Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements.

TatA and TatB generate a hydrophobic mismatch important for the function and assembly of the Tat translocon in Escherichia coli.

The twin-arginine translocation (Tat) system serves to translocate folded proteins across energy-transducing membranes in bacteria, archaea, plastids, and some mitochondria. In Escherichia coli, TatA, TatB, and TatC constitute functional translocons. TatA and TatB both possess an N-terminal transmembrane helix (TMH) followed by an amphipathic helix.

PvdM of fluorescent pseudomonads is required for the oxidation of ferribactin by PvdP in periplasmic pyoverdine maturation.

Fluorescent pseudomonads such as Pseudomonas aeruginosa or Pseudomonas fluorescens produce pyoverdine siderophores that ensure iron-supply in iron-limited environments. After its synthesis in the cytoplasm, the nonfluorescent pyoverdine precursor ferribactin is exported into the periplasm, where the enzymes PvdQ, PvdP, PvdO, PvdN, and PtaA are responsible for fluorophore maturation and tailoring steps. While the roles of all these enzymes are clear, little is known about the role of PvdM, a human renal dipeptidase-related protein that is predicted to be periplasmic and that is essential for pyoverdine biogenesis.

An unusual overrepresentation of genetic factors related to iron homeostasis in the genome of the fluorescent Pseudomonas sp. ABC1.

Members of the genus Pseudomonas inhabit diverse environments, such as soil, water, plants and humans. The variability of habitats is reflected in the diversity of the structure and composition of their genomes. This cosmopolitan bacterial genus includes species of biotechnological, medical and environmental importance.

Artificial intelligence and machine learning in clinical development: a translational perspective.

Future of clinical development is on the verge of a major transformation due to convergence of large new digital data sources, computing power to identify clinically meaningful patterns in the data using efficient artificial intelligence and machine-learning algorithms, and regulators embracing this change through new collaborations. This perspective summarizes insights, recent developments, and recommendations for infusing actionable computational evidence into clinical development and health care from academy, biotechnology industry, nonprofit foundations, regulators, and technology corporations. Analysis and learning from publically available biomedical and clinical trial data sets, real-world evidence from sensors, and health records by machine-learning architectures are discussed.

Innovation in Regulatory Science Is Meeting Evolution of Clinical Evidence Generation.

At the turn of the century, the pharmaceutical industry began a transition toward a focus on oncology, rare diseases, and other areas of high unmet need that required a new, more complex approach to drug development. For many of these disease states and novel approaches to therapy, traditional approaches to clinical trial design fall short, and a number of innovative trial designs have emerged. In light of these changes, regulators across the globe are implementing new programs to provide regular development program support, facilitate accelerated access, use real-world data, and use digital tools to improve patients' lives.

The biosynthesis of pyoverdines.

Pyoverdines are fluorescent siderophores of pseudomonads that play important roles for growth under iron-limiting conditions. The production of pyoverdines by fluorescent pseudomonads permits their colonization of hosts ranging from humans to plants. Prominent examples include pathogenic or non-pathogenic species such as , , , or .

PvdO is required for the oxidation of dihydropyoverdine as the last step of fluorophore formation in .

Pyoverdines are important siderophores that guarantee iron supply to important pathogenic and non-pathogenic pseudomonads in host habitats. A key characteristic of all pyoverdines is the fluorescent dihydroxyquinoline group that contributes two ligands to the iron complexes. Pyoverdines are derived from the non-ribosomally synthesized peptide ferribactin, and their fluorophore is generated by periplasmic oxidation and cyclization reactions of d-tyrosine and l-diaminobutyric acid.

The periplasmic transaminase PtaA of converts the glutamic acid residue at the pyoverdine fluorophore to α-ketoglutaric acid.

The periplasmic conversion of ferribactin to pyoverdine is essential for siderophore biogenesis in fluorescent pseudomonads, such as pathogenic or plant growth-promoting The non-ribosomal peptide ferribactin undergoes cyclizations and oxidations that result in the fluorophore, and a strictly conserved fluorophore-bound glutamic acid residue is converted to a range of variants, including succinamide, succinic acid, and α-ketoglutaric acid residues. We recently discovered that the pyridoxal phosphate-containing enzyme PvdN is responsible for the generation of the succinamide, which can be hydrolyzed to succinic acid. Based on this, a distinct unknown enzyme was postulated to be responsible for the conversion of the glutamic acid to α-ketoglutaric acid.

Do large mergers increase or decrease the productivity of pharmaceutical R&D?

There is current uncertainty regarding the effects of mergers on pharmaceutical R&D productivity, with various mechanisms reported by which mergers could either help or harm R&D, and mixed empirical findings in prior analyses. Here, we present an analysis that is novel in several ways: we use downstream measures of R&D productivity, account for both inputs and outputs in our calculations, and use a self-controlled design. We find that recent large pharmaceutical mergers are associated with statistically significant increases in R&D productivity.

Quantifying Geographic Variation in Health Care Outcomes in the United States before and after Risk-Adjustment.

Background: Despite numerous studies of geographic variation in healthcare cost and utilization at the local, regional, and state levels across the U.S., a comprehensive characterization of geographic variation in outcomes has not been published.