Discovering The New Chemical Entities of Therapeutic Interest

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Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Comparison of Conventional and Microwave Treatment on Soymilk for Inactivation of Trypsin Inhibitors and In Vitro Protein Digestibility

Soymilk is lower in calories compared to cow’s milk, since it is derived from a plant source (no cholesterol) and is an excellent source of protein. Despite the beneficial factors, soymilk is considered as one of the most controversial foods in the world. It contains serine protease inhibitors which lower its nutritional value and digestibility. Processing techniques for the elimination of trypsin inhibitors and lipoxygenase, which have shorter processing time and lower production costs are required for the large-scale manufacturing of soymilk. In this study, the suitable conditions of time and temperature are optimized during microwave processing to obtain soymilk with maximum digestibility with inactivation of trypsin inhibitors, in comparison to the conventional thermal treatment. The microwave processing conditions at a frequency of 2.45 GHz and temperatures of 70 °C, 85 °C and 100 °C for 2, 5 and 8 min were investigated and were compared to conventional thermal treatments at the same temperature for 10, 20 and 30 min. Response surface methodology is used to design and optimize the experimental conditions. Thermal processing was able to increase digestibility by 7% (microwave) and 11% (conventional) compared to control, while trypsin inhibitor activity reduced to 1% in microwave processing and 3% in conventional thermal treatment when compared to 10% in raw soybean

Comparison of Bacterial and Viral Reduction Across Different Wastewater Treatment Processes

Today billions of people live without access to basic sanitation facilities, and thousands die every week due to diseases caused by fecal contamination associated with improper sanitation. It has thus become crucial for decision makers to have access to relevant and sufficient data to implement appropriate solutions to these problems. The Global Water Pathogen Project http://www.waterpathogens.org/ is dedicated to providing an up-to-date source of data on pathogen reduction associated with different sanitation technologies that are important if the world is to achieve the Sustainable Development Goals (SDGs) related to health and sanitation provision. In this research, a subset of the Global Water Pathogen Project (GWPP) data is used to access the reduction of bacteria and viruses across different mechanical and natural sanitation technologies. The order of expected removal for bacteria during wastewater treatment was reported as highest for a membrane bioreactor (4.4 log10), waste stabilization pond (2.3 log10), conventional activated sludge (1.43 log10), anaerobic anoxic oxic activated sludge (1.9 log10), trickling filter (1.16 log10), and upflow anaerobic sludge blanket reactor (1.2 log10). Furthermore, the order of expected removal for viruses was reported as highest for a membrane bioreactor (3.3 log10), conventional activated sludge (1.84 log10), anaerobic anoxic oxic activated sludge (1.67 log10), waste stabilization pond (1 log10), upflow anaerobic sludge blanket reactor (0.3 log10) and trickling filter (0.29 log10). It was found that hydraulic retention time (HRT) had a statistically significant relation to the reduction of bacteria in an anaerobic, anoxic oxic treatment system. Similarly, a significant relation was found between the number of waste stabilization ponds in series and the expected reduction of bacteria. HRT was also found to be a significant factor in virus reduction in waste stabilization ponds. Additionally, it was observed that waste stabilization ponds, trickling filters, and UASB reactors could obtain a greater reduction in bacteria (5-7 log10) when combined with additional treatment (e.g., chemical disinfection or use of maturation ponds). Also, mechanized systems, such as activated sludge systems and membrane bioreactors, obtained a greater reduction (2-3 log10) of viruses when compared to a natural system. It was concluded that the selection of the best suitable technology for pathogen reduction depends on environmental, design, and operational factors as well as considering the performance of specific wastewater treatment systems individually as well as when combined with other treatment technologies that may provide added removal of microbial constituents

Effects of conventional and microwave treatments on inhibitory activity and structural conformation of trypsin inhibitor protein

Food processing and preservation techniques provide high quality nutritive food, reduce the risk of contracting food-borne diseases and increase the shelf life of food products. Processing techniques further increase the digestibility of food, resulting in greater bioavailability of the nutrients and also in the elimination of undesirable factors. Though extensive studies have been performed using various commercial processing methods such as sterilization, pasteurization, autoclaving, extrusion, homogenization, blanching, batch boiling, steam injection, ultra-high temperature (UHT), high temperature and pressure combination, ohmic heating and high pressure processing (HPP), for producing quality food, limited knowledge is available in terms of the effects of processing at atomic and molecular level. Thus, the studies to understand the changes at molecular level could help industrialists to design processing methods with increased nutritive and sensory appeal of food products.In this study, the effects of conventional thermal and microwave treatments on raw soymilk samples for the inactivation of soybean trypsin inhibitors were evaluated. In- vitro protein digestibility (IVPD) studies were also conducted for understanding the effects of aforementioned processing techniques on soymilk proteins. The levels of microwave processing (70⁰C, 85⁰C and 100⁰C for 2, 5, 8 min) and conventional treatment (70⁰C, 85⁰C and 100⁰C for 10, 20, 30 min) were optimized using Response Surface Methodology (RSM).Molecular dynamics (MD) simulation modelling techniques have been applied to explore and visualize the behavior of proteins, at ambient conditions and under the influence of external electric field stress, temperature and time. Soybean trypsin inhibitor (STI) protein was selected for MD simulations. By performing these simulations under the electric field strength of 0.5 V/nm, a valuable insight into the effects of electric field on protein conformation was noted and evaluated using through Root Mean Square Deviation (RMSD), Solvent Accessible Surface Area (SASA) and Ramachandran plot analysis. It was observed that STI has an unusual β-sheet structural stability under the influence of oscillating electric fields. Ramachandran plots were also used to analyze the stability of the molecules obtained on treatment with temperatures (300 K to 393 K) and oscillating electric fields (0.5 V/nm at 2.45 GHz).The experimental results showed that the in-vitro protein digestibility increased with increase in time and temperature during microwave processing and conventional thermal processing. Similarly reduced trypsin inhibitor activity (TIA) values were obtained with an increase in time and temperature of the processing conditions. Therefore, microwave processing can be used as a potential alternative method of processing to improve the overall quality of soymilk. MD simulations have been introduced as a tool to visualize the changes in the stability of secondary protein structures during various processing conditions of time and temperature. The studies also established the relation between various processing methods and conformations of secondary structure of proteins. The solvent accessible area of cysteine residues increased with an increase in the temperature (300 K to 394 K), both in the presence and absence of the oscillating electric field, influencing the disulphide bridge stability. The results showed that the core tryptophan residues of the STI protein increased significantly by changing the conformation of the secondary structure during conventional heating and microwave processing, thus affecting the functional properties of the protein.Les techniques de traitement et conservation des denrées périssables permettent de fabriquer des aliments nutritif et salubre, et d'augmenter la durée de conservation des produits alimentaires. Certaines de ces techniques permettent d'accroître la digestibilité des aliments, entraînant une plus grande biodisponibilité des nutriments et l'élimination de facteurs indésirables. Bien que plusieurs études ont été effectuées pour établir la validité de diverses méthodes de traitement comme la stérilisation, la pasteurisation, l'extrusion, l'homogénéisation, le blanchiment, l'injection de vapeur, les ultra-hautes températures, l'utilisation combinée de hautes températures et pressions, le chauffage ohmique et les traitements à très haute pressions, on constate que l'état de la connaissance sur les effets de la transformation au niveau atomique et moléculaire des aliments est limité. Une meilleure compréhension des changements au niveau moléculaire causés par les procédés de transformation est nécessaire pour développer de nouveaux procédés industriels pour la fabrication d'aliments nutritifs, savoureux et sécuritaires. Dans cette étude, les effets des traitements thermiques conventionnels et par micro-ondes sur des échantillons de lait de soja brut pour l'inactivation des inhibiteurs de la trypsine ont été évalués. Des essais sur la digestibilité in-vitro des protéines ont été menés pour mieux comprendre les effets de ces procédés sur les protéines de lait de soja. Les traitements par micro-ondes (70⁰C, 85⁰C et 100⁰C pour 2, 5, et 8 min) ont été comparés aux traitements thermiques conventionnels (70⁰C, 85⁰C et 100⁰C pour 10, 20, et 30 min) et optimisés en utilisant la méthodologie des surfaces de réponses.Des techniques de simulation de la dynamique moléculaire ont été utilisées pour étudier et visualiser le comportement des protéines exposées à des stresses externes causés par les champs micro-ondes, les températures élevées et les durées de traitement. La protéine de soya qui agit comme inhibiteur de l'activité enzymatique de la trypsine et de la chymotrypsine a été utilisée pour les simulations MD. Lors de ces simulations, l'intensité du champ électromagnétique était de 0,5 V/nm et la fréquence de 2450 MHz. Cette simulation a permis d'avoir un aperçu de l'effet du champ électromagnétique sur la conformation des protéines. Ces effets ont été évalués et comparés par le biais des déviations de l'écart quadratique moyen (RMSD), les surfaces de la zone accessible aux solvants (SASA) et les tracés de Ramachandran. Les tracés de Ramachandran ont également été utilisés pour analyser la stabilité des molécules obtenues après le traitement à des températures allant de 300 à 393 K et exposées aux microondes. Les résultats ont démontré que la digestibilité in-vitro des protéines augmentait avec l'augmentation du temps et de la température de traitement (micro-ondes et thermique conventionnel). De plus, l'activité d'inhibiteur de trypsine (AIT) a diminué avec l'augmentation du temps et de la température des traitements. Le sur-traitement thermique conventionnel requis pour la désactivation des inhibiteurs de trypsine a endommagé d'autres protéines du soya et du fait réduit sa qualité nutritive. Du fait, cette étude a démontré que le traitement par micro-ondes du lait de soya permettaient de fabriquer un lait de meilleur qualité. De plus, il a été observé que les surfaces de la zone accessible aux solvants des résidus de cystéine augmentaient avec l'augmentation de la température (300 K à 394K), à la fois en présence et en l'absence du champ électrique oscillant, et influencé la stabilité des ponts disulfure. On a trouvé que les résidus de noyaux de tryptophane de la protéine STI avaient augmenté de manière significative en modifiant la conformation de la structure secondaire, lors du traitement thermique conventionnel et par traitement de micro-ondes, ce qui a altéré les propriétés fonctionnelles de la protéine

Vitiligo: Clinical profiles in Vadodara, Gujarat

<b>Purpose:</b> Vitiligo is an acquired depigmentary condition involving a progressive loss of melanocytes from the epidermis and hair follicles We have earlier reported impairment of systemic antioxidant status of Baroda vitiligo patients (<i> Pigment Cell Res 2004; 17; 289-94)</i> and we now show analysis of the clinical profiles of these patients. <b> Procedure:</b> The study comprised of 424 vitiligo patients. Clinical and demographic details of all the patients were obtained from the vitiligo clinical proformas. Lipid peroxidation levels (LPO) in erythrocytes of vitiligo patients and healthy controls were estimated. <b> Result: </b> Out of four hundred and twenty four outpatients, males constituted 38.44&#x0025; and females were 61.56&#x0025;. Mean age of the patients was 25.59 years. The sites of onset were the lower limb, face, trunk, upper limb, genital, hand, labia and scalp in the descending order of frequency. Koebner&#x2032;s phenomenon was observed in 12.74&#x0025;, diabetes mellitus in 1.18&#x0025;, leukotrichia in 9.2&#x0025; and premature graying of hair in 23.11&#x0025; patients. A family history of vitiligo was present in 21.93&#x0025; of the patients. Significant increase (<i> P</i> < 0.002) in the LPO levels of the vitiliginous patients was observed compared to the controls. <b> Conclusion:</b> Vitiligo vulgaris was the most common form of the disease which constituted 52.36&#x0025; of the patients followed by focal vitiligo (28.54&#x0025;), segmental vitiligo (6.84), acrofacial (7.55&#x0025;), mucosal (2.83&#x0025;) and universal vitiligo (1.89&#x0025;). Systemic oxidative stress may have a pathophysiological role in precipitating all clinical types of vitiligo in Vadodara vitiliginous patients

Interviewing Witnesses: Eliciting Coarse-Grain Information

Eyewitnesses to crimes sometimes report inaccurate fine-grain details but fail to report accessible and potentially accurate coarse-grain details. We asked college students and community members (aged 17 to 62 years) who viewed a video of a simulated crime to answer interviewers’ questions at coarse- and fine-grained levels of detail and measured the quantity and accuracy of their responses. Three experiments (overall N = 219) also (a) provided comparative data for participants who were interviewed using the open-ended Self-Administered Interview (Gabbert, Hope, & Fisher, 2009) or one of two “report everything” open-ended procedures, (b) tested the efficacy of the procedure using both written and verbal interviews, and (c) examined the generality of the findings across different encoding stimuli which required variations in the types of cued recall questions asked. Coarse-grain reporting seldom occurred under the free recall interview conditions. Witnesses provided abundant coarse-grain details when required to respond to probes about specific details (i.e., cued recall forced report conditions) – without obvious cost to overall accuracy relative to accuracy of similar detail reported under free recall conditions – regardless of whether they responded on a written questionnaire or in a face-to-face individual interview. These experiments suggest that a procedure that requires cued recall forced reporting of coarse-grain detail may offer potential in certain investigative situations as an adjunct to the widely recommended open-ended forensic interviewing techniques. Public Significance Statement. Witnesses to crimes sometimes volunteer inaccurate fine-grain detail (e.g., purple getaway car) rather than accurate coarse-grain or broad detail (e.g., dark-colored getaway car) despite the latter being potentially valuable in some investigative contexts (e.g., review of CCTV footage). Requiring witnesses to give coarse-grain or general answers to interviewers’ questions produced a substantial amount of accurate information that was not volunteered in open-ended interviews, suggesting a possible way of supplementing currently recommended open-interviewing techniques