This article uses the examples of the 'kinship consequences' of assisted conception, the contemporary enthusiasm for tracing family histories, and a mone general interest in family resemblances to ...argue that there is a contemporary fascination with kinship which existing sociological and anthropological theory do not entirely explain. It proposes a conceptual framework for understanding what is both distinctive and fascinating about kinship, based on four dimensions of affinity: fixed affinities, negotiated and creative affinities, ethereal affinities and sensory affinities. These are dimensions where kinship is engaged with, defined, known and expressed. Collectively, these are referred to as 'tangible' affinities, not because they are all literally tangible but because of their resonance in lived experience and their vivid and palpable (or almost palpable) character.
The central recombination enzyme RAD51 has been implicated in replication fork processing and restart in response to replication stress. Here, we use a separation-of-function allele of RAD51 that ...retains DNA binding, but not D-loop activity, to reveal mechanistic aspects of RAD51's roles in the response to replication stress. Here, we find that cells lacking RAD51's enzymatic activity protect replication forks from MRE11-dependent degradation, as expected from previous studies. Unexpectedly, we find that RAD51's strand exchange activity is not required to convert stalled forks to a form that can be degraded by DNA2. Such conversion was shown previously to require replication fork regression, supporting a model in which fork regression depends on a non-enzymatic function of RAD51. We also show RAD51 promotes replication restart by both strand exchange-dependent and strand exchange-independent mechanisms.
To develop and test a new adverse drug reaction (ADR) causality assessment tool (CAT).
A comparison between seven assessors of a new CAT, formulated by an expert focus group, compared with the ...Naranjo CAT in 80 cases from a prospective observational study and 37 published ADR case reports (819 causality assessments in total).
Utilisation of causality categories, measure of disagreements, inter-rater reliability (IRR).
The Liverpool ADR CAT, using 40 cases from an observational study, showed causality categories of 1 unlikely, 62 possible, 92 probable and 125 definite (1, 62, 92, 125) and 'moderate' IRR (kappa 0.48), compared to Naranjo (0, 100, 172, 8) with 'moderate' IRR (kappa 0.45). In a further 40 cases, the Liverpool tool (0, 66, 81, 133) showed 'good' IRR (kappa 0.6) while Naranjo (1, 90, 185, 4) remained 'moderate'.
The Liverpool tool assigns the full range of causality categories and shows good IRR. Further assessment by different investigators in different settings is needed to fully assess the utility of this tool.
Subtelomeric regions have several unusual characteristics, including complex repetitive structures, increased rates of evolution, and enrichment for genes involved in niche adaptation. The adaptive ...telomere failure hypothesis suggests that certain environmental stresses can induce a low level of telomere failure, potentially leading to elevated subtelomeric recombination that could result in adaptive mutational changes within subtelomeric genes. Here, we tested a key prediction of the adaptive telomere failure hypothesis-that telomere dysfunction mild enough to have little or no overall effect on cell fitness could still lead to substantial increases in the mutation rates of subtelomeric genes. Our results show that a mutant of
with stably short telomeres produced a large increase in the frequency of mutations affecting the native subtelomeric β-galactosidase (
) gene. All
mutants examined from strains with severe telomere dysfunction underwent terminal deletion/duplication events consistent with being due to break-induced replication. In contrast, although cells with mild telomere dysfunction also exhibited similar terminal deletion and duplication events, up to 50% of
mutants from this background unexpectedly contained base changes within the
coding region. This mutational bias for producing base changes demonstrates that mild telomere dysfunction can be well suited as a force for altering the adaptive potential of subtelomeric genes.
Telomeres serve as protective caps that help the cell differentiate between the naturally occurring ends of chromosomes and double-stranded breaks. When telomere capping function becomes compromised, ...chromosome ends are subjected to elevated rates of chromosome alterations. These effects can be particularly dramatic in the telomere-adjacent subtelomeric region. While the catastrophic impact of severe telomere dysfunction on genome stability has been well documented, the adaptive telomere failure hypothesis considers an alternative role telomere dysfunction may play in adaptive evolution. This hypothesis suggests that low levels of telomere failure, induced by certain environmental stresses, can lead to elevated subtelomeric recombination. Mutational loss, duplication, or modification of subtelomeric contingency genes could ultimately facilitate adaptation by generating novel mutants better able to survive environmental stress. In this perspective, we discuss recent work that examined mild telomere dysfunction and its role in altering the adaptive potential of subtelomeric genes.
Specialty care may improve diabetic foot ulcer outcomes. Medically underserved populations receive less specialty care. We aimed to determine the association between specialty care and ulcer ...progression, major amputation, or death. If a beneficial association is found, increasing access to specialty care might help advance health equity.
We retrospectively analyzed a cohort of Wisconsin and Illinois Medicare patients with diabetic foot ulcers (n = 55,409), stratified by ulcer severity (i.e., early stage, osteomyelitis, or gangrene). Within each stratum, we constructed Kaplan-Meier curves for event-free survival, defining events as: ulcer progression, major amputation, or death. Patients were grouped based on whether they received specialty care from at least one of six disciplines: endocrinology, infectious disease, orthopedic surgery, plastic surgery, podiatry, and vascular surgery. Multivariate Cox proportional hazard models estimated the association between specialty care and event-free survival, adjusting for sociodemographic factors and comorbidities, and stratifying on ulcer severity.
Patients who received specialty care had longer event-free survival compared to those who did not (log-rank p<0.001 for all ulcer severity strata). After adjusting, receipt of specialty care, compared to never, remained associated with improved outcomes for all ulcer severities (early stage adjusted hazard ratio 0.34, 95% CI 0.33-0.35, p<0.001; osteomyelitis aHR 0.22, 95% CI 0.20-0.23, p<0.001; gangrene aHR 0.22, 95% CI 0.20-0.24, p<0.001).
Specialty care was associated with longer event-free survivals for patients with diabetic foot ulcers. Increased, equitable access to specialty care might improve diabetic foot ulcer outcomes and disparities.
The RAD54 family DNA translocases have several biochemical activities. One activity, demonstrated previously for the budding yeast translocases, is ATPase-dependent disruption of RAD51-dsDNA binding. ...This activity is thought to promote dissociation of RAD51 from heteroduplex DNA following strand exchange during homologous recombination. In addition, previous experiments in budding yeast have shown that the same activity of Rad54 removes Rad51 from undamaged sites on chromosomes; mutants lacking Rad54 accumulate nonrepair-associated complexes that can block growth and lead to chromosome loss. Here, we show that human RAD54 also promotes the dissociation of RAD51 from dsDNA and not ssDNA. We also show that translocase depletion in tumor cell lines leads to the accumulation of RAD51 on chromosomes, forming complexes that are not associated with markers of DNA damage. We further show that combined depletion of RAD54L and RAD54B and/or artificial induction of RAD51 overexpression blocks replication and promotes chromosome segregation defects. These results support a model in which RAD54L and RAD54B counteract genome-destabilizing effects of direct binding of RAD51 to dsDNA in human tumor cells. Thus, in addition to having genome-stabilizing DNA repair activity, human RAD51 has genome-destabilizing activity when expressed at high levels, as is the case in many human tumors.
WEE1 kinase phosphorylates CDK1 and CDK2 to regulate origin firing and mitotic entry. Inhibition of WEE1 has become an attractive target for cancer therapy due to the simultaneous induction of ...replication stress and inhibition of the G2/M checkpoint. WEE1 inhibition in cancer cells with high levels of replication stress results in induction of replication catastrophe and mitotic catastrophe. To increase potential as a single agent chemotherapeutic, a better understanding of genetic alterations that impact cellular responses to WEE1 inhibition is warranted. Here, we investigate the impact of loss of the helicase, FBH1, on the cellular response to WEE1 inhibition. FBH1-deficient cells have a reduction in ssDNA and double strand break signaling indicating FBH1 is required for induction of replication stress response in cells treated with WEE1 inhibitors. Despite the defect in the replication stress response, FBH1-deficiency sensitizes cells to WEE1 inhibition by increasing mitotic catastrophe. We propose loss of FBH1 is resulting in replication-associated damage that requires the WEE1-dependent G2 checkpoint for repair.
The inherent uncertainty of geospatial data has engendered a critical research agenda addressing all facets of uncertainty visualization due to the communicative efficiency of graphical ...representation. To organize this broad research area, we have reviewed literature on geospatial uncertainty visualization and systematically and iteratively classified research in this field. Upon creating a classification, we developed several visual summaries over time, refining the classification and subsequent graphic as new relevant topics emerged. This visual summary extends current existing approaches to taxonomies by allowing users a quick visual overview of relevant topics in a research area at a glance. For each research paper on uncertainty visualization, this classification can be used to visually represent which domains are covered. In order to ensure that the visual summary approach and the corresponding domains developed in this article can be used reliably, we performed an inter-rater agreement task. The high agreement reveals that the domains in the classification that were identified are intuitive and can lead to objective, reproducible classifications (visual summaries) of research papers. In future research, we plan to refine the visual classification/summary approach by providing guided classification via a web interface to visually classify the entire body of literature on geospatial uncertainty visualization and visually explore any trends in research topics, how they have changed over the years, and identify sparser topics that still need to be addressed.
While metformin is generally accepted as the first-line agent in treatment of type 2 diabetes, there are insufficient evidence and extensive debate about the best second-line agent. We aimed to ...assess the benefits and harms of four commonly used antihyperglycemia treatment regimens considering clinical effectiveness, quality of life, and cost.
We developed and validated a new population-based glycemic control Markov model that simulates natural variation in HbA1c progression. The model was calibrated using a U.S. data set of privately insured individuals diagnosed with type 2 diabetes. We compared treatment intensification of metformin monotherapy with sulfonylurea, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, or insulin. Outcome measures included life-years (LYs), quality-adjusted life-years (QALYs), mean time to insulin dependence, and expected medication cost per QALY from diagnosis to first diabetes complication (ischemic heart disease, myocardial infarction, congestive heart failure, stroke, blindness, renal failure, amputation) or death.
According to our model, all regimens resulted in similar LYs and QALYs regardless of glycemic control goal, but the regimen with sulfonylurea incurred significantly lower cost per QALY and resulted in the longest time to insulin dependence. An HbA1c goal of 7% (53 mmol/mol) produced higher QALYs compared with a goal of 8% (64 mmol/mol) for all regimens.
Use of sulfonylurea as second-line therapy for type 2 diabetes generated glycemic control and QALYs comparable with those associated with other agents but at lower cost. A model that incorporates HbA1c and diabetes complications can serve as a useful clinical decision tool for selection of treatment options.
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