Melioidosis: acute respiratory distress syndrome and sepsis

Melioidosis is a serious infection caused by the bacterium Burkholderia pseudomallei (B. pseudomallei) mostly found in endemic areas like Southeast Asia. Herein, we presented a case of melioidosis in a 32-year-old man who presented with respiratory distress, was a known case of type 2 diabetes not on any treatment presented to the emergency department (ED) with a history of pustules over skin, shortness of breath, and fever. He was initially misdiagnosed and treated as pulmonary tuberculosis in another hospital prior to his latest presentation. Melioidosis is a severe infection that can be misdiagnosed due to variable presentation and low awareness among healthcare workers of the disease. Diagnosis requires high clinical suspicion, especially in patients who are coming from endemic areas with appropriate risk factors such as diabetes mellitus. Treatment with appropriate antibiotics for a long duration, and outpatient follow-up is vital to reduce the risk of recurrence

How the adherens junction proteins PLEKHA7 and PDZD11 regulate Staphylococcus aureus α-toxin cytotoxicity

In a genetic screen, PLEKHA7, and other junctional proteins were identified as host factors mediating death by S.aureus α-toxin. Here, I clarify the underlying molecular mechanism using cell biological and biochemical methods. In summary, I identified a macromolecular complex that consists of PLEKHA7-PDZD11-tetraspanin33-afadin that clusters α-toxin receptor ADAM10 at the apical junctions through a dock-and-lock mechanism. In addition, I also identified a pool of ADAM10 that is distributed on the lateral surfaces, and which is independent of PLEKHA7-PDZD11 complex. Junctionally clustered ADAM10 seeds the formation of stable α-toxin pores, resulting in prolonged injury and cell death. The disruption of PLEKHA7-PDZD11 complex inhibits the formation of junctionally clustered ADAM10 and toxin pores. And the laterally distributed toxin pores are unstable and are removed by macropinocytosis, causing intrinsically weaker injury, resulting in cell recovery and survival. Thus I identify a novel mechanism through which cell junction proteins regulate S.aureus α-toxin cytotoxicity

Area Optimized H.264 Intra Prediction Architecture for 1080p HD Resolution

High performance video standards use prediction techniques to achieve high picture quality at low bit rates. The type of prediction decides the bit rates and the image quality. Intra Prediction achieves high video quality with significant reduction in bit rate. This paper present an area optimized architecture for Intra prediction, for H.264 decoding at HDTV resolution with a target of achieving 60 fps. The architecture was validated on Virtex-5 FPGA based platform. The architecture achieves a frame rate of 64 fps. The architecture is based on multi-level memory hierarchy to reduce latency and ensure optimum resources utilization. It removes redundancy by reusing same functional blocks across different modes. The proposed architecture uses only 13% of the total LUTs available on the Xilinx FPGA XC5VLX50T

HD resolution intra prediction architecture for H.264 decoder

High performance video standards use prediction techniques to achieve high picture quality at low bit rates. The type of prediction decides the bit rates and the image quality. Intra Prediction achieves high video quality with significant reduction in bit rate. This paper presents novel area optimized architecture for Intra prediction of H.264 decoding at HDTV resolution. The architecture has been validated on a Xilinx Virtex-5 FPGA based platform and achieved a frame rate of 64 fps. The architecture is based on multi-level memory hierarchy to reduce latency and ensure optimum resources utilization. It removes redundancy by reusing same functional blocks across different modes. The proposed architecture uses only 13% of the total LUTs available on the Xilinx FPGA XC5VLX50T

“CLINICAL TRIALS IN INDIA”

The larger context of clinical trials in India is poverty and the absence of affordable healthcare. For more than a decade, government policy has been to reduce public support for healthcare services, and these services are under-resourced. Health economists have pointed out that only 15 per cent of the Rs 1,500 billion spent in the health sector in India comes from the government. Clinical trials (also called medical research studies) are used to determine whether new drugs or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people. If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV are 'post-approval' studies. The level of concern about the impact of the CTD on clinical research activities is intense and widespread overall stakeholder groups. Opinions and quantitative survey results draw a picture of increased bureaucracy and costs, reduction of important research without creating benefits for patients. However, concrete, comprehensive figures about the clinical trial activities are only available from competent authorities. Figures on the CTD’s impact on organisation, staffing, costs and processes of the different stakeholders are missing.These trials violated the the Indian Council of Medical Research’s Ethical guidelines for biomedical research on human subjects and the World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. The trial designs do not seem to have violated regulations for the conduct of clinical research in India. The existing regulatory apparatus therefore permits unethical trials of no benefit to Indians. Clearly, trials are being conducted in India that could not be conducted in developed countries, taking advantage of people’s lack of access to affordable, good quality care. The benefits of research do not reach the community as drugs found effective following these trials may not be affordable to the community in which they were tested. Such practices are in violation of the Declaration of Helsinki as well as the general principles laid down in the Indian Council of Medical Research’s ethical guidelines for biomedical research.The infrastructure for regulation, ethics review and monitoring is insufficient. The government’s priority seems to be ensuring that clinical research in India produces good quality data according to Good Clinical Practice standards. Ethical guidelines – including its own ethical guidelines – seem to be of secondary importance. The ethical concerns raised by these clinical trials; the weak regulatory apparatus to protect trial participants, government policy to encourage international clinical trials without taking active steps to put in place a system to protect participants from harm; people’s desperation for affordable health care – all this will only worsen the harm being done to trial participants in India.tum since the dis &nbsp

Epithelial junctions and Rho family GTPases: the zonular signalosome

The establishment and maintenance of epithelial cell-cell junctions is crucially important to regulate adhesion, apico-basal polarity and motility of epithelial cells, and ultimately controls the architecture and physiology of epithelial organs. Junctions are supported, shaped and regulated by cytoskeletal filaments, whose dynamic organization and contractility are finely tuned by GTPases of the Rho family, primarily RhoA, Rac1 and Cdc42. Recent research has identified new molecular mechanisms underlying the cross-talk between these GTPases and epithelial junctions. Here we briefly summarize the current knowledge about the organization, molecular evolution and cytoskeletal anchoring of cell-cell junctions, and we comment on the most recent advances in the characterization of the interactions between Rho GTPases and junctional proteins, and their consequences with regards to junction assembly and regulation of cell behavior in vertebrate model systems. The concept of “zonular signalosome” is proposed, which highlights the close functional relationship between proteins of zonular junctions (zonulae occludentes and adhaerentes) and the control of cytoskeletal organization and signaling through Rho GTPases, transcription factors, and their effectors

Adeno-associated vector-delivered CRISPR/SaCas9 system reduces Feline Leukemia Virus production in vitro

Feline leukemia virus (FeLV) is a retrovirus of cats worldwide. High viral loads are associated with progressive infection and the death of the host, due to FeLV-associated disease. In contrast, low viral loads, an effective immune response, and a better clinical outcome can be observed in cats with regressive infection. We hypothesize that by lowering viral loads in progressively infected cats, using CRISPR/SaCas9-assisted gene therapy, the cat’s immune system may be permitted to direct the infection towards a regressive outcome. In a step towards this goal, the present study evaluates different adeno-associated vectors (AAVs) for their competence in delivering a gene editing system into feline cells, followed by investigations of the CRISPR/SaCas9 targeting efficiency for different sites within the FeLV provirus. Nine natural AAV serotypes, two AAV hybrid strains, and Anc80L65, an in silico predicted AAV ancestor, were tested for their potential to infect different feline cell lines and feline primary cells. AAV-DJ revealed superior infection efficiency and was thus employed in subsequent transduction experiments. The introduction of double-strand breaks, using the CRISPR/SaCas9 system targeting 12 selected FeLV provirus sites, was confirmed by T7 endonuclease 1 (T7E1), as well as Tracking of Indels by Decomposition (TIDE) analysis. The highest percentage (up to 80%) of nonhomologous end-joining (NHEJ) was found in the highly conserved gag and pol regions. Subsequent transduction experiments, using AAV-DJ, confirmed indel formation and showed a significant reduction in FeLV p27 antigen for some targets. The targeting of the FeLV provirus was efficient when using the CRISPR/SaCas9 approach in vitro. Whether the observed extent of provirus targeting will be sufficient to provide progressively FeLV-infected cats with the means to overcome the infection needs to be further investigated in vivo

PLEKHA7: Cytoskeletal adaptor protein at center stage in junctional organization and signaling

PLEKHA7 is a recently characterized component of the cytoplasmic region of epithelial adherens junctions (AJ). It comprises two WW domains, a pleckstrin-homology domain, and proline-rich and coiled-coil domains. PLEKHA7 interacts with cytoplasmic components of the AJ (p120-catenin, paracingulin, afadin), stabilizes the E-cadherin complex by linking it to the minus ends of noncentrosomal microtubules, and stabilizes junctional nectins through the newly identified interactor PDZD11. Similarly to afadin, and unlike E-cadherin and p120-catenin, the localization of PLEKHA7 at AJ is strictly zonular (in the zonula adhaerens subdomain of AJ), and does not extend along the basolateral contacts. Genome-wide association studies and experiments on animal and cellular models show that although PLEKHA7 is not required for organism viability, it is implicated in cardiovascular physiology, hypertension, primary angle closure glaucoma, susceptibility to staphylococcal α-toxin, and epithelial morphogenesis and growth. Thus, PLEKHA7 is a cytoskeletal adaptor protein important for AJ organization, and at the center of junction-associated signaling pathways which fine-tune important pathophysiological processes.</p