Restructure and Reform: Products-Liability Law in North Carolina

This Article suggests that, although previous revisions to the North Carolina Products Liability Act brought progress, more revisions are needed, and these revisions will be best accomplished by incorporating additional measures into the act, especially those that have gained wide acceptance elsewhere. Part I of this Article provides a brief introduction to the early development of products liability law. Part I.A discusses tort-law influences in products liability, and Part I.B focuses on contributions from contract law. Parts II.A and II.B briefly describe MUPLA and the Restatement (Third) of Torts: Products Liability, respectively. Part III discusses the current state of products-liability law in North Carolina and suggests a number of proposed improvements to North Carolina’s products-liability act

Seminaphthofluorescein-Based Fluorescent Probes for Imaging Nitric Oxide in Live Cells

Fluorescent turn-on probes for nitric oxide based on seminaphthofluorescein scaffolds were prepared and spectroscopically characterized. The Cu(II) complexes of these fluorescent probes react with NO under anaerobic conditions to yield a 20–45-fold increase in integrated emission. The seminaphthofluorescein-based probes emit at longer wavelengths than the parent FL1 and FL2 fluorescein-based generations of NO probes, maintaining emission maxima between 550 and 625 nm. The emission profiles depend on the excitation wavelength; maximum fluorescence turn-on is achieved at excitations between 535 and 575 nm. The probes are highly selective for NO over other biologically relevant reactive nitrogen and oxygen species including NO3–, NO2–, HNO, ONOO–, NO2, OCl–, and H2O2. The seminaphthofluorescein-based probes can be used to visualize endogenously produced NO in live cells, as demonstrated using Raw 264.7 macrophages.National Science Foundation (U.S.) (CHE-0611944)National Institutes of Health (U.S.) (K99GM092970

A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC

Enemies Within: Redefining the insider threat in organizational security policy

The critical importance of electronic information exchanges in the daily operation of most large modern organizations is causing them to broaden their security provision to include the custodians of exchanged data – the insiders. The prevailing data loss threat model mainly focuses upon the criminal outsider and mainly regards the insider threat as ‘outsiders by proxy’, thus shaping the relationship between the worker and workplace in information security policy. A policy that increasingly takes the form of social policy for the information age as it acquires the power to include and exclude sections of society and potentially to re-stratify it? This article draws upon empirical sources to critically explore the insider threat in organizations. It looks at the prevailing threat model before deconstructing ‘the insider’ into various risk profiles, including the well-meaning insider, before drawing conclusions about what the building blocks of information security policy around the insider might be

Network Analysis of Gut Microbiome Throughout a Whole Foods Based High Fiber Dietary Intervention Reveals Complex Community Dynamics in Melanoma Survivors

https://openworks.mdanderson.org/sumexp22/1139/thumbnail.jp

Mortgage design in an equilibrium model of the housing market

How can mortgages be redesigned to reduce macrovolatility and default? We address this question using a quantitative equilibrium life‐cycle model. Designs with countercyclical payments outperform fixed payments. Among those, designs that front‐load payment reductions in recessions outperform those that spread relief over the full term. Front‐loading alleviates liquidity constraints when they bind most, reducing default and stimulating housing demand. To illustrate, a fixed‐rate mortgage (FRM) with an option to convert to adjustable‐rate mortgage, which front‐loads payment reductions relative to an FRM with an option to refinance underwater, reduces price and consumption declines six times as much and default three times as much.Funding Provided by NSF under grant "Mortgage Design in an Equilibrium Model of the Housing Market" (1623801 - National Science Foundation)Accepted manuscrip

Effects of aripiprazole once-monthly on domains of personal and social performance: Results from 2 multicenter, randomized, double-blind studies

Objective: To assess the effects of maintenance therapy with aripiprazole once-monthly 400 mg on personal and social functioning. Methods: Data were analyzed from 2 randomized, double-blind trials of patients with schizophrenia requiring chronic antipsychotic treatment. One study was a 52-week trial of aripiprazole once-monthly 400 mg versus placebo; the other was a 38-week trial of aripiprazole once-monthly 400 mg, oral aripiprazole (10-30 mg daily), and aripiprazole once-monthly 50 mg (subtherapeutic dose to test assay sensitivity). Functioning was assessed using the Personal and Social Performance (PSP) scale, comprising 4 domain subscales. Results: In the 52-week study, 403 patients stabilized on aripiprazole once-monthly 400 mg were randomized to receive aripiprazole once-monthly 400 mg (n=269) or placebo (n=134). In the 38-week study, 662 patients stabilized on oral aripiprazole were randomized to receive aripiprazole once-monthly 400 mg (n=265), oral aripiprazole (n=266), or aripiprazole once-monthly 50 mg (subtherapeutic dose; n=131). In the 52-week study, mean changes from baseline were significantly worsened with placebo compared with aripiprazole once-monthly 400 mg for PSP total score (

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Mechanistic insight into the sensing of nitroaromatic compounds by metal-organic frameworks

There has been extensive research on the sensing of explosive nitroaromatic compounds (NACs) using fluorescent metal-organic frameworks (MOFs). However, ambiguity in the sensing mechanism has hampered the development of efficient explosive sensors. Here we report the synthesis of a hydroxyl-functionalized MOF for rapid and efficient sensing of NACs and examine in detail its fluorescence quenching mechanisms. In chloroform, quenching takes place primarily by exciton migration to the ground-state complex formed between the MOF and the analytes. A combination of hydrogen-bonding interactions and ??????? stacking interactions are responsible for fluorescence quenching, and this observation is supported by single-crystal structures. In water, the quenching mechanism shifts toward resonance energy transfer and photo-induced electron transfer, after exciton migration as in chloroform. This study provides insight into florescence-quenching mechanisms for the selective sensing of NACs and reduces the ambiguity regarding the nature of interactions between the MOF and NACs

Eyes wide open: perceived exploitation and its consequences

Drawing on the array of literature on exploitation from several social science disciplines, we propose a new way of seeing employer-employee relationships by introducing the concept of perceived exploitative employee-organization relationships, distinguish it from related concepts, and conduct five studies to develop a scale and test our theoretical model of the effects of such employee perceptions. Contributing to the Employee-Organization Relationships and workplace emotions literatures, perceived exploitation is defined as employees’ perceptions that they have been purposefully taken advantage of in their relationship with the organization, to the benefit of the organization itself. We propose and find that such perceptions are associated with both outward-focused emotions of anger and hostility toward the organization and inward-focused ones of shame and guilt at remaining in an exploitative job. In two studies including construction workers and a time-lagged study of medical residents, we find that the emotions of anger and hostility partially mediate the effects of perceived exploitation on employee engagement, revenge against the organization, organizational commitment, and turnover intentions, whereas the emotions of shame and guilt partially mediate the effects of perceived exploitation on employee burnout, silence, and psychological withdrawal