Development of 2024 p/m aluminium alloy–SiCp nanocomposites via mechanical alloying

Aluminum alloy 2024 is the best known most widely used aircraft structural alloy. Now a days it is also gaining ground in automotive industry. In the present studies, 2024 P/M Al alloy and SiC particulates have been chosen as matrix and reinforcement materials, respectively. Mechanical alloying (MA) was used to obtain uniform SiCp dispersion in the matrix. MA powder was vacuum degassed and consolidated by hot pressing and subsequent hot forging. Thereafter the composites were heat treated to give T-6 temper. Optical and scanning electron microscopy of the composite was carried out and evaluation of mechanical properties was done. The principal objective of the present investigations was to determine how the particulate volume fraction and extent of mechanical alloying affect the microstructure and tensile properties of 2024 P/M Al alloy-SiCp composites. In these efforts it could be possible to develop nano composites of 2024 P/M Al alloy-SiCp having tensile strength of 504 MPa and modulus of elasticity of 105 GPa

Comparison between the two models of dephasing in mesoscopic systems

In mesoscopic systems to study the role of inelastic scattering on the phase coherent motion of electrons two phenomenological models have been proposed. In the first one, due to B\"uttiker, one adds a voltage probe into the system (or in the scattering matrix). The second model invokes the complex (or optical) potential in the system Hamiltonian. Studying a simple geometry of a metallic loop in the presence of Aharonov-Bohm magnetic flux, we show that the two probe conductance is symmetric in the reversal of the magnetic field in B\"uttiker's approach. Whereas the two probe conductance within the complex potential model is asymmetric in the magnetic flux reversal contrary to the expected behavior.Comment: 11 pages RevTex, 4 figures inculded, Communicated to PR

B Cell Depletion Eliminates FVIII Memory B Cells and Enhances AAV8-coF8 Immune Tolerance Induction When Combined With Rapamycin

Hemophilia A is an inherited coagulation disorder resulting in the loss of functional clotting factor VIII (FVIII). Presently, the most effective treatment is prophylactic protein replacement therapy. However, this requires frequent life-long intravenous infusions of plasma derived or recombinant clotting factors and is not a cure. A major complication is the development of inhibitory antibodies that nullify the replacement factor. Immune tolerance induction (ITI) therapy to reverse inhibitors can last from months to years, requires daily or every other day infusions of supraphysiological levels of FVIII and is effective in only up to 70% of hemophilia A patients. Preclinical and recent clinical studies have shown that gene replacement therapy with AAV vectors can effectively cure hemophilia A patients. However, it is unclear how hemophilia patients with high risk inhibitor F8 mutations or with established inhibitors will respond to gene therapy, as these patients have been excluded from ongoing clinical trials. AAV8-coF8 gene transfer in naïve BALB/c-F8e16−/Y mice (BALB/c-HA) results in anti-FVIII IgG1 inhibitors following gene transfer, which can be prevented by transient immune modulation with anti-mCD20 (18B12) and oral rapamycin. We investigated if we could improve ITI in inhibitor positive mice by combining anti-mCD20 and rapamycin with AAV8-coF8 gene therapy. Our hypothesis was that continuous expression of FVIII protein from gene transfer compared to transient FVIII from weekly protein therapy, would enhance regulatory T cell induction and promote deletion of FVIII reactive B cells, following reconstitution. Mice that received anti-CD20 had a sharp decline in inhibitors, which corresponded to FVIII memory B (Bmem) cell deletion. Importantly, only mice receiving both anti-mCD20 and rapamycin failed to increase inhibitors following rechallenge with intravenous FVIII protein therapy. Our data show that B and T cell immune modulation complements AAV8-coF8 gene therapy in naïve and inhibitor positive hemophilia A mice and suggest that such protocols should be considered for AAV gene therapy in high risk or inhibitor positive hemophilia patients

A complicated case of Plasmodium falciparum malaria with symmetrical peripheral gangrene with a review of literature

Malaria causes nearly one million deaths each year and with its recent re-emergence, several fatal complications are seen such as cerebral malaria, hypotension or shock, renal failure, pulmonary oedema/adult respiratory distress syndrome, and hypoglycaemia. Symmetric peripheral gangrene (SPG) is a severe but extremely rare complication of malaria. It has a rapid and sudden onset leading to necrosis which cannot be reversed. A 26 year old male was admitted and treated for complicated malaria and developed SPG. He was given intravenous artesunate, doxycyline, clopidogrel and acetyl salicyclic acid for the gangrene; however, he went into multiple organ dysfunction syndrome and septic shock and thus could not be resuscitated. We report this case to highlight that physicians treating malaria should always look for these signs for timely correction and to improve the patient outcome

Coagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassette

Hepatic gene transfer with adeno-associated viral (AAV) vectors shows much promise for the treatment of the X-linked bleeding disorder hemophilia B in multiple clinical trials. In an effort to further innovate this approach and to introduce alternative vector designs with potentially superior features into clinical development, we recently built a vector platform based on AAV serotype 3 because of its superior tropism for human hepatocytes. A vector genome with serotype-matched inverted terminal repeats expressing hyperactive human coagulation factor IX (FIX)-Padua was designed for clinical use that is optimized for translation using hepatocyte-specific codon-usage bias and is depleted of immune stimulatory CpG motifs. Here, this vector genome was packaged into AAV3 (T492V + S663V) capsid for hepatic gene transfer in non-human primates. FIX activity within or near the normal range was obtained at a low vector dose of 5 x 10(11) vector genomes/kg. Pre-existing neutralizing antibodies, however, completely or partially blocked hepatic gene transfer at that dose. No CD8(+) T cell response against capsid was observed. Antibodies against the human FIX transgene product formed at a 10-fold higher vector dose, albeit hepatic gene transfer was remarkably consistent, and sustained FIX activity in the normal range was nonetheless achieved in two of three animals for the 3-month duration of the study. These results support the use of this vector at low vector doses for gene therapy of hemophilia B in humans

Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia

Fusion proteins, which consist of factor VIII or factor IX and the transmucosal carrier cholera toxin subunit B, expressed in chloroplasts and bioencapsulated within plant cells, initiate tolerogenic immune responses in the intestine when administered orally. This approach induces regulatory T cells (Treg), which suppress inhibitory antibody formation directed at hemophilia proteins induced by intravenous replacement therapy in hemophilia A and B mice. Further analyses of Treg CD4+ lymphocyte sub-populations in hemophilia B mice reveal a marked increase in the frequency of CD4+CD25-FoxP3-LAP+ T cells in the lamina propria of the small but not large intestine. By contrast, no changes in frequencies of CD4+CD25+FoxP3+ T cells were observed. Here we demonstrate that, surprisingly, the adoptive transfer of very small numbers of CD4+CD25-LAP+ Treg isolated from the spleen of tolerized mice significantly suppress antibodies directed against FIX. By contrast, equal numbers of splenic CD4+CD25+ T cells do not have an effect on antibody formation. Thus, tolerance induction by oral delivery of antigens bioencapsulated in plant cells occurs via the unique immune system of the small intestine and that suppression of antibody formation is primarily carried out by induced latency-associated peptide (LAP) expressing Treg. The observation that CD4+CD25-LAP+ Treg migrate to the spleen are useful for the design of clinical protocols

Development of new promising varieties of faba bean through traditional pedigree method for commercial cultivation in plain zone of India

A long term experiment was carried out in MAP Section, Department of Genetics & Plant Breeding,  CCS Haryana Agricultural University, Hisar from 2005-06 to 2018-19 on identification of elite genotypes from germplasm and their utilization in the development of high yielding variety through hybridization followed by traditional pedigree method to obtain desirable transgressive segregants in Faba bean. In the present investigation a number of germplasm lines were screened for seed yield and other related traits including national check Vikrant during 2005-06 under AICRN in augmented block design. As a result, ten elite genotypes identified i.e. EC117755, EC117799, EC248710, EC329675, HB123, HB180, HB430, HB204, HB 430, HB 502, HB 503 & one check variety, Vikrant. By using these elite genotypes, a number of F1 hybrids were made during 2005-06 and F2 to F6 generations were evaluated to identify the superior progenies during 2007-08 to 2011-12. After a long process of evaluation, rejection and selection, 20 superior transgressive segregant homozygous progenies were identified to make new entries. Later on, during 2012-2013, the superior entries (viz. HB12-1, HB12-5, HB12-8, HB12-9, HB12-11, HB12-12, HB12-13, HB12-14, HB12-15, HB12-26, HB12-28, HB12-29, HB12-30, HB12-31, HB12-34, HB12-36, HB12-37,HB12-38, HB12-39 and HB12-42) were evaluated at Hisar centre against Vikrant and found promising. Therefore, all these 20 genotypes were evaluated in SST during 2013-14, LST during 2014-15 and FYT during 2015-16. On the basis of above results, only five genotypes viz. HB12-8 (47.77q/ha), HB12-42 (47.70q/ha), HB12-15 (46.70q/ha), HB12-34 (46.14q/ha) and HB12-37 (45. 31q/ha) were found promising. These were further evaluated in multi-location trials at seven locations (i.e. Ambikpur, Delhi, Faizabad, Faridkot, Hisar, Ludhiana & Ranchi) for seed yield, quality and resistance against insect pest & disease in IVT and AVT during 2016-17 & 2017-18, respectively. Out of these, HB12-34 exhibited yield superiority over national checks,Vikrant and HFB-1 and free from insect pest and disease as well as low in vicine-covicine and high in protein content. Therefore, HB12-34 may be recommended for commercial cultivation in plain zone at national level

Light-driven chloride transport kinetics of halorhodopsin

Despite growing interest in light-driven ion pumps for use in optogenetics, current estimates of their transport rates span two orders of magnitude due to challenges in measuring slow transport processes and determining protein concentration and/or orientation in membranes in vitro. In this study, we report, to our knowledge, the first direct quantitative measurement of light-driven Cl transport rates of the anion pump halorohodopsin from Natronomonas pharaonis (NpHR). We used light-interfaced voltage clamp measurements on NpHR-expressing oocytes to obtain a transport rate of 219 (± 98) Cl /protein/s for a photon flux of 630 photons/protein/s. The measurement is consistent with the literature-reported quantum efficiency of ∼30% for NpHR, i.e., 0.3 isomerizations per photon absorbed. To reconcile our measurements with an earlier-reported 20 ms rate-limiting step, or 35 turnovers/protein/s, we conducted, to our knowledge, novel consecutive single-turnover flash experiments that demonstrate that under continuous illumination, NpHR bypasses this step in the photocycle

Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier

Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity