collection, caused by defect-induced electric field screening, is most likely the primary performance bottleneck in regular-geometry SS-OPV cells. We justify this hypothesis by: (i) detailed numerical simulations, (ii) electrical characterization experiments of functional SS-OPV devices using multiple polymers as active layer materials, and (iii) impedance spectroscopy measurements. Furthermore, we show that the collection-limited photocurrent theory consistently interprets typical characteristics of regular SS-OPV devices. These insights should encourage the design and OPV implementation of high-purity, high-mobility polymers, and other soft materials that have shown promise in organic field-effect transistor applications, but have not performed well in BHJ OPV devices, wherein they adopt less-than-ideal nanostructures when blended with electron-accepting materials.

Association of Metabolic Syndrome with Hyper Apolipoprotein B status in Young People with Acute Coronary Syndrome.

Prevalence of Metabolic Syndrome (MetS) and acute coronary syndrome (ACS) in young people is progressively increasing. This was originally a case control study to predict the risk of ACS with hyper apolipoprotein B (Hyper apoB) status in young people, with 50 cases of 18-45 years of age of both sex with first attack of acute coronary syndrome admitted in Coronary care unit of Mymensingh Medical College Hospital from June 2009 to May 2010 and for comparison, equal number of age and sex matched healthy controls were chosen. In present study only cases were analyzed regarding their anthropometric, fasting blood glucose, blood pressure and lipoprotein lipid profiles. Regarding anthropometric measurement, body mass index (BMI), Waist Circumference (WC) and Waist-to Hip ratio (WHR) was calculated. Thirty one cases had increased and 19 had normal WHR, of them 28 cases had hyper and 3 had normal ApoB and 14 cases out of 19 with normal WHR had hyper ApoB and hyper ApoB status was significantly found to be present in ACS patients with increased waist-hip ratio (p=0.03). In this study WHR, instead of WC was used by the author to define abdominal obesity for the diagnosis of MetS along with other criteria according to IDF (International Diabetic Federation) consensus worldwide definition of Mets. Out of 50 young ACS cases 14 cases had metabolic syndrome of those 12 had hyper ApoB status and was statistically significant (p=0.04).

Risk Factor Pattern of Ischemic Heart Disease in Young Male Patients with Vertex Baldness.

Acute coronary syndrome (ACS) is increasingly evident in all parts of the globe as well in our country. There are accumulating evidences regarding many physical markers, like vertex baldness to predict ACS. This cross sectional study was conducted in the Department of Cardiology, Mymensingh Medical College Hospital, Mymensingh, Bangladesh from October 2014 to September 2015. The main objective of the study was to assess the risk factors of premature coronary artery disease (CAD) of male patient of Acute Coronary Syndrome with or without vertex baldness. A total of 100 male patients with age between 25 to 55 years was included as study population. The study population was divided into two groups; each group consisted of 50 patients. Acute coronary syndrome in patients with vertex baldness mentioned as Group A and ACS in patients without vertex baldness mentioned as Group B. All risk factors were higher in group A than group B. But diabetes mellitus, metabolic syndrome and family history of ischemic heart disease (IHD) were significantly higher in group A than in group B (p=0.003, p=0.008, <0.001). Probably as first study in Bangladesh, it may label vertex baldness as a cutaneous marker of premature CAD.

Cooperative catalysis by bovine serum albumin-iodine towards cascade oxidative coupling-C(sp(2))-H sulfenylation of indoles/hydroxyaryls with thiophenols on water.

Cooperative cascade catalysis by bovine serum albumin (BSA)-iodine allows for the first time the performance of C(sp(2))-H sulfenylation of indole from readily available thiophenol (-SH bond) via in situ generation/cleavage of disulfide (S-S bond) in air under aqueous conditions, whereas BSA or I2 individually do not permit this two step sequence to occur in the same pot towards C-S bond formation. This green cooperative protocol is extendable to sulfenylation of hydroxyaryls (i.e. 2-naphthol or 4-hydroxycoumarin) with diverse thiols (aryl/heteroaryl) without using any toxic metal catalysts, bases or oxidants, thus rendering the process environmentally and economically reliable. Further, the gram scale synthesis of a COX-2 inhibitor (3-(pyridin-2-ylthio)-1H-indole), regioselectivity and recyclability (up to four cycles) are the additional merits of this cooperative cascade bio-chemocatalytic (BSA-I2) protocol. Moreover, HPLC and ESI-MS provide powerful insights into the mechanistic aspects of the above cascade sulfenylation reaction.

Apolipoprotein B versus Non- High Density Lipoprotein Cholesterol as a Discriminating Factor for Acute Coronary Syndrome in Young People.

This study aimed to compare Apolipoprotein B(Apo B) with non-HDL-C as a predictor and discriminating factor of acute coronary syndrome (ACS). This is a case control study among 50 cases of first attack of ACS among 18-45 years of age of both sex, admitted in coronary care unit of Mymensingh Medical College Hospital, Bangladesh from June 2009 to May 2010. Data was recently reanalyzed. Apo B is more sensitive than non-HDL C (84% vs. 62%) as well with more negative predictive value (NPV) (76.5% vs. 62.7%) but with similar positive predictive value (PPV) (63%). Specificity was more for non HDL C than Apo B (64% vs. 52%). Highest specificity and PPV observed for HDL- C, 88% and 71.4% respectively but with low sensitivity (30%). In this study diagnostic value of LDL-C, TC and TG was low. Apo B was a more discriminating factor as well predictor for ACS cases than non-HDL-C (OR: 5.678, 95% CI 2.227 - 14.528, P=0.001) vs. (OR: 2.901, 95% CI 1.288 - 6.534, P=0.01). Area under the Receiver Operating Characteristic (ROC) curve was greater for Apo B than non-HDL-C (0.680 vs. 0.630). Though ApoB and non-HDL-C theoretically often equally reflects the atherogenic burden, Apo B was a more discriminating factor for ACS cases than non-HDL-C.

Mass Screening of Apolipoprotein B May Detect Young People at Risk of Acute Coronary Syndrome.

Incidence of acute coronary syndrome in young people is progressively increasing. Apolipoprotein B is now regarded as a nobel parameter over conventional lipid profile, predicting acute coronary syndrome. A case control study was carried out in Department of Cardiology of Mymensingh Medical College Hospital from June 2009 to May 2010. Total 50 cases of 18-45 years of age with first attack of acute coronary syndrome and 50 healthy controls of same age and sex distribution were studied. Of them 42(84.0%) of cases and 24(48%) of controls had hyper apoB condition. Mass screening of apolipoprotein B in apparently healthy young people may detect persons with hyper apoB status, who may develop acute coronary syndrome in future.

Correlation between Troponin-I and B-Type Natriuretic Peptide Level in Acute Myocardial Infarction Patients with Heart Failure.

Troponins are regarded as markers of choice for the diagnosis of acute myocardial infarction (AMI). But B-type natriuretic peptide (BNP) level is also elevated in AMI and is a quantitative biochemical marker related to the extent of infarction and the left ventricle systolic dysfunction. Thus, BNP has prognostic value. In this study, we investigate the correlation of Troponin-I with BNP levels in patients presenting with AMI with or without Acute Heart Failure. Rationale of this study is to see, whether quantitative Troponin alone can serve for both diagnosis and prognosis of AMI Patients with heart failure or not. This cross-sectional analytical study was conducted in the Department of Cardiology in Mymensingh Medical College Hospital from January 2014 to December 2014. Total 100 patients were studied and divided into two groups - 50 patients in each group. Group I: Patients with first attack of acute myocardial infarction (without heart failure) & Group II: Patients with first attack of acute myocardial infarction with acute heart failure. Mean Troponin-I of Group I and Group II were 3.10±2.68 and 62.93±32.75ng/ml respectively & mean BNP value of Group I and Group II were 20.96±14.18 and 615.65±249.27pg/ml respectively. In this study, it was shown that the levels of BNP had positive correlation with Troponin-I levels, with medium strength of association (r=0.734, p<0.05). Echocardiography shows that patients with high BNP level has low ejection fraction (LVEF) and patients with low BNP level has preserved ejection fraction (LVEF). Thus, the present study shows that the higher the Troponin-I levels, the higher the BNP levels in first attack of AMI patients and the more severe the heart failure (more severe left ventricle dysfunction). There is positive correlation between Troponin-I and BNP levels in first attack of AMI patients with acute heart failure.

Risk of Acute Coronary Syndrome is Better Predicted by Apolipoprotein B in Young People than Dyslipidemic Parameter of Conventional Lipid Profile.

The traditional lipidic parameters when present and clusters within reference range, often fails to predict the risk of acute coronary syndrome in young population in this region. Measurement of Apolipoprotein B (Apo B), a parameter of the lipoprotein-lipid profile, provides a method of quantifying the concentration of lipoproteins, rather than their cholesterol content. Present study aimed to quantify the risk of acute coronary syndrome (ACS) in young people with having none to less number of traditional lipidic parameters for dyslipidemia. This is a case control study among 50 cases of first attack of ACS among 18-45 years of age of both sexes, admitted in coronary care unit of Mymensingh Medical College Hospital, Mymensingh, Bangladesh from June 2009 to May 2010. Data was recently reanalyzed. Out of five sub-sets of lipid profile, namely TC, TG, HDL-C, LDL-C and non-HDL-C, 16(32%) cases were dyslipidemic by 0 (none) parameter, 13(26%) cases by one parameter, 7(14%) cases by two parameters, 4(8%) cases by three cases, 7(14%) cases by four parameters and 3(6%) cases by all five parameters. It was found that none to lesser the number of dyslipidemic parameters, greater the percentage of ACS cases and they are having hyper ApoB with statistically significant association (p<0.05).

Lipid Profile in Post-Acute Coronary Syndrome Setting: Lipidic Risk Assessment in Young People beyond LDL-C.

This case-control study was carried out in Department of Cardiology, Mymensingh Medical College Hospital, Bangladesh, within the period from June 2009 to May 2010. A total 50 case of 18-45 years of age with first attack of acute coronary syndrome admitted in coronary care unit and 50 healthy controls of same age and sex distribution were studied. Among the lipid parameters, TC, HDL-C, LDL-C and non-HDL-C were significantly lower in cases than in controls. Apo B was significantly higher in the cases (98.7±25.1 mg/dl vs. 77.5±35.2 mg/dl in control). Importantly, among the cases with hyper Apo B condition, 25 (50.0%) had LDL-C level within normal limit, thus conventional lipid profile underestimated the ACS risk. In multivariate analysis Apo B was an independent determinant of ACS. Among the controls 23(46.0%) with high LDL-C had hyper Apo condition. Hyper-Apo B in these controls may cause acute coronary syndrome in future. The present study shows estimation of Apo B can predict basal or residual risk of acute coronary syndrome in young people, what from calculated LDL-C level cannot be inferred.