Shadow enhancers flanking the HoxB cluster direct dynamic Hox expression in early heart and endoderm development.

The products of Hox genes function in assigning positional identity along the anterior-posterior body axis during animal development. In mouse embryos, Hox genes located at the 3' end of HoxA and HoxB complexes are expressed in nested patterns in the progenitors of the secondary heart field during early cardiogenesis and the combined activities of both of these clusters are required for proper looping of the heart. Using Hox bacterial artificial chromosomes (BACs), transposon reporters, and transgenic analyses in mice, we present the identification of several novel enhancers flanking the HoxB complex which can work over a long range to mediate dynamic reporter expression in the endoderm and embryonic heart during development. These enhancers respond to exogenously added retinoic acid and we have identified two retinoic acid response elements (RAREs) within these control modules that play a role in potentiating their regulatory activity. Deletion analysis in HoxB BAC reporters reveals that these control modules, spread throughout the flanking intergenic region, have regulatory activities that overlap with other local enhancers. This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development. Regulatory analysis of the HoxA complex reveals that it also has enhancers in the 3' flanking region which contain RAREs and have the potential to modulate expression in endoderm and heart tissues. Together, the similarities in their location, enhancer output, and dependence on retinoid signaling suggest that a conserved cis-regulatory cassette located in the 3' proximal regions adjacent to the HoxA and HoxB complexes evolved to modulate Hox gene expression during mammalian cardiac and endoderm development. This suggests a common regulatory mechanism, whereby the conserved control modules act over a long range on multiple Hox genes to generate nested patterns of HoxA and HoxB expression during cardiogenesis.

A pan-serotype antiviral to prevent and treat dengue: A journey from discovery to clinical development driven by public-private partnerships.

While progress has been made in fighting diseases disproportionally affecting underserved populations, unmet medical needs persist for many neglected tropical diseases. The World Health Organization has encouraged strong public-private partnerships to address this issue and several public and private organizations have set an example in the past showing a strong commitment to combat these diseases. Pharmaceutical companies are contributing in different ways to address the imbalance in research efforts. With this review, we exemplify the role of a public-private partnership in research and development by the journey of our dengue antiviral molecule that is now in early clinical development. We detail the different steps of drug development and outline the contribution of each partner to this process. Years of intensive collaboration resulted in the identification of two antiviral compounds, JNJ-A07 and JNJ-1802, the latter of which has advanced to clinical development.

Surveillance and Epidemiology of Drug Resistant Infections Consortium (SEDRIC): Supporting the transition from strategy to action.

In recognition of the central importance of surveillance and epidemiology in the control of antimicrobial resistance and the need to strengthen surveillance at all levels, Wellcome has brought together a new international expert group SEDRIC (Surveillance and Epidemiology of Drug Resistant Infections Consortium). SEDRIC aims to advance and transform the ways of tracking, sharing and analysing rates of infection and drug resistance, burden of disease, information on antibiotic use, opportunities for preventative measures such as vaccines, and contamination of the environment. SEDRIC will strengthen the availability of information needed to monitor and track risks, including an evaluation of access to, and utility of data generated by pharma and research activities, and will support the translation of surveillance data into interventions, changes in policy and more effective practices. Ways of working will include the provision of independent scientific analysis, advocacy and expert advice to groups, such as the Wellcome Drug Resistant Infection Priority Programme. A priority for SEDRIC's first Working Group is to review mechanisms to strengthen the generation, collection, collation and dissemination of high quality data, together with the need for creativity in the use of existing data and proxy measures, and linking to existing in-country networking infrastructure. SEDRIC will also promote the translation of technological innovations into public health solutions.

Accelerating global innovation to address antibacterial resistance: introducing CARB-X.

A global response to the chronic shortfall in antibiotic innovation is urgently needed to combat antimicrobial resistance. Here, we introduce CARB-X, a new global public-private partnership that will invest more than US$350 million in the next 5 years to accelerate the progression of a diverse portfolio of innovative antibacterial products into clinical trials.