New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Protein Stabilization by Engineered Metal Chelation

A ligand can shift a protein's folding/unfolding equilibrium by binding with higher affinity to the native state. A metal–chelating site consisting of two histidines separated by three residues (His–X_3–His) engineered into an α–helix provides a general and easily–implemented means for protein stabilization by this mechanism. We have tested this approach with the iso–1–cytochrome c of Saccharomyces cerevisiae substituted with histidine at positions 4 and 8 in its N–terminal α–helix. One mM Cu(II) complexed to iminodiacetate stabilizes the cytochrome c variant by ca. 1 kcal/mol, as determined by guanidinium chloride–induced unfolding. The protein's folding/unfolding equilibrium is shifted by a free energy equal to that calculated from the metal ion's preferential binding to the native protein. Given the ubiquity of surface α–helices and the additional possibility of inserting di–histidine chelating sites into turns and β–structures, we conclude that this is a useful method for protein stabilization

A Narrative Overview of Active Surveillance for Clinically Localised Prostate Cancer

Background-Active surveillance (AS) is a strategy employed as an alternative to immediate standard active treatments for patients with low-risk localised prostate cancer (PCa). Active treatments such as radical prostatectomy and radiotherapy are associated with significant adverse effects which impair quality of life. The majority of patients with low-risk PCa undergo a slow and predictable course of cancer growth and do not require immediate curative treatment. AS provides a means to identify and monitor patients with low-risk PCa through regular PSA testing, imaging using MRI scans and regular repeat prostate biopsies. These measures enable the identification of progression, or increase in cancer extent or aggressiveness, which necessitates curative treatment. Alternatively, some patients may choose to leave AS to pursue curative interventions due to anxiety. The main benefit of AS is the avoidance of unnecessary radical treatments for patients at the early stages of the disease, hence avoiding over-treatment, whilst identifying those at risk of progression to be treated actively. The objective of this article is to provide a narrative summary of contemporary practice regarding AS based on a review of the available evidence base and clinical practice guidelines. Elements of discussion include the clinical effectiveness and harms of AS, what AS involves for healthcare professionals, and patient perspectives. The pitfalls and challenges for healthcare professionals are also discussed. Data sources: We consulted international guidelines, collaborative studies and seminal prospective studies on AS in the management of clinically localised PCa. Conclusion: AS is a feasible alternative to radical treatment options for low-risk PCa, primarily as a means of avoiding over-treatment, whilst identifying those who are at risk of disease progression for active treatment. There is emerging data demonstrating the long-term safety of AS as an oncological management strategy. Uncertainties remain regarding variation in definitions, criteria, thresholds and the most effective types of diagnostic interventions pertaining to patient selection, monitoring and reclassification. Efforts have been made to standardise the practice and conduct of AS. As data from high-quality prospective comparative studies mature, the practice of AS will continue to evolve. Implications for Nursing Practice: The practice of AS involves a multi-disciplinary team of healthcare professionals consisting of nurses, urologists, oncologists, pathologists and radiologists. Nurses play a prominent role in managing AS programmes, and are closely involved in patient selection and recruitment, counselling, organising and administering diagnostic interventions including prostate biopsies, and ensuring patients' needs are being met throughout the duration of AS