Demise of Arbitration Agreements in Long-Term Care Contracts, The

This Article argues that pre-dispute compulsory arbitration provisions in nursing home contracts should not be enforced and encourages the elimination of such clauses in long-term care contracts. This Article will lay out the historical background and development of arbitration and then will address the use of arbitration clauses in nursing home admission contracts. Finally, this Article will explore recent developments of arbitration law in long-term care contracts, both federally and in the state of Missouri, with particular attention given to the Supreme Court of Missouri\u27s decision in Lawrence v. Beverly Manor

Emotion regulation mediates the association between HRV reactivity and relationship success

Two hundred single post-secondary students participated in a longitudinal study including online, laboratory, and speed dating components. This methodology was used to examine the link between romantic relationship formation and the heart, specifically heart rate variability. Relationship success was operationally defined as matching during a speed dating session or forming a romantic relationship over a prospective 6-month period. Both HRV reactivity and resting HRV were related to relationship success, each through different mechanisms. In a moderated mediation model, higher HRV reactivity predicted greater use of the emotion regulation strategy of reappraisal which, in turn, interacted with body mass index (BMI) to predict relationship success. Higher use of reappraisal increased relationship success amongst higher-BMI individuals, but hindered relationship success amongst lower-BMI individuals. In a separate moderation model, a pattern of increasing HRV in response to a stressor conferred an advantage in relationship success only to participants with lower resting HRV. Finally, resting HRV was found to predict relationship success through the mediator of mate value. Higher resting HRV was associated with higher mate value, which predicted higher subsequent matching and relationship formation. These results are discussed in the context of the generalized unsafety theory of stress. This investigation of human relationship formation through a biological lens provides insights into how otherwise imperceptible cardiac experiences are contributory to romantic relationship formation

HRV reactivity and new romance: cause or consequence?

This study explored two competing hypotheses explaining the association of heart rate variability (HRV) and romantic relationships. HRV refers to the variation between successive heartbeats and is considered to be a noninvasive index of the social engagement system. Recent cross-sectional research has shown differences in HRV reactivity (the difference between HRV during the presentation of positive and negative stimuli) between single and newly coupled individuals. Two opposing explanations for this association were hypothesized. First, beginning a romantic relationship may decrease HRV reactivity through increased activation of the social engagement system during courting. Alternatively, this association could be explained by individuals with initially lower HRV reactivity being more likely to form romantic relationships. In the present study, single female undergraduate students were presented with film clips of various valences while having their cardiac activity monitored. These participants then returned for follow-up either when they had begun a romantic relationship, or at the end of the 6-month observation period if they remained uncoupled. Moderating influences of body mass index (BMI), self-esteem, attachment, and emotional distress were assessed. Results revealed single and coupled participants were comparable in terms of their HRV reactivity at follow-up; neither group showed a significant decline in HRV during the negative film clip. Further, HRV was not systematically affected by a change in relationship status from single to newly coupled. However, lower HRV reactivity was predictive of coupling for low BMI women while the reverse was true for high BMI women. This interaction may be the result of differing success rates of various mating strategies for low and high BMI women. Results support the hypothesis that HRV reactivity, along with BMI, can predict the formation of romantic relationships

PrimPol is required for replicative tolerance of G quadruplexes in vertebrate cells

G quadruplexes (G4s) can present potent blocks to DNA replication. Accurate and timely replication of G4s in vertebrates requires multiple specialized DNA helicases and polymerases to prevent genetic and epigenetic instability. Here we report that PrimPol, a recently described primase-polymerase (PrimPol), plays a crucial role in the bypass of leading strand G4 structures. While PrimPol is unable to directly replicate G4s, it can bind and reprime downstream of these structures. Disruption of either the catalytic activity or zinc-finger of PrimPol results in extreme G4-dependent epigenetic instability at the BU-1 locus in avian DT40 cells, indicative of extensive uncoupling of the replicative helicase and polymerase. Together, these observations implicate PrimPol in promoting restart of DNA synthesis downstream of, but closely coupled to, G4 replication impediments

Assessing the Awareness of Lead Hazards in the Greater Burlington Area

Introduction. Lead is a heavy metal found in and around homes built before 1978, comprising more than 80% of the housing stock in Chittenden County, Vermont. Lead exposure during infancy and childhood can have deleterious effects on development. Our study assessed baseline community understanding of potential household lead hazards in Chittenden County, Vermont. Methods.. 123 paper, 10-question surveys were randomly administered to Chittenden County, VT residents to assess recognition of lead toxicology symptoms and awareness of lead safety programs. Scores were treated as continuous variables, demographically grouped, and analyzed using non-parametric statistical analysis (Mann-Whitney & Kruskal-Wallis). Individual questions were treated as dichotomous variables, demographically grouped and analyzed using chi-squared testing. Results.. 48% of survey participants understood the interaction between ADHD and lead or knew the importance of window maintenance. 54.5% were aware of the Burlington Lead Program\u27s assistance program. Participants earning less than $60,000 and those with less than a graduate degree scored statistically lower (p Conclusion.. Lesser-known lead poisoning symptoms and home interventions that decrease lead exposure should be emphasized to the community. High-risk groups requiring targeted education include those who rent, have lower income and education levels. Primary care providers could serve a larger role in educating patients. Additional efforts should be made to publicize services offered by the Burlington Lead Program.https://scholarworks.uvm.edu/comphp_gallery/1241/thumbnail.jp

PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication

DNA damage can stall the DNA replication machinery, leading to genomic instability. Thus, numerous mechanisms exist to complete genome duplication in the absence of a pristine DNA template, but identification of the enzymes involved remains incomplete. Here, we establish that Primase-Polymerase (PrimPol; CCDC111), an archaeal-eukaryotic primase (AEP) in eukaryotic cells, is involved in chromosomal DNA replication. PrimPol is required for replication fork progression on ultraviolet (UV) lightdamaged DNA templates, possibly mediated by its ability to catalyze translesion synthesis (TLS) of these lesions. This PrimPol UV lesion bypass pathway is not epistatic with the Pol h-dependent pathway and, as a consequence, protects xeroderma pigmentosum variant (XP-V) patient cells from UV-induced cytotoxicity. In addition, we establish that PrimPol is also required for efficient replication fork progression during an unperturbed S phase. These and other findings indicate that PrimPol is an important player in replication fork progression in eukaryotic cells

PrimPol-deficient cells exhibit a pronounced G2 checkpoint response following UV damage

PrimPol is a recently identified member of the archaeo-eukaryote primase (AEP) family of primase-polymerases. It has been shown that this mitochondrial and nuclear localised enzyme plays roles in the maintenance of both unperturbed replication fork progression and in the bypass of lesions after DNA damage. Here, we utilised an avian (DT40) knockout cell line to further study the consequences of loss of PrimPol (PrimPol-/-) on the downstream maintenance of cells after UV damage. We report that PrimPol-/- cells are more sensitive to UV-C irradiation in colony survival assays than Pol η-deficient cells. Although this increased UV sensitivity is not evident in cell viability assays, we show that this discrepancy is due to an enhanced checkpoint arrest after UV-C damage in the absence of PrimPol. PrimPol-/- arrested cells become stalled in G2, where they are protected from UV-induced cell death. Despite lacking an enzyme required for the bypass and maintenance of replication fork progression in the presence of UV damage, we show that PrimPol-/- cells actually have an advantage in the presence of a Chk1 inhibitor due to their slow progression through S-phase

Human PrimPol mutation associated with high myopia has a DNA replication defect

PrimPol is a primase-polymerase found in humans, and other eukaryotes, involved in bypassing lesions encountered during DNA replication. PrimPol employs both translesion synthesis and repriming mechanisms to facilitate lesion bypass by the replisome. PrimPol has been reported to be a potential susceptibility gene associated with the development of myopia. Mutation of tyrosine 89 to aspartic acid (PrimPolY89D) has been identified in a number of cases of high myopia, implicating it in the aetiology of this disorder. Here, we examined whether this mutation resulted in any changes in the molecular and cellular activities associated with human PrimPol. We show that PrimPolY89D has a striking decrease in primase and polymerase activities. The hydrophobic ring of tyrosine is important for retaining wild-type extension activity. We also demonstrate that the decreased activity of PrimPolY89D is associated with reduced affinities for DNA and nucleotides, resulting in diminished catalytic efficiency. Although the structure and stability of PrimPolY89D is altered, its fidelity remains unchanged. This mutation also reduces cell viability after DNA damage and significantly slows replication fork rates in vivo. Together, these findings establish that the major DNA replication defect associated with this PrimPol mutant is likely to contribute to the onset of high myopia

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers