Tuberculosis chemotherapy: current drug delivery approaches

Tuberculosis is a leading killer of young adults worldwide and the global scourge of multi-drug resistant tuberculosis is reaching epidemic proportions. It is endemic in most developing countries and resurgent in developed and developing countries with high rates of human immunodeficiency virus infection. This article reviews the current situation in terms of drug delivery approaches for tuberculosis chemotherapy. A number of novel implant-, microparticulate-, and various other carrier-based drug delivery systems incorporating the principal anti-tuberculosis agents have been fabricated that either target the site of tuberculosis infection or reduce the dosing frequency with the aim of improving patient outcomes. These developments in drug delivery represent attractive options with significant merit, however, there is a requisite to manufacture an oral system, which directly addresses issues of unacceptable rifampicin bioavailability in fixed-dose combinations. This is fostered by the need to deliver medications to patients more efficiently and with fewer side effects, especially in developing countries. The fabrication of a polymeric once-daily oral multiparticulate fixed-dose combination of the principal anti-tuberculosis drugs, which attains segregated delivery of rifampicin and isoniazid for improved rifampicin bioavailability, could be a step in the right direction in addressing issues of treatment failure due to patient non-compliance

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData availability: All data are available upon request. The sequence variants in WNK3 (NM_004656.3) reported in the paper have been deposited in ClinVar database. Their respective accession numbers (SCV002107163 to SCV002107168) are indicated in Tables 1 and S1.Purpose WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. Method We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). Results We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. Conclusion Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.Estonian Research CouncilNational Natural Science Foundation of ChinaRoyal SocietySouth Carolina Department of Disabilities and Special Needs (SCDDSN)National Institute of Neurological Disorders and Stroke (NINDS

3-Bromotetrazine: labelling of macromolecules via monosubstituted bifunctional s-tetrazines

We report the synthesis and first characterisation of the novel chemical probe 3-bromotetrazine and establish its reactivity towards nucleophiles. This led to the synthesis of several novel classes of 3-monosubstituted s-tetrazines. A remarkable functional group selectivity is observed and is utilised to site-selectively functionalise different complex molecules. The stability of 3-bromotetrazine under the reaction conditions facilitated the development of a protocol for protein functionalisation, which enabled a “minimal”, bifunctional tetrazine unit as a bio-orthogonal handle for inverse electron demand Diels–Alder reactions. Additionally, a novel tetrazine-based chemical probe was developed and its application in the context of thiol-targeted natural product isolation and labelling of mammalian cells is demonstrated

Intermittency route to combustion instability in a laboratory spray combustor

In the present study, we investigate the phenomenon of transition of a thermoacoustic system involving two-phase flow, from aperiodic oscillations to limit cycle oscillations. Experiments were performed in a laboratory scale model of a spray combustor. A needle spray injector is used to generate a droplet spray having one-dimensional velocity field. This simplified design of the injector helps in keeping away the geometric complexities involved in the real spray atomizers. We investigate the stability of the spray combustor in response to the variation of the flame location inside the combustor. Equivalence ratio is maintained constant throughout the experiment. The dynamics of the system is captured by measuring the unsteady pressure fluctuations present in the system. As the flame location is gradually varied, self-excited high-amplitude acoustic oscillations are observed in the combustor. We observe the transition of the system behavior from low-amplitude aperiodic oscillations to large amplitude limit cycle oscillations occurring through intermittency. This intermittent state mainly consists of a sequence of high-amplitude bursts of periodic oscillations separated by low-amplitude aperiodic regions. Moreover, the experimental results highlight that during intermittency, the maximum amplitude of bursts, near to the onset of intermittency, is as much as three times higher than the maximum amplitude of the limit cycle oscillations. These high-amplitude intermittent loads can have stronger adverse effects on the structural properties of the engine than the low-amplitude cyclic loading caused by the sustained limit cycle oscillations. Evolution of the three different dynamical states of the spray combustion system (viz. stable, intermittency and limit cycle) is studied in three-dimensional phase space by using a phase space reconstruction tool from the dynamical system theory. We report the first experimental observation of type-II intermittency in a spray combustion system. The statistical distributions of the length of aperiodic (turbulent) phase with respect to the control parameter, first return map and Recurrence Plot (RP) techniques are employed to confirm the type of intermittency