The RAG1 and RAG2 proteins are required to assemble mature Ag receptor genes in developing lymphocytes. Hypomorphic mutations in the gene encoding RAG1 are associated with Omenn syndrome, a primary immunodeficiency. We explored the biochemical defects resulting from a mutation identified in an Omenn syndrome patient which generates an amino acid substitution in the RAG1 RING finger/ubiquitin ligase domain (C325Y in murine RAG1) as well as an adjacent substitution (P326G). RAG1 C325Y demonstrated a 50-fold reduction in recombination activity in cultured pro-B cells despite the fact that its expression and localization to the nucleus were similar to the wild-type protein. The C325Y substitution severely abrogated ubiquitin ligase activity of the purified RAG1 RING finger domain, and the tertiary structure of the domain was altered. The P326G substitution also abrogated ubiquitin ligase activity but had a less severe effect on protein folding. RAG1 P326G also demonstrated a recombination impairment that was most pronounced when RAG1 levels were limiting. Thus, a correctly folded RAG1 RING finger domain is required for normal V(D)J recombination, and RAG1 ubiquitin ligase activity can contribute when the protein is present at relatively low levels.
In the absence of adequate levels of cellular acidic phospholipids, Escherichia coli remain viable but are arrested for growth. Expression of a DnaA protein that contains a single amino acid substitution in the membrane-binding domain, DnaA(L366K), in concert with expression of wild-type DnaA protein, restores growth. DnaA protein has high affinity for ATP and ADP, and in vitro lipid bilayers that are fluid and contain acidic phospholipids reactivate inert ADP-DnaA by promoting an exchange of ATP for ADP. Here, nucleotide and lipid interactions and replication activity of purified DnaA(L366K) were examined to gain insight into the mechanism of how it restores growth to cells lacking acidic phospholipids. DnaA(L366K) behaved like wildtype DnaA with respect to nucleotide binding affinities and hydrolysis properties, specificity of acidic phospholipids for nucleotide release, and origin binding. Yet, DnaA(L366K) was feeble at initiating replication from oriC unless augmented with a limiting quantity of wildtype DnaA, reflecting the in vivo requirement that both wild-type and a mutant form of DnaA must be expressed and act together to restore growth to acidic phospholipid deficient cells.
We explore the role of workplace accommodations in reducing employment barriers and improving the employment of people with disabilities. We do so using data from the 2015 Survey of Disability and Employment on people with disabilities who applied for vocational rehabilitation services in three states. The results show that at least one third of nonworking people with disabilities reported employment barriers that could be addressed by workplace accommodations, such as lack of transportation and an inaccessible workplace. We also find that receiving certain types of workplace accommodations, such as help with transportation, flexible work schedules, or a personal care attendant, is positively correlated with being employed at the time of the survey. Finally, people who are in poor health or have physical disabilities were more likely to perceive workplace inaccessibility as a barrier but less likely to have received accommodations in their current or most recent job. This suggests that people with these characteristics may be good candidates to target for greater access to workplace accommodations.
Objective
To estimate the additional hospital costs associated with inpatient medical harms occurring during an index inpatient admission and costs from subsequent readmissions within 90 days.
Data Source
2009 to 2011 Healthcare Cost and Utilization Project's State Inpatient Databases from 12 states.
Study Design
We compare hospital costs incurred by patients experiencing a specific harm during their hospital stay to the costs incurred by similar patients who did not experience that harm.
Data Extraction
We extracted records for adult patients admitted for a reason other than rehabilitation or mental health, were at risk of a harm, and were admitted for less than a year.
Principal Findings
The costliest inpatient harms, such as surgical site infections and severe pressure ulcers, are associated with approximately $30 000 in additional index stay costs per harm. Less costly harms, such as catheter‐ or hospital‐associated urinary tract infections and venous thromboembolism, can add $6000 to $13 000. Birth and obstetric traumas add as little as $100.
Conclusions
Our analysis represents rigorous estimates of the hospital costs of a variety of inpatient harms; these should be of interest to health care administrators and policy makers to identify areas for cost savings to the health care system.
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