Biporous Metal-Organic Framework with Tunable CO2/CH4 Separation Performance Facilitated by Intrinsic Flexibility.

In this work, we report the synthesis of SION-8, a novel metal-organic framework (MOF) based on Ca(II) and a tetracarboxylate ligand TBAPy4- endowed with two chemically distinct types of pores characterized by their hydrophobic and hydrophilic properties. By altering the activation conditions, we gained access to two bulk materials: the fully activated SION-8F and the partially activated SION-8P with exclusively the hydrophobic pores activated. SION-8P shows high affinity for both CO2 ( Qst = 28.4 kJ/mol) and CH4 ( Qst = 21.4 kJ/mol), while upon full activation, the difference in affinity for CO2 ( Qst = 23.4 kJ/mol) and CH4 ( Qst = 16.0 kJ/mol) is more pronounced. The intrinsic flexibility of both materials results in complex adsorption behavior and greater adsorption of gas molecules than if the materials were rigid. Their CO2/CH4 separation performance was tested in fixed-bed breakthrough experiments using binary gas mixtures of different compositions and rationalized in terms of molecular interactions. SION-8F showed a 40-160% increase (depending on the temperature and the gas mixture composition probed) of the CO2/CH4 dynamic breakthrough selectivity compared to SION-8P, demonstrating the possibility to rationally tune the separation performance of a single MOF by manipulating the stepwise activation made possible by the MOF's biporous nature

Generation and characterization of ABab.I transgenic mice: a novel tool for the isolation of human T cell receptors selected on a distinct human HLA class I haplotype for adoptive T cell therapy of cancer

For efficacious adoptive T cell therapy (ATT), the appropriate selection of tumor-specific antigens (TSAs) is crucial. Recurrent somatic driver mutations yield ideal TSAs for ATT to achieve complete tumor elimination, possibly without relapse. In silico algorithms predict epitopes as TSAs for ATT, however, with low probability. Thus, the accuracy of prediction algorithms still needs validation in describing processed neoepitopes. Simultaneous validation of proteasomal processing of predicted TSAs and identification of neoantigen-specific T cell receptors (TCRs) is possible from transgenic mice. One such model developed by Li et al. in 2010 was the ABabDII mice having the complete human TCR gene loci, knocked out for murine TCR and MHC class I gene loci, and it is transgenic for human HLA class I allele, HLA-A*02:01 (HLA-A2). Though isolation of human TCRs is possible from ABabDII mice, the model is limited as a source of obtaining only HLA-A2-restricted TCRs, thereby restricting epitope identification to HLA-A2 antigens. In this doctoral study, a novel mouse model with six human HLA alleles as a single haplotype, named ABab.I, was developed on ABabDII background to diversify HLA genes in the existing ABabDII mice for epitope discovery and broaden TCR repertoire for non-HLA-A2 restricted TCR isolation. In silico screening for putative neoepitopes predicted to bind high-ranked HLA alleles selected the six alleles in ABab.I mice; novel class I haplotype like in humans as every individual bears six HLA class I alleles. Initially, the in silico screening predicted 23 and 152 high-affinity TSAs (IC50 < 50 nM) from recurrent point mutations (n=266) that bound HLA-A2, and other frequent class I alleles (n=18), respectively. In the first phase of this doctoral thesis, epitope immunogenicity was tested in 4 out of 23 HLA- A2-binders in ABabDII mice. Only 1 out of 4 immunized epitopes elicited CD8+ T cell (CTL) responses. However, this was confirmed to be not endogenously processed when tested with TCRs raised from ABabDII mice. This form of reverse immunology is laborious and still a concern with open questions. A previous study on identifying epitopes from the vaccinia virus by Assarsson et al. in 2007 aligns with the in silico screen predicted data examined in this thesis. Thus, prediction algorithms offer a low probability to select immunogenic epitopes. In the second phase, the ABab.I mouse model with a novel set of chimeric class I fusion alleles, HLA-A*03:01, A*11:01, B*07:02, B*15:01, C*04:01, and C*07:02, was developed using PiggyBac transposon strategy. The introduction of six HLA alleles as a single genotype resembling a natural human situation broadened the TCR repertoire four-fold by enriching the peripheral pool with five times more unique and rarer V(D)J-TCRß clonotypes than ABabDII mice. Ultimately, ABab.I mice would serve as a versatile in vivo model system for epitope discovery, besides being a valuable tool to identify novel TCRs against high HLA-affinity tumor-specific antigens (IC50 < 50 nM) derived from recurrent somatic point mutations.Für eine wirksame adoptive T-Zell-Therapie (ATT) ist die Wahl geeigneter tumorspezifischer Antigene (TSAs) entscheidend. Sogenannte „Treiber-Mutationen“ - somatische Mutationen, die an der Tumorentstehung beteiligt sind und gehäuft in Tumoren auftreten, stellen ideale TSAs für eine ATT mit dem Ziel einer vollständigen Tumoreliminierung, und bestenfalls ohne Rückfall, dar. In silico-Algorithmen können Epitope als TSAs für die ATT vorhersagen, jedoch nur mit geringer Wahrscheinlichkeit. Eine experimentelle Validierung dieser Vorhersagen und Bestätigung tatsächlich prozessierter Neoepitope ist somit weiterhin notwendig. Die gleichzeitige Validierung der Prozessierung vorhergesagter TSAs und die Isolierung neoantigenspezifischer T-Zell-Rezeptoren (TCRs) ist in transgenen Mäusen möglich. Ein solches transgenes Model ist die ABabDII-Maus, die von Li et al. entwickelt wurde. Diese verfügt über die vollständigen humanen TCR-Genloci sowie eines knock-out der murinen TCR- und MHC-Klasse-I-Loci und ist transgen für das humane HLA-Allel A*02:01 (HLA-A2). Auch wenn die Isolierung von humanen TCRs aus den ABabDII-Mäusen möglich ist, ist das Modell auf HLA-A2-restringierte TCRs und die Identifikation HLA-A2-bindender Epitope begrenzt. In dieser Arbeit wurde ein neues Modell (ABab.I) mit einem einzelnen Haplotyp bestehend aus sechs humanen HLA-Allelen auf Basis der ABabDII-Maus entwickelt, um die Identifikation von neuen nicht-HLA-A2-restringierten Epitopen und TCRs zu ermöglichen. Durch in silico- Screening nach mutmaßlichen Neoepitopen, denen eine Bindung an häufig vorkommende HLA-Allele vorhergesagt wurde, wurden die sechs Allele der ABab.I-Maus ausgewählt; ein neuartiger Klasse-I-Haplotyp mit, wie im Menschen vorkommend, sechs HLA-Klasse-I-Allelen. Zunächst wurden durch das in silico-Screening 23 und 152 hochaffine TSAs (IC50 < 50 nM) aus gehäuft in Tumoren auftretenden Punktmutationen (n=266) vorhergesagt, die HLA-A2 oder andere häufige Klasse-I-Allele (n=18) binden. Im ersten Teil dieser Arbeit wurde die Immunogenität von vier der 23 HLA-A2-Binder in ABabDII-Mäusen getestet. Nur eines von vier immunisierten Peptiden löste eine CD8+ T-Zell- Antwort aus. Eine Testung mit aus ABabDII-Mäusen isolierten TCRs ergab jedoch, dass dieses Epitop nicht endogen prozessiert wird. Diese Form der reversen Immunologie ist aufwendig und hinterlässt häufig offene Fragen. Die Vorhersagealgorithmen bieten daher eine zu geringe Wahrscheinlichkeit, immunogene Epitope zu identifizieren. Im zweiten Teil wurde das ABab.I-Mausmodell mit einem neuartigen Satz von chimären Klasse-I-Fusionsallelen – HLA-A*03:01, A*11:01, B*07:02, B*15:01, C*04:01, und C*07:02 – mit Hilfe der PiggyBac-Transposon-Strategie entwickelt. Die Einführung von sechs HLA- Allelen erweiterte das TCR-Repertoire um das Vierfache, der periphere T-Zell-Pool enthielt fünfmal mehr einzigartige und seltenere V(D)J-TCRß-Klonotypen als der in ABabDII-Mäusen. Die ABab.I-Mäuse können als vielseitiges in vivo-Modellsystem für die Entdeckung von Epitopen dienen und darüber hinaus ein wertvolles Werkzeug zur Isolierung neuartiger TCRs gegen tumorspezifische Antigene mit hoher HLA-Affinität (IC50 < 50 nM) sein

Autonomic nervous system dysfunction in Parkinson’s disease patients

Background: Parkinson’s disease (PD) PD ranks second among the common neurodegenerative disease next only to Alzheimer’s dementia. Autonomic symptoms in Parkinson’s disease is very common.  This study assesses the autonomic dysfunction in PD, their prevalence, type and severity in related to staging.Methods: The study was conducted in Rajiv Gandhi government general hospital, Institute of neurology Madras medical college between 2011 to 2013, 141 patients fulfilling the criteria of Parkinson’s disease brain bank society were included in the study. All the patients were clinically examined with special attention to history, clinical features and symptoms and signs of Autonomic dysfunction. The patients were graded using the Hoehn and Yahr staging system.Results: Among 141 patients, 118 (83.7%) had autonomic dysfunction. Among 87 males, 72 patients had ANS dysfunction and among 54 females, 46 patients had ANS dysfunction. Stage wise 39 patients of 53 patients (73.6%) belonging to Stage I; 37 of 44 (84.1%) belonging to Stage II; 26 of 28 (92.8%) belonging to Stage III and all patients belonging to Stage IV and V had ANS dysfunction.Conclusions: ANS dysfunction in Parkinson’s disease is a common problem and the prevalence of it is 82.75% in males and 85.2% in females and overall in 83.7% of patients. The prevalence of ANS dysfunction in Males and females increases as the Hoehn and Yahr stage increases as evidenced by 68.7% of males and 80.9% of females have ANS dysfunction in stage I, while 100% of males and females in stage IV and V have ANS dysfunction. Sexual dysfunction (84.7%) ranks first followed by gastrointestinal (56.9%), and thermoregulatory (51.3%) autonomic disturbances in males and urinary disturbances (78.3%), ranks first followed by thermoregulatory (65.2%), and cardiovascular disturbances (56.5%) in females

HER2/neu immunohistochemical expression in gastric carcinoma

Background: Gastric carcinoma is a deadly disease with high mortality. A better understanding of the molecular basis of gastric cancer has contributed to the development of rationally designed molecular targeted therapies which will improve the survival rate. A genetic alteration that could help in targeted therapy and prognostication includes Human Epidermal Growth Factor Receptor 2 (HER2/neu) overexpression in gastric carcinoma. The objective of the present study was to identify and evaluate the HER2/neu protein immunohistochemical expression in gastric cancer from biopsies and surgical resection specimens and to evaluate their correlation with histopathological features.Methods: Total/subtotal gastrectomy specimens and gastric biopsies from a tertiary care center in South India were included in the study and assessed by light microscopy and Immunohistochemistry (IHC).Results: HER2/neu overexpression was seen in 28.6% of gastric adenocarcinoma. HER2/neu overexpression was seen in 44.2% of intestinal-type and 20% of mixed type with none of the diffuse type exhibited HER2/neu positivity and this was statistically highly significant with p value of &lt;0.01. HER2/neu positivity was found in 50% well-differentiated and 36.4% moderately differentiated tumors with none of the poorly differentiated tumors exhibiting HER2/neu positivity and this was statistically highly significant with p value of &lt;0.01.Conclusions: This study highlights the importance of the identification of HER2/neu overexpression in gastric adenocarcinoma. This will help in prognostication and identifying patients suitable for novel therapeutic interventions which will help in prolongation of survival of patients with this deadly disease

Association of CD4 count with anthropometric parameters and metabolic alterations in treatment naive human immunodeficiency virus infected patients

Background: Body fat abnormalities and metabolic derangements are well known to occur in human immunodeficiency virus (HIV) infection. The objective of present study was to evaluate the anthropometric parameters, fasting lipid profile and fasting blood sugar in treatment naïve HIV patients and to assess any relation with CD4 count.Methods: Anthropometric measurements, latest CD4 count were recorded from HIV patients. Blood was collected from patients for lipid profile and sugar measurements.Results: Anthropometric parameters showed a gradual increase in waist circumference (WC), increase in waist hip ratio (WHR) and decrease in body mass index (BMI) as CD4 count declined. Fasting lipid profile showed a gradual decrease in total cholesterol, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) and increase in triglycerides (TG) and very low density lipoprotein cholesterol (VLDL-C) as CD4 count declined which were statistically highly significant (P<0.001). Compared to higher CD4 group (350-500/ mm3), the lower CD4 group (<50/mm3) showed a decrease in mean total cholesterol by 60 mg/dL, LDL-C by 76 mg/dL and HDL-C by 13 mg/dL. The increase in mean TG and VLDL-C were 154 mg/dL and 30 mg/dL respectively. Comparison of fating blood sugar (FBS) between CD4 groups showed a gradual rise in FBS as CD4 count declined.Conclusions: As CD4 count declines, metabolic alterations occur in treatment-naïve HIV patients with substantial decrease in serum total cholesterol, HDL-C, LDL-C and an increase in TG and VLDL-C and increased incidence of impaired FBS. Morphological alteration in advanced HIV is evidenced by increased WC, WHR and decreased BMI

PERFORMANCE EVALUATION OF A SMALL-SCALE MAGNETORHEOLOGICAL DAMPER FOR CIVIL ENGINEERING APPLICATIONS

Magnetorheological dampers (MRDs) are devices that adjust their damping properties in response to an external magnetic field. Large-scale MRDs have been successfully used as vibration control devices in structures. This study focuses on modelling and optimizing an MRD using COMSOL Multiphysics. Various parameters, such as coil turns and current, are optimized to achieve the maximum flux value in the MRD. The simulation yielded a maximum magnetic flux of 0,44 T with 500 coil turns. Based on the optimized MRD parameters, a numerical equation is then used to calculate the total damping force. The maximum numerical and experimental damping forces corresponding to a 2,0 A current were 989,39 and 1004,63 N, respectively. The numerical damping force is then compared to the experimental results to validate the accuracy of the model. The MRD is integrated into a scaled-down reinforced concrete frame and subjected to a cyclic loading test for performance evaluation. The results show that the MR dampers improve the performance of the frame structure, increasing its load-carrying capacity and energy dissipation by 19,45 % and 20,43 %, respectively. The findings of the study provide valuable insights into the behaviour of MRDs and their optimization using numerical simulations, as well as highlight the importance of experimental validation for accurate prediction of the performance of MRDs in practical civil engineering applications

Russell’s viper venom induced reverse takotsubo cardiomyopathy

Reverse takotsubo cardiomyopathy is a rare variant of takotsubo cardiomyopathy characterized by basal akinesis/hypokinesis associated with apical hyperkinesis, with no evident obstructive coronary artery disease, which often resolves spontaneously. This condition was observed in a 15-year-old girl after being bitten by Russell’s viper. She presented with pain and swelling at the bitten area. Further evaluation, showed elevated cardiac biomarkers, ECG showed ST-segment changes and echocardiographic findings of basal akinesis with preserved apical function. After receiving anti-snake venom and supportive care treatment, she fully recovered and her cardiac function returned to normal. This case emphasizes the significance of assessing the heart in situations of viper bites among patients.

Study of Autonomic Nervous System Dysfunction in Parkinson’s Patients.

Parkinson’s disease (PD)1 is a chronic neurodegenerative progressive neurological disease with clinical features viz rigidity, bradykinesia, rest tremor and postural instability. Assymetry is a prominent feature of this disease. PD ranks second among the common neurodegenerative disease next only to Alzheimer’s dementia. The pathological characteristic of PD is intraneuronal alpha synuclein positive Lewy bodies and loss of neuronal cell. Apart from classical motor symptoms PD patients also develop non motor symptoms. Non motor symptoms cause a major disability in PD and the prominently contribute to decreasing quality of life especially in advanced stages of disease. The major non motor symptoms are olfactory loss, psychiatric disturbances of depression and anxiety, sleep disorders, cognitive dysfunction, and chiefly the Autonomic Dysfunction. Autonomic symptoms in Parkinson’s disease (PD) were first reported in 1817 by James Parkinson himself. He described abnormalities of salivation and sweating, and dysfunction of the alimentary tract and urinary bladder. Patients rarely volunteer symptoms of autonomic disturbance in clinic, and perhaps because of this, there has been little interest in autonomic dysfunction in PD until recent years. Demonstration of the importance of dysautonomia in Parkinsonism patients, led to a recent resurgence in this area. The introduction of standardised diagnostic criteria for PD has improved diagnostic accuracy, and reports since the introduction of these guidelines continue to suggest that between 50% and 80% of subjects have objective evidence of autonomic involvement. Autonomic nervous system dysfunction in Parkinson’s disease is a common problem and it has to be identified early to initiate proper treatment. We conclude the following from our study. 1. The prevalence of ANS dysfunction is significantly high in PD patients of 83.7% . The prevalence is 82.75% in males and 85.2% in females. 2. The prevalence of ANS dysfunction in Males increases as the Hoehn and Yahr stage increases as evidenced by 68.7% of males in stage I and 100% of males in stage IV and V have ANS dysfunction. 3. The prevalence of ANS dysfunction in Females increases as the Hoehn and Yahr stage increases as evidenced by 80.9% of females in stage I and 100% of Females in stage IV and V have ANS dysfunction. 4. Sexual dysfunction(84.7%) is the most common ANS dysfunction in males followed by gastrointestinal(56.9%), and thermoregulatory (51.3%) autonomic disturbances. 5. Urinary disturbances(78.3%), is the most common ANS dysfunction in females followed by thermoregulatory(65.2%),, and cardiovascular disturbances(56.5%). 6. There is a significant correlation between the age and ANS dysfunction. The severity of dysfunction worsens as the age advances, which is statistically significant (p value<0.0001) 7. There is no significant correlation between the sex and severity of ANS dysfunction. 8. As the disease duration advances the severity of dysfunction increases which is statistically significant (p value<0.0001). Patient with disease duration less than 5 years had no or only mild ANS dysfunction, whereas with patients with disease duration more than 10 years had predominantly moderate to severe ANS dysfunction in all patients. 9. There exists a significant correlation between Hoehn and Yahr staging and severity of ANS dysfunction. Patient in stage I had no ANS dysfunction(26.4%) or only mild dysfunction(62.3%) whereas patients in stage IV and V have severe ANS dysfunction (100%)

A case of Streptococcus cristatus infective endocarditis mimicking anti-neutrophil cytoplasmic antibody associated vasculitis

We report a case of a 55-year-old female presenting with infective endocarditis caused by Streptococcus cristatus (S. cristatus) along with c-anti-neutrophil cytoplasmic antibody (ANCA) positivity. S. cristatus is an infrequent cause of infective endocarditis with only 6 reported cases. ANCA positivity is rare in infective endocarditis. In our case ANCA positivity had the potential to mislead towards an autoimmune etiology, but the positive test was eventually understood to be caused by the S. cristatus infection. Our case also had unusual presentations like erythema nodosum and thrombotic events. This case also adds scientific literature on the capacity of Streptococcus cristatus to produce serious infections like endocarditis