Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes.

Even as genetic studies identify alleles that influence human disease susceptibility, it remains challenging to understand their functional significance and how they contribute to disease phenotypes. Here, we describe an approach to translate discoveries from human genetics into functional and therapeutic hypotheses by relating human genetic variation to small-molecule sensitivities. We use small-molecule probes modulating a breadth of targets and processes to reveal disease allele-dependent sensitivities, using cells from multiple individuals with an extreme form of diabetes (maturity onset diabetes of the young type 1, caused by mutation in the orphan nuclear receptor HNF4α). This approach enabled the discovery of small molecules that show mechanistically revealing and therapeutically relevant interactions with HNF4α in both lymphoblasts and pancreatic ß-cells, including compounds that physically interact with HNF4α. Compounds including US Food and Drug Administration-approved drugs were identified that favorably modulate a critical disease phenotype, insulin secretion from ß-cells. This method may suggest therapeutic hypotheses for other nonblood disorders.

Degree of personalisation in tailored activities and its effect on behavioural and psychological symptoms and quality of life among people with dementia: a systematic review and meta-analysis.

OBJECTIVES: To understand and assess the degree of personalisation of tailored activities for people with dementia (PWD); and to estimate the magnitude of the effects of levels of personalisation on reducing behavioural and psychological symptoms of dementia (BPSD), improving quality of life (QoL) and level of engagement. DESIGN: Systematic review with meta-analysis. DATA SOURCES: ProQuest, PubMed, Ovid, Cochrane Library, Web of Science and CINAHL were searched from the start of indexing to May 2020. ELIGIBILITY CRITERIA: We included randomised controlled trials and quasi-experimental studies assessing the effects of tailored activities for people aged 60 years or older with dementia or cognitive impairment on the outcomes of BPSD, QoL, depression and level of engagement with control groups. DATA EXTRACTION AND SYNTHESIS: Two researchers screened studies, extracted data and assessed risks of bias. A rating scheme to assess the degree of personalisation of tailored activities was developed to classify tailored activities into high/medium/low groups. Effect sizes were expressed using standardised mean differences at 95% Confidence Interval (CI). Subgroup analyses were conducted to assess whether the degree of personalisation of tailored activities affected outcomes of interest. RESULTS: Thirty-five studies covering 2390 participants from 16 countries/regions were identified. Studies with a high-level of personalisation interventions (n=8) had a significant and moderate effect on reducing BPSD (standardised mean differences, SMD=-0.52, p<0.05), followed by medium (n=6; SMD=-0.38, p=0.071) and low-level personalisation interventions (n=6; SMD=-0.15, p=0.076). Tailored activities with a high-level of personalisation had a moderate effect size on improving QoL (n=5; SMD=0.52, p<0.05), followed by a medium level (n=3; SMD=0.41, p<0.05) of personalisation. CONCLUSIONS: To develop high-level tailored activities to reduce BPSD and improve QoL among PWD, we recommend applying comprehensive assessments to identify and address two or more PWD characteristics in designed tailored activities and allow modification of interventions to respond to changing PWD needs/circumstances. PROSPERO REGISTRATION NUMBER: CRD42020168556.

Infection-dependent phenotypes in MHC-congenic mice are not due to MHC: can we trust congenic animals?

BACKGROUND: Congenic strains of mice are assumed to differ only at a single gene or region of the genome. These mice have great importance in evaluating the function of genes. However, their utility depends on the maintenance of this true congenic nature. Although, accumulating evidence suggests that congenic strains suffer genetic divergence that could compromise interpretation of experimental results, this problem is usually ignored. During coinfection studies with Salmonella typhimurium and Theiler's murine encephalomyelitis virus (TMEV) in major histocompatibility complex (MHC)-congenic mice, we conducted the proper F2 controls and discovered significant differences between these F2 animals and MHC-genotype-matched P0 and F1 animals in weight gain and pathogen load. To systematically evaluate the apparent non-MHC differences in these mice, we infected all three generations (P0, F1 and F2) for 5 MHC genotypes (b/b, b/q and q/q as well as d/d, d/q, and q/q) with Salmonella and TMEV. RESULTS: Infected P0 MHC q/q congenic homozygotes lost significantly more weight (p = 0.02) and had significantly higher Salmonella (p < 0.01) and TMEV (p = 0.02) titers than the infected F2 q/q homozygotes. Neither weight nor pathogen load differences were present in sham-infected controls. CONCLUSIONS: These data suggest that these strains differ for genes other than those in the MHC congenic region. The most likely explanation is that deleterious recessive mutations affecting response to infection have accumulated in the more than 40 years that this B10.Q-H-2q MHC-congenic strain has been separated from its B10-H-2b parental strain. During typical experiments with congenic strains, the phenotypes of these accumulated mutations will be falsely ascribed to the congenic gene(s). This problem likely affects any strains separated for appreciable time and while usually ignored, can be avoided with the use of F2 segregants.