The HY5-PIF regulatory module coordinates light and temperature control of photosynthetic gene transcription.

The ability to interpret daily and seasonal alterations in light and temperature signals is essential for plant survival. This is particularly important during seedling establishment when the phytochrome photoreceptors activate photosynthetic pigment production for photoautotrophic growth. Phytochromes accomplish this partly through the suppression of phytochrome interacting factors (PIFs), negative regulators of chlorophyll and carotenoid biosynthesis. While the bZIP transcription factor long hypocotyl 5 (HY5), a potent PIF antagonist, promotes photosynthetic pigment accumulation in response to light. Here we demonstrate that by directly targeting a common promoter cis-element (G-box), HY5 and PIFs form a dynamic activation-suppression transcriptional module responsive to light and temperature cues. This antagonistic regulatory module provides a simple, direct mechanism through which environmental change can redirect transcriptional control of genes required for photosynthesis and photoprotection. In the regulation of photopigment biosynthesis genes, HY5 and PIFs do not operate alone, but with the circadian clock. However, sudden changes in light or temperature conditions can trigger changes in HY5 and PIFs abundance that adjust the expression of common target genes to optimise photosynthetic performance and growth.

Linked circadian outputs control elongation growth and flowering in response to photoperiod and temperature.

Clock-regulated pathways coordinate the response of many developmental processes to changes in photoperiod and temperature. We model two of the best-understood clock output pathways in Arabidopsis, which control key regulators of flowering and elongation growth. In flowering, the model predicted regulatory links from the clock to cycling DOF factor 1 (CDF1) and flavin-binding, KELCH repeat, F-box 1 (FKF1) transcription. Physical interaction data support these links, which create threefold feed-forward motifs from two clock components to the floral regulator FT. In hypocotyl growth, the model described clock-regulated transcription of phytochrome-interacting factor 4 and 5 (PIF4, PIF5), interacting with post-translational regulation of PIF proteins by phytochrome B (phyB) and other light-activated pathways. The model predicted bimodal and end-of-day PIF activity profiles that are observed across hundreds of PIF-regulated target genes. In the response to temperature, warmth-enhanced PIF4 activity explained the observed hypocotyl growth dynamics but additional, temperature-dependent regulators were implicated in the flowering response. Integrating these two pathways with the clock model highlights the molecular mechanisms that coordinate plant development across changing conditions.

HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 is required for circadian periodicity through the promotion of nucleo-cytoplasmic mRNA export in Arabidopsis.

Cold acclimation has been shown to be attenuated by the degradation of the INDUCER OF CBF EXPRESSION1 protein by the E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 (HOS1). However, recent work has suggested that HOS1 may have a wider range of roles in plants than previously appreciated. Here, we show that hos1 mutants are affected in circadian clock function, exhibiting a long-period phenotype in a wide range of temperature and light environments. We demonstrate that hos1 mutants accumulate polyadenylated mRNA in the nucleus and that the circadian defect in hos1 is shared by multiple mutants with aberrant mRNA export, but not in a mutant attenuated in nucleo-cytoplasmic transport of microRNAs. As revealed by RNA sequencing, hos1 exhibits gross changes to the transcriptome with genes in multiple functional categories being affected. In addition, we show that hos1 and other previously described mutants with altered mRNA export affect cold signaling in a similar manner. Our data support a model in which altered mRNA export is important for the manifestation of hos1 circadian clock defects and suggest that HOS1 may indirectly affect cold signaling through disruption of the circadian clock.

LGI3/2-ADAM23 interactions cluster Kv1 channels in myelinated axons to regulate refractory period.

Along myelinated axons, Shaker-type potassium channels (Kv1) accumulate at high density in the juxtaparanodal region, directly adjacent to the paranodal axon-glia junctions that flank the nodes of Ranvier. However, the mechanisms that control the clustering of Kv1 channels, as well as their function at this site, are still poorly understood. Here we demonstrate that axonal ADAM23 is essential for both the accumulation and stability of juxtaparanodal Kv1 complexes. The function of ADAM23 is critically dependent on its interaction with its extracellular ligands LGI2 and LGI3. Furthermore, we demonstrate that juxtaparanodal Kv1 complexes affect the refractory period, thus enabling high-frequency burst firing of action potentials. Our findings not only reveal a previously unknown molecular pathway that regulates Kv1 channel clustering, but they also demonstrate that the juxtaparanodal Kv1 channels that are concealed below the myelin sheath, play a significant role in modifying axonal physiology.

Ongoing Initiatives to Improve the Quality and Efficiency of Medicine Use within the Public Healthcare System in South Africa; A Preliminary Study.

Introduction: South Africa has an appreciable burden of both communicable and non-communicable diseases as well as high maternal, neonatal, and child morbidity. In recent years there have been significant strides with improving the public health system, and addressing current inequalities, with the right to health a constitutional provision in South Africa. Initiatives include the introduction of National Health Insurance, programmes to enhance access to medicines for patients with chronic diseases, as well as activities to improve care in hospitals, including improving pharmacovigilance. Consequently, the objective of this paper is to review ongoing initiatives within the public healthcare sector in South Africa and their influence to provide future direction. Method: Principally a structured review of current and planned activities. Results: There have been a number of major activities and initiatives surrounding the availability and access to medicines in the public system in recent years in South Africa. This includes a National Surveillance Centre and an innovative early warning system for the supply of medicines as well as the development of a National Health Care Pricing Authority and initiatives to improve contracting. There have also been developments to improve the supply chain including instigating Medicine Procurement Units in the provinces and enhancing forecasting capabilities. Access to medicines is improving though the instigation of stable chronic disease management initiatives to increase the number of external pick-up points for medicines. There are also ongoing programmes to enhance adherence to medicines as well as enhance adherence to the Standard Treatment Guidelines and the Essential Medicines List with their increasing availability. In addition, there is a movement to enhance the role of health technology assessment in future decision making. Hospital initiatives include increased focus on reducing antimicrobial resistance through instigating stewardship programmes as well as improving adverse drug reaction reporting and associated activities. Conclusion: Overall, there are an appreciable number of ongoing activities within the public healthcare system in South Africa attempting to ensure and sustain universal healthcare. It is too early to assess their impact, which will be the subject of future research.

A novel aldo-keto reductase from Escherichia coli can increase resistance to methylglyoxal toxicity.

A novel aldo-keto reductase (AKR) from Escherichia coli has been cloned, expressed and purified. This protein, YghZ, is distantly related (<40%) to mammalian aflatoxin dialdehyde reductases of the aldo-keto reductase AKR7 family and to potassium channel beta-subunits in the AKR6 family. The enzyme has been placed in a new AKR family (AKR14), with the designation AKR14A1. Sequences encoding putative homologues of this enzyme exist in many other bacteria. The enzyme can reduce several aldehyde and diketone substrates, including the toxic metabolite methylglyoxal. The K(m) for the model substrate 4-nitrobenzaldehyde is 1.06 mM and for the endogenous dicarbonyl methylglyoxal it is 3.4 mM. Overexpression of the recombinant enzyme in E. coli leads to increased resistance to methylglyoxal. It is possible that this enzyme plays a role in the metabolism of methylglyoxal, and can influence its levels in vivo.

Novel licensure pathways for expeditious introduction of new tuberculosis vaccines: a discussion of the adaptive licensure concept.

The ultimate goal of vaccine development is licensure of a safe and efficacious product that has a well-defined manufacturing process resulting in a high quality product. In general, clinical development and regulatory approval occurs in a linear, sequential manner: Phase 1 - safety, immunogenicity; Phase 2 - immunogenicity, safety, dose ranging and preliminary efficacy; Phase 3 - definitive efficacy, safety, lot consistency; and, following regulatory approval, Phase 4 - post-marketing safety and effectiveness. For candidate TB vaccines, where correlates of protection are not yet identified, phase 2 and 3 efficacy of disease prevention trials are, by necessity, very large. Each trial would span 2-5 years, with full licensure expected only after 1 or even 2 decades of development. Given the urgent unmet need for a new TB vaccine, a satellite discussion was held at the International African Vaccinology Conference in Cape Town, South Africa in November 2012, to explore the possibility of expediting licensure by use of an "adaptive licensure" process, based on a risk/benefit assessment that is specific to regional needs informed by epidemiology. This may be appropriate for diseases such as TB, where high rates of morbidity, mortality, particularly in high disease burden countries, impose an urgent need for disease prevention. The discussion focused on two contexts: licensure within the South African regulatory environment - a high burden country where TB vaccine efficacy trials are on-going, and licensure by the United States FDA --a well-resourced regulatory agency where approval could facilitate global licensure of a novel TB vaccine.

Preparing developing countries for efficacy trials.

PURPOSE OF REVIEW: For the first time, Africa is poised to test the efficacy of two candidate vaccines. This raises many scientific, logistic, regulatory and ethical challenges for the continent. This review outlines recent developments relating to the epidemiologic, scientific, site development, and standard of care issues relevant to the conduct of these trials in developing countries. RECENT FINDINGS: The AIDS epidemic in Africa has reached crisis proportions. Despite more than 20 years having passed since the discovery of HIV, there are no effective biomedical interventions. The testing of two adenovirus type 5-vectored HIV vaccine candidates for efficacy is crucial. These vaccines, which seek to elicit cytotoxic T lymphocyte responses, may not prevent infection, but may ameliorate infection and potentially prevent secondary HIV transmission. Efficacy of these vaccines may be impacted by the presence of pre-existing immunity to the vectors and the genetic diversity of HIV. Trials will be conducted in areas of the world with high HIV incidence, and special efforts should be made to enroll young women and adolescents. The development of clinical trial site capacity, technology transfer of immunogenicity assays to in-country laboratories, and expediting high-quality regulatory and ethical review and executing efficacy trials of the highest standard should be seen as paramount by donors, vaccine developers, clinical trial networks and developing world governments. SUMMARY: HIV vaccine efficacy trials will soon be conducted in Africa.