Small-molecule antibiotic drug development:need and challenges

The need for new antibiotics is urgent. Antimicrobial resistance is rising, although currently many more people die from drug-sensitive bacterial infections. The continued evolution of drug resistance is inevitable, fuelled by pathogen population size and exposure to antibiotics. Additionally, opportunistic pathogens will always pose a threat to vulnerable patients whose immune systems cannot efficiently fight them, even if they are sensitive to available antibiotics according to clinical microbiology tests. These problems are intertwined and will worsen as human populations age, increase in density, and experience disruptions such as war, extreme weather events, or declines in standard of living. The development of appropriate drugs to treat all the world’s bacterial infections should be a priority and future success will likely require combinations of multiple approaches. However, the highest burden of bacterial infection is in Low- and Middle-Income Countries where limited medical infrastructure is a major challenge. For effectively managing infections in these contexts, small-molecule-based treatments offer significant advantages. Unfortunately, support for ongoing small-molecule antibiotic discovery has recently suffered from significant challenges related to both the scientific difficulties in treating bacterial infections and to market barriers. Nevertheless, small-molecule antibiotics remain essential and irreplaceable tools for fighting infections, and efforts to develop novel and improved versions deserve ongoing investment. Here, we first describe the global historical context of antibiotic treatment, then highlight some of the challenges surrounding small-molecule development and potential solutions. Many of these challenges are likely to be common to all modalities of antibacterial treatment and should be addressed directly

Potential applications of nanocellulose-containing materials in the biomedical field

Because of its high biocompatibility, bio-degradability, low-cost and easy availability, cellulose finds application in disparate areas of research. Here we focus our attention on the most recent and attractive potential applications of cellulose in the biomedical field. We first describe the chemical/structural composition of cellulose fibers, the cellulose sources/features and cellulose chemical modifications employed to improve its properties. We then move to the description of cellulose potential applications in biomedicine. In this field, cellulose is most considered in recent research in the form of nano-sized particle, i.e., nanofiber cellulose (NFC) or cellulose nanocrystal (CNC). NFC is obtained from cellulose via chemical and mechanical methods. CNC can be obtained from macroscopic or microscopic forms of cellulose following strong acid hydrolysis. NFC and CNC are used for several reasons including the mechanical properties, the extended surface area and the low toxicity. Here we present some potential applications of nano-sized cellulose in the fields of wound healing, bone-cartilage regeneration, dental application and different human diseases including cancer. To witness the close proximity of nano-sized cellulose to the practical biomedical use, examples of recent clinical trials are also reported. Altogether, the described examples strongly support the enormous application potential of nano-sized cellulose in the biomedical field

Case studies on Smart Specialisation

This report comprises 10 case study reports at regional and national on the implementation of the Smart Specialisation policy across 4 EU countries. This analytical work seeks to provide a wide assessment of the smart specialisation policy experience along with some reflections for the 2021-2027 EU Cohesion policy. The reports were produced by national experts using a common conceptual framework and set of guidelines for data collection. They were also redacted according to a common structure which facilitates comparative analysis and information search in general. The case studies included in this report consists of three sections on (i) governance, (ii) the entrepreneurial discovery process and, (iii) monitoring and evaluation, plus a succinct account of some relevant implementation measures characterised by being experimental The section on governance provides an overview of the smart specialisation governance and comprises four parts focused on political support and leadership; autonomy and accountability of the smart specialisation management body; horizontal and vertical coordination; and stakeholder engagement. The section on the entrepreneurial discovery process looks at the main dimensions of the process and develops four parts focused on understanding the continuous entrepreneurial discovery process concept; the entrepreneurial discovery process organisation: structure, role, processes, resources, and the mobilisation and engagement of stakeholders; and capacity building. The last section on monitoring and evaluation consists of four parts focused on the general objectives and main results of the smart specialisation strategy; the specificity and usefulness of the smart specialisation monitoring system; the smart specialisation monitoring system usage; and the smart specialisation evaluation.JRC.B.7 - Knowledge for Finance, Innovation and Growt

Phenotypic and genetic characterization of a family carrying two Xq21.1-21.3 interstitial deletions associated with syndromic hearing loss

Sensorineural hearing impairment is a common pathological manifestation in patients affected by X-linked intellectual disability. A few cases of interstitial deletions at Xq21 with several different phenotypic characteristics have been described, but to date, a complete molecular characterization of the deletions harboring disease-causing genes is still missing. Thus, the aim of this study is to realize a detailed clinical and molecular analysis of a family affected by syndromic X-linked hearing loss with intellectual disability

Prioritization of molecular targets for antimalarial drug discovery

There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated i

The Smart Specialisation Policy Experience: Perspective of National and Regional Authorities

This publication presents the results of a survey, launched in 2020 as part of a research project performed by the Smart Specialisation platform to gain new insights on the Smart Specialisation (S3) policy experience across the European Union (EU). The survey aimed at gathering the views and reflections of S3 implementing authorities on their policy experience. The questionnaire addressed the main tenets of the Smart Specialisation policy concept and consisted of four sections: implementation, governance, Entrepreneurial Discovery Process (EDP) and monitoring and evaluation. Survey results provides evidence on the state of implementation, challenges and critical aspects as well as some of the results achieved by this policy experiment in view of the new Cohesion Policy 2021-2027. Overall, we can observe that most strategies are implemented according to the original plans. Nevertheless, the situation varies considerably across categories of territories, with less developed regions exhibiting a poorer implementation performance. Smart Specialisation has supported the adoption and diffusion of more inclusive forms of governance in innovation policy across the EU. Despite the general increase in pressure for coordination and the changes introduced by this policy experiment, the effectiveness of inter-government coordination mechanisms is still considered weak by many national and regional authorities. Clearly, there is room for further improvements in this area. More efforts are also needed in relation to the skills and resources to perform the policy functions of the management body. Overall, the quality of the contribution of different stakeholders to the entrepreneurial discovery process is considered adequate by the public authorities responsible for the management of the strategy. Relevant partners are considered to have high technical/specialist skills, while their capacities to participate in policy decision-making processes are generally lower. In person meetings are the preferred options to engage stakeholders. This is not surprising, given the potential these meetings offer for deeper interaction. Online platforms appear less popular. However, considered the accelerated learning on virtual forms of engagement that is taking place with the COVID-19 pandemic, the perception on the use of online platforms is likely to change. Finally, survey results show that most of the strategies have a system of result indicators in place. However, the capacity of these indicators to monitor strategy progress is often inadequate. Lack of adequate and timely data is another major critical issue of the S3 monitoring systems, while the integration of the findings of the monitoring and evaluation systems into the next programming period is present in just over 40% of the cases.JRC.B.3 - Territorial Developmen

A Submarine Journey: The Pyrrole-Imidazole Alkaloids †

In his most celebrated tale “The Picture of Dorian Gray”, Oscar Wilde stated that “those who go beneath the surface do so at their peril”. This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity – from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters. While the biosynthesis and the role in the sponge economy of most of these alkaloids still lies in the realm of speculations, significant biological activities for some of them have clearly emerged. This review will account for the progress in achieving the total synthesis of the more biologically enticing members of this class of natural products

MIR205HG/LEADR Long Noncoding RNA Binds to Primed Proximal Regulatory Regions in Prostate Basal Cells Through a Triplex- and Alu-Mediated Mechanism

Aside serving as host gene for miR-205, MIR205HG transcribes for a chromatin-associated long noncoding RNA (lncRNA) able to restrain the differentiation of prostate basal cells, thus being reannotated as LEADR (Long Epithelial Alu-interacting Differentiation-related RNA). We previously showed the presence of Alu sequences in the promoters of genes modulated upon MIR205HG/LEADR manipulation. Notably, an Alu element also spans the first and second exons of MIR205HG/LEADR, suggesting its possible involvement in target selection/binding. Here, we performed ChIRP-seq to map MIR205HG/LEADR chromatin occupancy at genome-wide level in prostate basal cells. Our results confirmed preferential binding to regions proximal to gene transcription start site (TSS). Moreover, enrichment of triplex-forming sequences was found upstream of MIR205HG/LEADR-bound genes, peaking at −1,500/−500 bp from TSS. Triplexes formed with one or two putative DNA binding sites within MIR205HG/LEADR sequence, located just upstream of the Alu element. Notably, triplex-forming regions of bound genes were themselves enriched in Alu elements. These data suggest, from one side, that triplex formation may be the prevalent mechanism by which MIR205HG/LEADR selects and physically interacts with target DNA, from the other that direct or protein-mediated Alu (RNA)/Alu (DNA) interaction may represent a further functional requirement. We also found that triplex-forming regions were enriched in specific histone modifications, including H3K4me1 in the absence of H3K27ac, H3K4me3 and H3K27me3, indicating that in prostate basal cells MIR205HG/LEADR may preferentially bind to primed proximal regulatory elements. This may underscore the need for basal cells to keep MIR205HG/LEADR target genes repressed but, at the same time, responsive to differentiation cues

Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase

Plasmodium falciparum (<i>Pf</i>) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit <i>Pf</i>ProRS enzyme activity versus Homo sapiens (<i>Hs</i>) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of <i>Pf</i>ProRS. We identified two new inhibitors of <i>Pf</i>ProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for <i>Pf</i>ProRS compared to <i>Hs</i>ProRS, demonstrating this class of compounds could overcome the toxicity related to <i>Hs</i>ProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with <i>Pf</i>ProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria