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\"She sweats every detail as a forensic firearms specialist--and as a forty-something single mother. She's got more responsibilities than she can count, more baggage than she wants to claim, and way too many regrets. But Muriel Mabley will do whatever it takes to put Philadelphia's most vicious killer in lockdown for good ... Until her troubled younger sister in witness protection receives a terrifying warning--and Muriel's long-time partner, Laughton, reveals he knows more than he should about her and Muriel's shattered past. And when Laughton's ex-wife and her new husband turn up dead, his own secrets will send Muriel down a twisted trail of lethal leads, disappeared witnesses, and the ultimate wrenching betrayal\"-- Provided by publisher.

Macrophages are versatile immune cells that can detect a variety of pathogen-associated molecular patterns through their Toll-like receptors (TLRs). In response to microbial challenge, the TLR-stimulated macrophage undergoes an activation program controlled by a dynamically inducible transcriptional regulatory network. Mapping a complex mammalian transcriptional network poses significant challenges and requires the integration of multiple experimental data types. In this work, we inferred a transcriptional network underlying TLR-stimulated murine macrophage activation. Microarray-based expression profiling and transcription factor binding site motif scanning were used to infer a network of associations between transcription factor genes and clusters of co-expressed target genes. The time-lagged correlation was used to analyze temporal expression data in order to identify potential causal influences in the network. A novel statistical test was developed to assess the significance of the time-lagged correlation. Several associations in the resulting inferred network were validated using targeted ChIP-on-chip experiments. The network incorporates known regulators and gives insight into the transcriptional control of macrophage activation. Our analysis identified a novel regulator (TGIF1) that may have a role in macrophage activation.

Although approximately 70% of American Indians/Alaska Natives (AI/ANs) reside in urban areas, our knowledge of risk and protective factors among AI/ANs seeking substance use treatment within urban areas is limited. We analyze substance and commercialized cigarette use, AI/AN cultural identity and involvement, physical health and cognitive functioning, and mental health symptoms among 63 AI/AN adults seeking substance use treatment within an urban area in California. Alcohol (37%), marijuana (27%), and methamphetamine (22%) were the most commonly reported substances. Sixty-two percent used commercialized tobacco use. The majority of AI/AN adults (78%) engaged in at least one traditional practice during the past month and endorsed high levels of spiritual connectedness. Those who engaged in traditional practices demonstrated significantly less depression (p = 0.007) and anxiety (p = 0.04). Medical and mental health issues were not prominent, although participants revealed high levels of cognitive impairment. Results highlight the importance of utilizing AI/AN traditional practices for AI/AN adults seeking substance use treatment within urban areas. Clinical Trials Registry Number NCT01356667.

There are few substance use treatment and prevention programs for AI/AN people that integrate culturally based practices with evidence-based treatment and prevention. The National Institutes of Health’s (NIH’s) Helping to End Addiction Long-term (HEAL) Prevention Cooperative supports two projects focused on AI/AN populations. One focuses on youth ages 15 to 20 years living within the Cherokee Nation reservation, a multicultural rural area in northeastern Oklahoma, and the second focuses on emerging adults ages 18 to 25 years living in diverse urban areas. We provide a brief overview of the two prevention trials and a case comparison across approaches using the framework of promising practices for intervention science with Indigenous communities (Whitesell et al., 2020) related to (1) integration of Indigenous and academic perspectives to respond to community needs, (2) community partnership and engagement, (3) alignment with Indigenous cultural values and practices, (4) capacity building and empowerment, (5) implementation within complex cultural contexts, and (6) tribal oversight. Overall, these two projects highlight the importance of long-standing relationships with community partners, engaging the community at all levels to ensure that programming is culturally and developmentally appropriate, and having tribal and elder oversight. These practices are key to establishing trust and building confidence in research in these communities and ensuring that research can benefit AI/AN people. These studies showcase how strong partnerships can advance health and support the conduct of rigorous science to help pinpoint optimal health solutions by identifying efficacious, culturally grounded intervention strategies. Although the sovereign status of tribes demands this type of partnership, this research serves as a model for all community research that has a goal of improving health.

American Indian/Alaska Native (AI/AN) communities are disproportionately affected by the opioid epidemic. AI/AN emerging adults (ages 18–25) in urban areas are at particularly high risk, with the overdose death rate among urban-dwelling AI/AN people 1.4 times higher than rural-dwelling AI/AN people. Despite these challenges, there are no evidence-based culturally tailored prevention or intervention programs to address opioid, alcohol and other drug use among urban AI/AN emerging adults. This study focused on understanding AI/AN emerging adults’ experiences with two culturally tailored programs addressing opioid, cannabis, and alcohol use as part of the randomized controlled trial for Traditions and Connections for Urban Native Americans (TACUNA) in order to enhance feasibility of this intervention. Using a convergent mixed methods design at 3-month follow-up, we collected satisfaction and experience ratings and written narratives (total n = 162; intervention n = 77; control n = 85) from a sample of urban-dwelling AI/AN emerging adults who participated in both programs. We analyzed data through simultaneous examination of qualitative and quantitative data. The quantitative ratings show that both programs were rated highly. The qualitative data contextualized these ratings, illustrating pathways through which specific components were perceived to cause desired or observed behavioral change in participants. Among the elements that mattered most to these participants were the convenience of the virtual format, having a comfortable and safe space to share personal stories, and learning new information about their social networks. Negative comments focused on workshop length and inconvenient scheduling. This is one of the first studies to explore participant satisfaction and experience with culturally tailored substance use programming among a historically marginalized and understudied population. It is important to consider the voices of urban-dwelling AI/AN people in program development because hidden factors, such as limited financial resources, limited time, and misalignment with cultural values may prevent existing programs from being feasible.

Background Coupling social network visualizations with Motivational Interviewing in substance use interventions has been shown to be acceptable and feasible in several pilot tests, and has been associated with changes in participants’ substance use and social networks. The objective of this study was to assess acceptability and feasibility of an adaptation of this behavior change approach into a culturally centered behavior change intervention for American Indian/Alaska Native (AI/AN) emerging adults living in urban areas. AI/AN populations experience high rates of health disparities and substance use. Although 70% of AI/AN people live outside of tribal lands, there are few culturally tailored health interventions for these AI/AN populations. Social networks can both increase and discourage substance use. Leveraging healthy social networks and increasing protective factors among urban AI/AN emerging adults may help increase resilience. Methods We conducted thirteen focus groups with 91 male and female participants (32 urban AI/AN emerging adults ages 18–25, 26 parents, and 33 providers) and one pilot test of the three workshop sessions with 15 AI/AN emerging adults. Focus group participants provided feedback on a proposed workshop-based intervention curriculum that combined group Motivational Interviewing (MI) and social network visualizations. Pilot workshop participants viewed their own social networks during group MI sessions focused on substance use and traditional practices and discussed their reactions to viewing and discussing their networks during these sessions. We used a combination of open coding of focus group and workshop session transcripts to identify themes across the group sessions and content analysis of comments entered into an online social network interview platform to assess the extent that participants had an intuitive understanding of the information conveyed through network diagrams. Results Focus group and pilot test participants reacted positively to the intervention content and approach and provided constructive feedback on components that should be changed. Themes that emerged included feasibility, acceptability, relevance, understandability, and usefulness of viewing personal network visualizations and discussing social networks during group MI workshops. Workshop participants demonstrated an intuitive understanding of network concepts (network composition and structure) when viewing their diagrams for the first time. Conclusions Social network visualizations are a promising tool for increasing awareness of social challenges and sources of resilience for urban AI/AN emerging adults. Coupled with Motivational Interviewing in a group context, social network visualizations may enhance discussions of network influences on substance use and engagement in traditional practices. Trial Registration : ClinicalTrials.gov Identifier: NCT04617938. Registered October 26, 2020

After an incubation period of weeks to months, up to 14% of cats infected with feline coronavirus (FCoV) develop feline infectious peritonitis (FIP): a potentially lethal pyogranulomatous perivasculitis. The aim of this study was to find out if stopping FCoV faecal shedding with antivirals prevents FIP. Guardians of cats from which FCoV had been eliminated at least 6 months earlier were contacted to find out the outcome of their cats; 27 households were identified containing 147 cats. Thirteen cats were treated for FIP, 109 cats shed FCoV and 25 did not; a 4–7-day course of oral GS-441524 antiviral stopped faecal FCoV shedding. Follow-up was from 6 months to 3.5 years; 11 of 147 cats died, but none developed FIP. A previous field study of 820 FCoV-exposed cats was used as a retrospective control group; 37 of 820 cats developed FIP. The difference was statistically highly significant (p = 0.0062). Cats from eight households recovered from chronic FCoV enteropathy. Conclusions: the early treatment of FCoV-infected cats with oral antivirals prevented FIP. Nevertheless, should FCoV be re-introduced into a household, then FIP can result. Further work is required to establish the role of FCoV in the aetiology of feline inflammatory bowel disease.

Sleep fragmentation often precedes Alzheimer's disease (AD) diagnosis and represents a potential modifiable risk factor, especially among women who have higher prevalence of both sleep disorders and AD.IntroductionSleep fragmentation often precedes Alzheimer's disease (AD) diagnosis and represents a potential modifiable risk factor, especially among women who have higher prevalence of both sleep disorders and AD.This study investigated how chronic sleep fragmentation affects neuroinflammation and amyloid-beta (Aβ) accumulation in male and female APPSAA knock-in mice, a physiologically relevant AD model expressing APP at normal levels. APPSAA mice of both sexes (N=8/sex/strain, 8 months old) underwent either 5 weeks of chronic sleep fragmentation administered during the light phase using an automated sweeper system or undisturbed sleep. Sleep-wake patterns and circadian rhythms were monitored using piezoelectric sensors. Following intervention, we assessed neuroinflammatory markers via immunohistochemistry and multiplex cytokine analysis, Aβ levels in different solubility fractions, and Aβ plaque characteristics through digital pathology.MethodsThis study investigated how chronic sleep fragmentation affects neuroinflammation and amyloid-beta (Aβ) accumulation in male and female APPSAA knock-in mice, a physiologically relevant AD model expressing APP at normal levels. APPSAA mice of both sexes (N=8/sex/strain, 8 months old) underwent either 5 weeks of chronic sleep fragmentation administered during the light phase using an automated sweeper system or undisturbed sleep. Sleep-wake patterns and circadian rhythms were monitored using piezoelectric sensors. Following intervention, we assessed neuroinflammatory markers via immunohistochemistry and multiplex cytokine analysis, Aβ levels in different solubility fractions, and Aβ plaque characteristics through digital pathology.Sleep fragmentation effectively disrupted sleep patterns in both sexes, reducing light-phase sleep and increasing intradaily variability. Sleep fragmentation increased GFAP immunoreactivity in both sexes, with larger effects in females than males. Surprisingly, sleep fragmentation decreased expression of the microglial activation markers MHCII and Dectin-1 in males. Pro-inflammatory cytokines (IL-1β, CCL2, CXCL2) were significantly elevated following sleep fragmentation, with distinct regional and sex-specific patterns. In females, sleep fragmentation increased PBS-soluble and formic acid-soluble Aβ in the neocortex and medium-sized plaque density in the hippocampus, while males showed decreased detergent-soluble Aβ in the neocortex following sleep fragmentation.ResultsSleep fragmentation effectively disrupted sleep patterns in both sexes, reducing light-phase sleep and increasing intradaily variability. Sleep fragmentation increased GFAP immunoreactivity in both sexes, with larger effects in females than males. Surprisingly, sleep fragmentation decreased expression of the microglial activation markers MHCII and Dectin-1 in males. Pro-inflammatory cytokines (IL-1β, CCL2, CXCL2) were significantly elevated following sleep fragmentation, with distinct regional and sex-specific patterns. In females, sleep fragmentation increased PBS-soluble and formic acid-soluble Aβ in the neocortex and medium-sized plaque density in the hippocampus, while males showed decreased detergent-soluble Aβ in the neocortex following sleep fragmentation.Chronic sleep fragmentation exacerbates AD-related pathology in APPSAA mice in a sex-dependent manner, with females showing greater vulnerability to Aβ accumulation and astrocyte reactivity following sleep disruption. These findings suggest that environmental sleep disruptions may contribute to the higher prevalence of AD in women and highlight the importance of addressing sleep fragmentation as a modifiable risk factor for AD.DiscussionChronic sleep fragmentation exacerbates AD-related pathology in APPSAA mice in a sex-dependent manner, with females showing greater vulnerability to Aβ accumulation and astrocyte reactivity following sleep disruption. These findings suggest that environmental sleep disruptions may contribute to the higher prevalence of AD in women and highlight the importance of addressing sleep fragmentation as a modifiable risk factor for AD.

Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3-deficient mice are more susceptible to endotoxic shock. Here, we demonstrate that ATF3 interacts with a cis-regulatory element of the IFN-γ gene in natural killer (NK) cells, and that ATF3null NK cells show increased transcription and secretion of IFN-γ. NK cell-derived IFN-γ has previously been demonstrated to be protective against murine cytomegalovirus (MCMV) infection, and we show here that ATF3null mice exhibit decreased hepatic viral load and reduced liver histopathology upon challenge with MCMV. Reconstitution of NK-deficient mice with ATF3null NK cells more effectively controlled MCMV infection than mice reconstituted with WT cells, indicating that ATF3 acts within NK cells to regulate antiviral responses.

The apoptotic initiator caspase‐2 has been implicated in oocyte death, in DNA damage‐ and heat shock‐induced death, and in mitotic catastrophe. We show here that the mitosis‐promoting kinase, cdk1–cyclin B1, suppresses apoptosis upstream of mitochondrial cytochrome c release by phosphorylating caspase‐2 within an evolutionarily conserved sequence at Ser 340. Phosphorylation of this residue, situated in the caspase‐2 interdomain, prevents caspase‐2 activation. S340 was susceptible to phosphatase 1 dephosphorylation, and an interaction between phosphatase 1 and caspase‐2 detected during interphase was lost in mitosis. Expression of S340A non‐phosphorylatable caspase‐2 abrogated mitotic suppression of caspase‐2 and apoptosis in various settings, including oocytes induced to undergo cdk1‐dependent maturation. Moreover, U2OS cells treated with nocodazole were found to undergo mitotic catastrophe more readily when endogenous caspase‐2 was replaced with the S340A mutant to lift mitotic inhibition. These data demonstrate that for apoptotic stimuli transduced by caspase‐2, cell death is prevented during mitosis through the inhibitory phosphorylation of caspase‐2 and suggest that under conditions of mitotic arrest, cdk1–cyclin B1 activity must be overcome for apoptosis to occur.