ESTABLISHING A PLATFORM FOR SPRAY DRYING INHALABLE VACCINES IN SOUTH AFRICA

Mycobacterium bovis BCG is the current vaccine for tuberculosis (TB). However, BCG as it is currently administered shows highly variable efficacy in protecting adults against TB. The natural route of infection of TB is via inhalation of bacilli-containing aerosols and it is postulated that immunization by the natural route of infection may lead to a greater immunity given the fact that the lungs are the primary target of infection. By eliciting both local and systemic immune responses, it is anticipated that an inhaled form of BCG will offer greater protection against pulmonary TB. Current commercial BCG vaccine preparations are filled as bacterial suspensions in vials, dried through lyophilization and stabilized through refrigeration with a one year shelf life. However, freeze-dried BCG does not exhibit a particle form conducive for delivery via the aerosol route and must be injected. Spray drying studies by Harvard University and Medicine in Need (MEND) scientists have demonstrated that BCG could be spray dried into a viable aerosol with up to 1 year of stability under refrigerated conditions, with the potential for room temperature stability. To support the further preclinical development of the BCG aerosol for application in the developing world, MEND established a state-of-the-art Biosafety level 3 spray drying facility with local expertise in South Africa, where the vaccine will be produced for an IND-enabling toxicology study meeting OECD Good Laboratory Practice (GLP) requirements. Frozen BCG bulk is spray dried and the resulting dry powder is characterized in terms of viability and aerosol properties. The dried BCG aerosol is then aseptically filled into capsules using a semi-automatic filling device for delivery using a low-cost hand-held inhaler. In conclusion, the spray drying technology was successfully transferred from Harvard University to the MEND facility in Pretoria. MEND is developing local expertise and infrastructure to support further preclinical and clinical development of BCG for inhalation

Proteomics: in pursuit of effective traumatic brain injury therapeutics

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

Clustering problems in optimization models

We discuss a variety of clustering problems arising in combinatorial applications and in classifying objects into homogenous groups. For each problem we discuss solution strategies that work well in practice. We also discuss the importance of careful modelling in clustering problems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44350/1/10614_2004_Article_BF00121636.pd

Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury

<p>Abstract</p> <p>Background</p> <p>Traumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5) activation by (<it>RS</it>)-2-chloro-5-hydroxyphenylglycine (CHPG) decreases microglial activation and release of associated pro-inflammatory factors <it>in vitro</it>, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice.</p> <p>Methods</p> <p>One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.</p> <p>Results</p> <p>Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field <it>ex vivo </it>diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.</p> <p>Conclusion</p> <p>Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.</p

The combined effects of obesity, abdominal obesity and major depression/anxiety on health-related quality of life: The lifelines cohort study

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Ketidakoptimalan Penanganan Perkara Pidana Rehabilitasi Penyalahguna Narkotika di Wilayah Hukum Kejaksaan Negeri Mejayan Kabupaten Madiun

ABSTRAK Rahmat Hidayat S331302008, 2015, Ketidakoptimalan Penanganan Perkara Pidana Rehabilitasi Penyalahguna Narkotika di Wilayah Hukum Kejaksaan Negeri Mejayan Kabupaten Madiun. Tujuan dari penulisan tesis ini yaitu pelaksanaan rehabilitasi bagi penyalahguna narkotika yang belum dilaksanakan dan upaya yang dilakukan agar rehabilitasi secara optimal dilaksanakan di wilayah hukum Kejaksaan Negeri Mejayan Kabupaten Madiun. Adapun rumusan masalah yang diangkat dalam penulisan tesis ini adalah Mengapa rehabilitasi bagi penyalahguna narkotika di wilayah Hukum Kejaksaan Negeri Mejayan Kabupaten Madiun belum dilaksanakan secara optimal dan Upaya apa yang suharusnya dilakukan agar rehabilitasi penyalahguna narkotika di wilayah Hukum Kejaksaan Negeri Mejayan Kabupaten Madiun dilaksanakan secara optimal. Penelitian dalam tesis ini adalah penelitian hukum yuridis normatif dan yuridis empiris, jenis pendekatan yang dipergunakan dalam penulisan tesis ini adalah kualitatif adalah suatu cara analisis hasil penelitian yang menghasilkan data deskriptif analitis, yaitu data yang dinyatakan oleh responden sacara tertulis atau lisan serta juga tingkah laku yang nyata, yang diteliti dan dipelajari sebagai sesuatu yang utuh. Pelaksanaan rehabilitasi belum dilaksanakan secara optimal oleh penegak hukum di wilayah hukum Kejaksaan Negeri Mejayan Kabupaten Madiun terhadap pelaku penyalahguna narkotika. Upaya-upaya terhadap pelaksanaan rehabilitasi penyalahguna narkotika, aparat penegak hukum di wilayah hukum Kejaksaan Negeri Mejayan Kabupaten Madiun dibantu oleh Pemerintah Kabupaten Madiun dalam proses awal penegakan hukum terhadap penyalahguna narkotika sedini mungkin dilakukannya Assesmen Terpadu. Kata kunci : Rehabilitasi Narkotika, Penanganan Perkara Pidana

Effect of strongly magnetized electrons and Ions on heat flow and symmetry of inertial fusion implosions

This Letter presents the first observation on how a strong, 500 kG, externally applied B field increases the mode-two asymmetry in shock-heated inertial fusion implosions. Using a direct-drive implosion with polar illumination and imposed field, we observed that magnetization produces a significant increase in the implosion oblateness (a 2.5 × larger P 2 amplitude in x-ray self-emission images) compared with reference experiments with identical drive but with no field applied. The implosions produce strongly magnetized electrons ( ω e τ e ≫ 1 ) and ions ( ω i τ i > 1 ) that, as shown using simulations, restrict the cross field heat flow necessary for lateral distribution of the laser and shock heating from the implosion pole to the waist, causing the enhanced mode-two shape