There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

/pdf/genome-wide-association-study-of-14-000-cases-of-seven-5ay7q0q3vy.pdf

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

/pdf/exploring-the-full-spectrum-of-macrophage-activation-b5rnrcgcen.pdf

Exploring the full spectrum of macrophage activation.

Autophagy in the Pathogenesis of Disease

Biofilms--matrix-enclosed microbial accretions that adhere to biological or non-biological surfaces--represent a significant and incompletely understood mode of growth for bacteria. Biofilm formation appears early in the fossil record (approximately 3.25 billion years ago) and is common throughout a diverse range of organisms in both the Archaea and Bacteria lineages, including the 'living fossils' in the most deeply dividing branches of the phylogenetic tree. It is evident that biofilm formation is an ancient and integral component of the prokaryotic life cycle, and is a key factor for survival in diverse environments. Recent advances show that biofilms are structurally complex, dynamic systems with attributes of both primordial multicellular organisms and multifaceted ecosystems. Biofilm formation represents a protected mode of growth that allows cells to survive in hostile environments and also disperse to colonize new niches. The implications of these survival and propagative mechanisms in the context of both the natural environment and infectious diseases are discussed in this review.

/pdf/bacterial-biofilms-from-the-natural-environment-to-4pdlw3zbzj.pdf

Bacterial biofilms: from the natural environment to infectious diseases.

Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

/pdf/autophagy-fights-disease-through-cellular-self-digestion-5i6zc9bv8a.pdf

Autophagy fights disease through cellular self-digestion

The present invention relates to methods for detecting P aeruginosa infection and bacterial burden in the lungs of patients who are at risk for P. aeruginosa infections, especially including patients with Cystic Fibrosis (CF). The present method provides numerous tests (breath, blood, urine) which are readily administered to a patient that will sensitively and specifically detect the presence and extent of lung infection P. aeruginosa (both mucoid and non-mucoid), and allow monitoring of bacterial load as a parameter in monitoring treatment.

Diagnosis of infection in the lungs of patients

Pseudomonas aeruginosa causes life threatening infections in several classes of patients with compromised natural defense systems. Among notorious examples are the systemic infections in severely burned patients and chronic respiratory infections in individuals with cystic fibrosis. Expression of virulence factors in this organism is controlled by several tiers of regulatory elements. Many of these regulatory factors belong to the superfamily of signal transduction systems originally termed bacterial two-component systems. For example, synthesis of the pill, two phospholipases, and the exopolysaccharide alginate are controlled by bona fide members of this superfamily of regulatory elements. In addition to these communication modules there are other sensory pathways which sometimes cooperate with the classical phosphotransfer response regulator/sensor systems. For instance, production of the alginate capsule-like protective coating and flagellin and pilin synthesis are controlled by alternative sigma factors. RNA polymerase a subunits are frequently subject to control by negative regulators which suppress their activity unless growth conditions demand expression of their subordinate genes. In case of the alternative sigma factor agu (σE), which controls alginate production and certain other aspects of bacterial stress responses, a permanent loss of this negative regulation causes conversion to mucoid, alginate overproducing P. aeruginosa forms, frequently encountered in cystic fibrosis lung.

Signal Transduction and Environmental Stress in Control of Pseudomonas Aeruginosa Virulence

The Atg8 family of ubiquitin-like proteins play pivotal roles in autophagy and other processes involving vesicle fusion and transport where the lysosome/ vacuole is the end station. Nuclear roles of Atg8 proteins are also emerging. Here, we review the structural and functional features of Atg8 family proteins and their protein-protein interaction modes in model organisms such as yeast, Arabidopsis, C. elegans and Drosophila to humans. Although varying in number of homologs, from one in yeast to seven in humans, and more than ten in some plants, there is a strong evolutionary conservation of structural features and

https://doi.org/10.1080/27694127.2023.2188523

Atg8 family proteins, LIR/AIM motifs and other interaction modes

Faculty Opinions recommendation of Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics.

Aggregation and accumulation of microtubule associated protein tau in neurons is major neuropathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Attempts have been made to promote clearance of pathological tau (p-Tau) from neurons via autophagy. Over expression of transcription factor EB (TFEB), has shown to clear pTau from neurons via autophagy. However, sustained TFEB activation and/or autophagy can create burden on cellular bioenergetics and can be deleterious. Thus, we engineered a minimally invasive optical system that could transiently alter autophagic flux. We optimized and tested an optogenetic gene expression system derived from a previously engineered bacterial transcription factor, EL222. For the first time, our group utilized this system not only to spatial-temporally control nuclear TFEB expression, we also show light-induced TFEB has the capacity to reduce p-Tau burden in AD patient-derived human iPSC-neurons. Together, these results suggest that optically-regulatable gene expression of TFEB unlocks opto-therapeutics to treat AD and other dementias.

/pdf/optical-induction-of-autophagy-via-transcription-factor-eb-hlburusyda.pdf

Vojo Deretic

Papers

Diagnosis of infection in the lungs of patients

Signal Transduction and Environmental Stress in Control of Pseudomonas Aeruginosa Virulence

Atg8 family proteins, LIR/AIM motifs and other interaction modes

Faculty Opinions recommendation of Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics.

Optical induction of autophagy via Transcription factor EB (TFEB) reduces pathological tau in neurons