Search

Basic and retrospective translational research has shown that the magnitude of resurgence is determined by the size of the decrease in alternative reinforcement, with larger decreases producing more resurgence. However, this finding has not been evaluated prospectively with a clinical population. In Experiment 1, five participants experienced a fixed progression of reinforcement schedule-thinning steps during treatment of their destructive behavior. Resurgence occurred infrequently across steps and participants, and when resurgence did occur, its clinical meaningfulness was often minimal. In Experiment 2, five new participants experienced these same schedule-thinning steps but in a counterbalanced order. Resurgence occurred most often and was generally largest with larger decreases in alternative reinforcement programmed earlier in the evaluation. Large decreases in alternative reinforcement may be more problematic clinically when they occur earlier in treatment. Whether larger transitions can be recommended in the clinic following the success of smaller ones will require additional research.

While research suggests that social emotional competencies (SECs) influence students' disciplinary outcomes, less is known of their potential to explain racial disparities or grade level differences in those outcomes. This study used survey and administrative data from 30,494 students in grades 3-12 to examine the degree to which SECs were related to discipline outcomes, and whether the relationship differed by race or grade tier. Results indicated that students with higher SEC had fewer behavior incidents, in-school suspensions, and out-of-school suspensions. Further analyses revealed that race and grade tier were predictive of all discipline outcomes. Regardless of SEC level, Black and mixed-race students had higher behavior incidents. When race and grade tier were included as factors, the relationship between SEC and discipline was diminished. Results suggest that SECs cannot explain racial disparities in discipline, but students who report low SEC in middle and high school could potentially benefit from intervention.

Abstract Despite the significant burden, cost, and worse prognosis of Alzheimer’s disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our cohort: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissues. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly associated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high-impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.

Abstract Depression is a common and devastating neuropsychiatric symptom in the elderly and in patients with dementia. In particular, nearly 80% of patients with Alzheimer’s Disease dementia experience depression during disease development and progression. However, it is unknown whether the depression in patients with dementia shares the same molecular mechanisms as depression presenting as primary psychiatric disease or occurs and persists through alternative mechanisms. In this review, we discuss how the clinical presentation and treatment differ between depression in dementia and as a primary psychiatric disease, with a focus on major depressive disorder. Then, we hypothesize several molecular mechanisms that may be unique to depression in dementia such as neuropathological changes, inflammation, and vascular events. Finally, we discuss existing issues and future directions for investigation and treatment of depression in dementia.

The objective of this Campbell systematic review is to examine the relationship between school-based law enforcement (SBLE) presence and school-related outcomes. The past several decades has witnessed a steady growth of the presence of SBLE around the world. There is no standard definition for SBLE, nor is there a common training, job description, or chain of authority. In the USA, the two most common approaches are to contract officers from a local law enforcement agency to work in the school, and school district police departments, in which the local school or district employs its own sworn police force. There is debate about whether SBLE is effective or harmful. This study synthesizes the empirical literature that examined the relationship between SBLE presence and school-related outcomes including: (a) crime and behavior problems; (b) perceptions of school; and (c) student learning.

Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism.

Sediment Barriers (SBs) are crucial for effective erosion control, and understanding their capacities and limitations is essential for environmental protection. This study compares the accuracy and effectiveness of Terrestrial Laser Scanning (TLS) and Robotic Total Station (RTS) techniques for quantifying sediment retention in SBs. To achieve this, erosion tests were conducted in a full-scale testing apparatus with TLS and RTS methods to collect morphological data of sediment retention surfaces before and after each experiment. The acquired datasets were processed and integrated into a Building Information Modeling (BIM) platform to create Digital Elevation Models (DEMs). These were then used to calculate the volume of accumulated sediment upstream of the SB system. The results indicated that TLS and RTS techniques could effectively measure sediment retention in a full-scale testing environment. However, TLS proved to be more accurate, exhibiting a standard deviation of 0.41 ft3 in contrast to 1.94 ft3 for RTS and more efficient, requiring approximately 15% to 50% less time per test than RTS. The main conclusions of this study highlight the benefits of using TLS over RTS for sediment retention measurement and provide valuable insights for improving erosion control strategies and sediment barrier design.

Abstract Background School‐based law enforcement (SBLE) has become a common intervention. Although SBLE is meant to make schools safer, critics suggest it may not accomplish this purpose, and may have unintended negative consequences such as increasing students’ exclusionary discipline or contact with the criminal justice system. There may also be secondary effects related to perceptions of the school or student learning. Objectives The purpose of this review is to synthesize the literature evaluating the use of SBLE, including outcomes related to (a) crime and behavior problems; (b) perceptions of safety; and (c) learning. Methods We conducted a systematic literature search to identify studies that examined outcomes associated with SBLE use. Eligible studies used experimental or quasi‐experimental designs; included samples of students, teachers/staff, schools, or school districts; reported on a policing strategy focused on crime prevention or school safety that did not involve officers teaching a curriculum; included a measure that reflects crime and behavior problems, perceptions of safety, or learning; and were in a primary or secondary school. Following a multi‐stage screening process to identify studies eligible for inclusion, we estimated a series of meta‐analytic models with robust variance estimation to calculate weighted mean effect sizes for each of three main categories of outcomes and commonly occurring subsets of these categories. We examined heterogeneity in these estimates across features of the primary studies’ design. Results The search and screening process yielded 1002 effect sizes from 32 reports. There were no true experiments, and the quasi‐experiments ranged from strictly correlational to permitting stronger causal inferences. SBLE use was associated with greater crime and behavior problems in studies that used schools as the unit of analysis. Within this category, SBLE use was associated with increased exclusionary discipline among studies that used both schools (g = 0.15, 95% confidence interval [CI] [0.02, 0.27]) and students (g = 0.003, 95% CI [0.002, 0.003]) as the unit of analysis. SBLE use was not associated with any measures of crime or violence in schools. SBLE use was associated with greater feelings of safety among studies that used schools as the unit of analysis (g = 0.18, 95% CI [0.13, 0.24]), although this estimate was based on only seven effect sizes from two correlational studies. All the other models, including those examining learning outcomes, yielded null results. None of the moderators tested showed meaningful relationships, indicating the findings were consistent across a variety of study design features. Authors’ Conclusions This study's findings provide no evidence that there is a safety‐promoting component of SBLE, and support the criticism that SBLE criminalizes students and schools. Although we found no evidence of differences across methodological features, risk of bias in the primary studies limits our confidence in making causal inferences. To the extent that the findings are causal, schools that invest in strategies to improve safety will likely benefit from divesting from SBLE and instead investing in evidence‐based strategies for enhancing school safety. Schools that continue to use SBLE should ensure that their model has no harmful effects and is providing safety benefits.

Rosacea is a chronic inflammatory skin condition associated with a significant health and economic burden from costs and loss of productivity due to seeking medical treatment. The disease encompasses multiple phenotypic manifestations involving a complex and multi-variate pathogenesis. Although the pathophysiology of rosacea is not completely understood, ongoing research is continually elucidating its mechanisms. In this review, current concepts of rosacea pathogenesis will be addressed which involve skin barrier and permeability dysfunction, the innate and adaptive immune systems, and the neurovascular system. More specifically, the cathelicidin pathway, transient potential receptor channels, mast cells, and the NLRP3 inflammasome pathway are various targets of current pharmacologic regimens. Future therapies may seek different mechanisms to act on current treatment targets, like the potential use of JAK/STAT inhibitors in ameliorating skin barrier dysfunction or TLR antagonists in alleviating cathelicidin mediated inflammation. Other potential treatments aim for entirely different molecular targets such as microvesicle particle mediated local and systemic inflammation. Ultimately rosacea is associated with a significant health and economic burden which warrants deeper research into its pathogenesis and resultant new treatment discovery.

Summary: Short polypeptides encoded by small open reading frames (smORFs) are ubiquitously found in eukaryotic genomes and are important regulators of physiology, development, and mitochondrial processes. Here, we focus on a subset of 298 smORFs that are evolutionarily conserved between Drosophila melanogaster and humans. Many of these smORFs are conserved broadly in the bilaterian lineage, and ∼182 are conserved in plants. We observe remarkably heterogeneous spatial and temporal expression patterns of smORF transcripts—indicating wide-spread tissue-specific and stage-specific mitochondrial architectures. In addition, an analysis of annotated functional domains reveals a predicted enrichment of smORF polypeptides localizing to mitochondria. We conduct an embryonic ribosome profiling experiment and find support for translation of 137 of these smORFs during embryogenesis. We further embark on functional characterization using CRISPR knockout/activation, RNAi knockdown, and cDNA overexpression, revealing diverse phenotypes. This study underscores the importance of identifying smORF function in disease and phenotypic diversity.

The bacterial pathogen Candidatus Liberibacter asiaticus (CLas) is the causal agent of citrus greening disease. This unusual plant pathogenic bacterium also infects its psyllid host, the Asian citrus psyllid (ACP). To investigate gene expression profiles with a focus on genes involved in infection and circulation within the psyllid host of CLas, RNA-seq libraries were constructed from CLas-infected and CLas-free ACP representing the five different developmental stages, namely, nymphal instars 1-2, 3, and 4-5, and teneral and mature adults. The Gbp paired-end reads (296) representing the transcriptional landscape of ACP across all life stages and the official gene set (OGSv3) were annotated based on the chromosomal-length v3 reference genome and used for de novo transcript discovery resulting in 25,410 genes with 124,177 isoforms. Differential expression analysis across all ACP developmental stages revealed instar-specific responses to CLas infection, with greater overall responses by nymphal instars, compared to mature adults. More genes were over-or under-expressed in the 4-5th nymphal instars and young (teneral) adults than in instars 1-3, or mature adults, indicating that late immature instars and young maturing adults were highly responsive to CLas infection. Genes identified with potential for direct or indirect involvement in the ACP-CLas circulative, propagative transmission pathway were predominantly responsive during early invasion and infection processes and included canonical cytoskeletal remodeling and endo-exocytosis pathway genes. Genes with predicted functions in defense, development, and immunity exhibited the greatest responsiveness to CLas infection. These results shed new light on ACP-CLas interactions essential for pathogenesis of the psyllid host, some that share striking similarities with effector protein-animal host mechanisms reported for other culturable and/or fastidious bacterial- or viral- host pathosystems.

The use of lattice structure in the Design for Additive Manufacturing (DfAM) engineering practice offers the ability to tailor the properties (and therefore the response) of an engineered component independent of the material and overall geometry. The selection of a lattice topology is critical in maximizing the value of the lattice structure and its unique properties for the intended application. To support this, we have compiled a catalog of lattice structures from the literature that includes all Triply Periodic Minimal Surfaces (TPMS) for which a low-order Fourier series fit is known (so that they can be modeled and manufactured). We also include equations that do not directly correspond to known TPMS but do produce a triply periodic structure without sharp corners that would give rise to stress concentrations. This catalog includes images, elastic mechanical property data, and CAD models useful for the visualization, selection, and implementation of these lattice structures for any engineered structure.

Abstract Background Nonalcoholic fatty liver disease affects about 24% of the world’s population and may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). While more common in those that are obese, NASH-HCC can develop in lean individuals. The mechanisms by which HCC develops and the role of epigenetic changes in the context of obesity and normal weight are not well understood. Methods In this study, we used previously generated mouse models of lean and obese HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to evaluate methylation differences in HCC progression in lean versus obese mice. Differentially methylated regions were determined using reduced representation bisulfite sequencing. Results A larger number of differentially methylated regions (DMRs) were seen in NASH-HCC progression in the obese mice compared to the non-obese mice. No overlap existed in the DMRs with the largest methylation differences between the two models. In lean NASH-HCC, methylation differences were seen in genes involved with cancer progression and prognosis (including HCC), such as CHCHD2, FSCN1, and ZDHHC12, and lipid metabolism, including PNPLA6 and LDLRAP1. In obese NASH- HCC, methylation differences were seen in genes known to be associated with HCC, including RNF217, GJA8, PTPRE, PSAPL1, and LRRC8D. Genes involved in Wnt-signaling pathways were enriched in hypomethylated DMRs in the obese NASH-HCC. Conclusions These data suggest that differential methylation may play a role in hepatocarcinogenesis in lean versus obese NASH. Hypomethylation of Wnt signaling pathway-related genes in obese mice may drive progression of HCC, while progression of HCC in lean mice may be driven through other signaling pathways, including lipid metabolism.

Antipsychotic drugs are still widely prescribed to control various severe neuropsychiatric symptoms in the elderly and dementia patients although they are off-label use in the United States. However, clinical practice shows greater side effects and lower efficacy of antipsychotics for this vulnerable population and the mechanisms surrounding this aged-related sensitivity are not well understood. Our previous studies have shown that aging-induced epigenetic alterations may be involved in the increasing severity of typical antipsychotic haloperidol induced side effects in aged mice. Still, it is unknown if similar epigenetic mechanisms extend to atypical antipsychotics, which are most often prescribed to dementia patients combined with severe neuropsychiatric symptoms. In this study, we report that atypical antipsychotic risperidone also causes increased motor side effect behaviors in aged mice and 5xFAD mice. Histone deacetylase (HDAC) inhibitor Valproic Acid and Entinostat can mitigate the risperidone induced motor side effects. We further showed besides D2R, reduced expression of 5-HT2A, one of the primary atypical antipsychotic targets in the striatum of aged mice that are also mitigated by HDAC inhibitors. Finally, we demonstrate that specific histone acetylation mark H3K27 is hypoacetylated at the 5htr2a and Drd2 promoters in aged mice and can be reversed with HDAC inhibitors. Our work here establishes evidence for a mechanism where aging reduces expression of 5-HT2A and D2R, the key atypical antipsychotic drug targets through epigenetic alteration. HDAC inhibitors can restore 5-HT2A and D2R expression in aged mice and decrease the motor side effects in aged and 5xFAD mice.

The efficacy of youth violence prevention policies, programs, and practices partly depends on understanding the reasons for why students are targeted for victimization. However, what is known about why some students are targeted for victimization over others is limited to researcher-generated reasons and therefore may risk ecological validity. This study used a qualitative open-coding content analyses to make sense of 8531 students' open-ended responses about the reasons why they were targeted for victimization at school. Results identified 35 commonly reported reasons, many of which are underrepresented in previous literature. Students primarily reported reasons related to relational dynamics, physical characteristics, non-physical personal characteristics, and characteristics external to themselves. These results portray reasons for being targeted as a social phenomenon with both individual and contextual components. Implications for theory, research, and practitioners are discussed.

Brown et al. apply integrated omics and phenotypic screening to assess the role of the gut microbiome in modulating host resilience in Drosophila melanogaster. They find that Acetobacter tropicalis in gnotobiotic animals, is sufficient to rescue increased atrazine toxicity, which could pave the way for biotic strategies to improve host resilience to environmental chemical exposure.

Introduction Multiple abortions are consistently associated with adverse health consequences. Prior abortion is a known risk factor for another abortion. Objective To determine the persistence of the association of a first-pregnancy abortion with the likelihood of subsequent pregnancy outcomes. Methods Data was extracted for a study population of 5453 continuously eligible Medicaid beneficiaries in states which funded and reported elective abortions 1999–2015. Women age 16 in 1999 were organized into three cohorts based upon the first pregnancy outcome: abortion, birth, natural loss. Results Women in the abortion cohort are more likely than those in the birth cohort to experience another abortion rather than a birth or natural loss, and less likely to experience a live birth rather than an abortion or natural loss, for every subsequent pregnancy. The tendency toward abortion (OR 2.99, CL 2.02-4.43) and away from birth (OR 0.49, CL 0.39-0.63) peaks at the sixth pregnancy, but persists throughout the reproductive period ages 16–32. The pattern is reversed, but similarly consistent, for women in the birth cohort. They remain likelier to have another birth rather than an abortion or natural loss in subsequent pregnancies. Compared to the birth cohort, the abortion cohort had 1.35 times as many pregnancies: 4.31 times the abortions, 1.53 times the natural losses, but only 0.52 times the births. They were 4.3 and 5.0 times as likely to have 2-plus and 3-plus abortions, but only 0.47 times and 0.31 times as likely to have 2-plus and 3-plus births. Of the abortion cohort, 37.1% had no births. By contrast, 73.6% of the birth cohort had no abortions. Conclusion The first-pregnancy abortion maintains a strong and persistent association with the likelihood of another abortion in subsequent pregnancies, enabling a cascade of adverse events associated with multiple abortions.

Background Despite an elevated risk of psychopathology stemming from COVID-19-related stress, many essential workers stigmatise and avoid psychiatric care. This randomised controlled trial was designed to compare five versions of a social-contact-based brief video intervention for essential workers, differing by protagonist gender and race/ethnicity. Aims We examined intervention efficacy on treatment-related stigma (‘stigma’) and openness to seeking treatment (‘openness’), especially among workers who had not received prior mental healthcare. We assessed effectiveness and whether viewer/protagonist demographic concordance heightened effectiveness. Method Essential workers (N = 2734) randomly viewed a control video or brief video of an actor portraying an essential worker describing hardships, COVID-related anxiety and depression, and psychotherapy benefits. Five video versions (Black/Latinx/White and male/female) followed an identical 3 min script. Half the intervention group participants rewatched their video 14 days later. Stigma and openness were assessed at baseline, post-intervention, and at 14- and 30-day follow-ups. Trial registration: NCT04964570. Results All video intervention groups reported immediately decreased stigma (P < 0.0001; Cohen's d = 0.10) and increased openness (P < 0.0001; d = 0.23). The initial increase in openness was largely maintained in the repeated-video group at day 14 (P < 0.0001; d = 0.18), particularly among viewers without history of psychiatric treatment (P < 0.0001; d = 0.32). Increases were not sustained at follow-up. Female participants viewing a female protagonist and Black participants viewing a Black protagonist demonstrated greater openness than other demographic pairings. Conclusions Brief video-based interventions improved immediate stigma and openness. Greater effects among female and Black individuals viewing demographically matched protagonists emphasise the value of tailored interventions, especially for socially oppressed groups. This easily disseminated intervention may proactively increase care-seeking, encouraging treatment among workers in need. Future studies should examine intervention mechanisms and whether linking referrals to psychiatric services generates treatment-seeking.

Abstract Background The role of microglia in Alzheimer’s disease (AD) pathogenesis is becoming increasingly important, as activation of these cell types likely contributes to both pathological and protective processes associated with all phases of the disease. During early AD pathogenesis, one of the first areas of degeneration is the locus coeruleus (LC), which provides broad innervation of the central nervous system and facilitates norepinephrine (NE) transmission. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging. Methods In this study, we evaluated the dynamic changes of neuroinflammation and neurodegeneration in the LC-NE system in the brain and spinal cord of APP/PS1 mice and aged WT mice using immunofluorescence and ELISA. Results Our results demonstrated increased expression of inflammatory cytokines and microglial activation observed in the cortex, hippocampus, and spinal cord of APP/PS1 compared to WT mice. LC-NE neuron and fiber loss as well as reduced norepinephrine transporter (NET) expression was more evident in APP/PS1 mice, although NE levels were similar between 12-month-old APP/PS1 and WT mice. Notably, the degree of microglial activation, LC-NE nerve fiber loss, and NET reduction in the brain and spinal cord were more severe in 12-month-old APP/PS1 compared to 12- and 24-month-old WT mice. Conclusion These results suggest that elevated neuroinflammation and microglial activation in the brain and spinal cord of APP/PS1 mice correlate with significant degeneration of the LC-NE system.

Background Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. Methods In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. Results Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. Conclusions Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis.

Abstract Within the animal kingdom, carnivores occupied a unique place in prehistoric societies. At times predators or competitors for resources and shelters, anthropogenic traces of their exploitation, often for non-nutritional purposes, permeate the archaeological record. Scarce but spectacular depictions in Palaeolithic art confirm peoples’ fascination with carnivores. In contrast with the European record, research on hominin/carnivore interactions in Africa has primarily revolved around the hunting or scavenging debate amongst early hominins. As such, the available information on the role of carnivores in Anatomically Modern Humans’ economic and cultural systems is limited. Here, we illustrate a particular relationship between humans and carnivores during the MIS5-4 Still Bay and Howiesons Poort techno-complexes at Diepkloof Rock Shelter, South Africa. The recovery of numerous felid remains, including cut-marked phalanges, tarsals and metapodials, constitutes direct evidence for carnivore skinning and, presumably, pelt use in the southern African Middle Stone Age. Carnivore exploitation at the site seems to have focused specifically on nocturnal, solitary and dangerous felines. The lines of evidence presented here suggest the capture and fur use of those felines in the context of highly codified and symbolically loaded cultural traditions.

Abstract Chronic pain often occurs in the elderly, particularly in the patients with neurodegenerative disorders such as Alzheimer’s disease (AD). Although studies indicate that chronic pain correlates with cognitive decline, it is unclear whether chronic pain accelerates AD pathogenesis. In this review, we provide evidence that supports a link between chronic pain and AD and discuss potential mechanisms underlying this connection based on currently available literature from human and animal studies. Specifically, we describe two intertwined processes, locus coeruleus noradrenergic system dysfunction and neuroinflammation resulting from microglial pro-inflammatory activation in brain areas mediating the affective component of pain and cognition that have been found to influence both chronic pain and AD. These represent a pathological overlap that likely leads chronic pain to accelerate AD pathogenesis. Further, we discuss potential therapeutic interventions targeting noradrenergic dysfunction and microglial activation that may improve patient outcomes for those with chronic pain and AD.

Background: Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1β) and Estrogen-Related Receptor Alpha (ERRα) are over-expressed in colorectal cancer and promote tumor survival. Methods: In this study, we use immunoprecipitation of epitope tagged endogenous PGC-1β and inducible PGC-1β mutants to show that amino acid motif LRELL on PGC-1β is responsible for the physical interaction with ERRα and promotes ERRα mRNA and protein expression. We use RNAsequencing to determine the genes regulated by both PGC-1β & ERRα and find that mitochondrial Phosphoenolpyruvate Carboxykinase 2 (PCK2) is the gene that decreased most significantly after depletion of both genes. Results: Depletion of PCK2 in colorectal cancer cells was sufficient to reduce anchorage-independent growth and inhibit glutamine utilization by the TCA cycle. Lastly, shRNA-mediated depletion of ERRα decreased anchorage-independent growth and glutamine metabolism, which could not be rescued by plasmid derived expression of PCK2. Discussion: These findings suggest that transcriptional control of PCK2 is one mechanism used by PGC-1β and ERRα to promote glutamine metabolism and colorectal cancer cell survival.

Introduction: The prevalence of induced abortion among women with children has been estimated indirectly by projections derived from survey research. However, an empirically derived, population-based conclusion on this question is absent from the published literature. Objective: The objective of this study was to describe the period prevalence of abortion among all other possible pregnancy outcomes within the reproductive histories of Medicaid-eligible women in the U.S. Methods: A retrospective, cross-sectional, longitudinal analysis of the pregnancy outcome sequences of eligible women over age 13 from the 17 states where Medicaid included coverage of most abortions, with at least one identifiable pregnancy between 1999 and 2014. A total of 1360 pregnancy outcome sequences were grouped into 8 categories which characterize various combinations of the 4 possible pregnancy outcomes: birth, abortion, natural loss, and undetermined loss. The reproductive histories of 4,884,101 women representing 7,799,784 pregnancy outcomes were distributed into these categories. Results: Women who had live births but no abortions or undetermined pregnancy losses represented 74.2% of the study population and accounted for 87.6% of total births. Women who have only abortions but no births constitute 6.6% of the study population, but they are 53.5% of women with abortions and have 51.5% of all abortions. Women with both births and abortions represent 5.7% of the study population and have 7.2% of total births. Conclusion: Abortion among low-income women with children is exceedingly uncommon, if not rare. The period prevalence of mothers without abortion is 13 times that of mothers with abortion.

Introduction/Objectives: Although a majority of women who have an abortion report having 1 or more children, there is no published research on the number of abortions which occur between live births, after a first child but before the last. The objectives of this research, therefore, were to estimate the period prevalence of an induced abortion separating live births in a population of Medicaid eligible enrollees and to identify the characteristics of enrollees significantly associated with the use of abortion to enable child spacing. Methods: A retrospective, cross-sectional, longitudinal analysis of the pregnancy outcome sequences of eligible enrollees over age 13 from the 17 states where Medicaid included coverage of all abortions, with at least one identifiable pregnancy outcome between 1999 and 2014. Eligibles with a defined sequence of birth-abortion-birth within up to 5 consecutive pregnancies were identified to estimate the number of eligibles who could have practiced birth spacing by abortion. Logistic regression was applied to identify the significant predictor variables of the birth-abortion-birth sequence. Results: There were 50 012 (1.02%) of 4 875 511 Medicaid eligible enrollees exhibited a birth-abortion-birth sequence. Eligibles with the birth-abortion-birth sequence are more likely to be Black than White (OR 2.641, CL 2.581-2.702), less likely to be Hispanic than White (OR 0.667, CL 0.648-0.687), and more likely to have received contraceptive counseling (OR 1.14, CL 1.118-1.163). Increases in months of Medicaid eligibility (OR 1.004, CL 1.003-1.004) and months from first pregnancy to second live birth (OR 1.015, CL 1.015-1.016) are associated with the likelihood of undergoing live births separated by one or more induced abortions. Increases in the age at first pregnancy are associated with a decreased likelihood of the birth-abortion-birth sequence (OR 0.962, CL 0.959-0.964). Conclusion: Birth spacing via abortion is uncommon among a low-income population for whom the financial barriers to abortion are somewhat alleviated.

The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here, we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.

Responding to Zika virus infections in Houston, Texas, USA, presented numerous challenges across the health system. As the nation’s fourth-largest city, in a subtropical region with high travel volume to Latin America and the Caribbean, Houston was an ideal location for studying experiences encountered by clinicians and public health officials as they responded to the Zika virus crisis. To identify the challenges encountered in the response and to explore strategies to improve future responses to emerging infectious diseases, we interviewed 38 key stakeholders who were clinical, scientific, operational, and public health leaders. From the responses, we identified 4 key challenges: testing, travel screening, patient demographics and immigration status, and insufficient collaboration (between public health officials and clinicians and among clinical providers). We also identified 5 strategic areas as potential solutions: improved electronic health record support, specialty centers and referral systems, standardized forms, centralized testing databases, and joint academic/public health task forces.

Black women have been experiencing induced abortions at a rate nearly 4 times that of White women for at least 3 decades, and likely much longer. The impact in years of potential life lost, given abortion’s high incidence and racially skewed distribution, indicates that it is the most demographically consequential occurrence for the minority population. The science community has refused to engage on the subject and the popular media has essentially ignored it. In the current unfolding environment, there may be no better metric for the value of Black lives.

Introduction: The number and outcomes of pregnancies experienced by a woman are consequential determinants of her health status. However, there is no published research comparing the patterns of subsequent pregnancy outcomes following a live birth, natural fetal loss, or induced abortion. Objectives: The objective of this study was to describe the characteristic patterns of subsequent pregnancy outcomes evolving from each of three initiating outcome events (birth, induced abortion, natural fetal loss) occurring in a Medicaid population fully insured for all reproductive health services. Methods: We identified 7,388,842 pregnancy outcomes occurring to Medicaid-eligible women in the 17 states which paid for abortion services between 1999-2014. The first known pregnancy outcome for each woman was marked as the index outcome which assigned each woman to one of three cohorts. All subsequent outcomes occurring up to the fifth known pregnancy were identified. Analyses of the three index outcome cohorts were conducted separately for all pregnancy outcomes, three age bands (

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder currently affecting 45 million people worldwide, ranking as the 6th highest cause of death. Throughout the development and progression of AD, over 90% of patients display behavioral and psychological symptoms of dementia (BPSD), with some of these symptoms occurring before memory deficits and therefore serving as potential early predictors of AD-related cognitive decline. However, the biochemical links between AD and BPSD are not known. In this study, we explored the molecular interactions between AD and BPSD using protein-protein interaction (PPI) networks built from OMIM (Online Mendelian Inheritance in Man) genes that were related to AD and two distinct BPSD domains, the Affective Domain and the Hyperactivity, Impulsivity, Disinhibition, and Aggression (HIDA) Domain. Our results yielded 8 unique proteins for the Affective Domain (RHOA, GRB2, PIK3R1, HSPA4, HSP90AA1, GSK3beta, PRKCZ, and FYN), 5 unique proteins for the HIDA Domain (LRP1, EGFR, YWHAB, SUMO1, and EGR1), and 6 shared proteins between both BPSD domains (APP, UBC, ELAV1, YWHAZ, YWHAE, and SRC) and AD. These proteins might suggest specific targets and pathways that are involved in the pathogenesis of these BPSD domains in AD.

Abstract Background KMT2/MLL proteins are commonly overexpressed or mutated in cancer and have been shown to support cancer maintenance. These proteins are responsible for methylating histone 3 at lysine 4 and promoting transcription and DNA synthesis; however, they are inactive outside of a multi-protein complex that requires WDR5. WDR5 has been implicated in cancer for its role in the COMPASS complex and its interaction with Myc; however, the role of WDR5 in colon cancer has not yet been elucidated. Methods WDR5 expression was evaluated using RT-qPCR and western blot analysis. Cell viability and colony forming assays were utilized to evaluate the effects of WDR5 depletion or inhibition in colon cancer cells. Downstream effects of WDR5 depletion and inhibition were observed by western blot. Results WDR5 is overexpressed in colon tumors and colon cancer cell lines at the mRNA and protein level. WDR5 depletion reduces cell viability in HCT116, LoVo, RKO, HCT15, SW480, SW620, and T84 colon cancer cells. Inhibition of the WDR5:KMT2/MLL interaction using OICR-9429 reduces cell viability in the same panel of cell lines albeit not to the same extent as RNAi-mediated WDR5 depletion. WDR5 depletion reduced H3K4Me3 and increased phosphorylation of H2AX in HCT116, SW620, and RKO colon cancer cells; however, OICR-9429 treatment did not recapitulate these effects in all cell lines potentially explaining the reduced toxicity of OICR-9429 treatment as compared to WDR5 depletion. WDR5 depletion also sensitized colon cancer cells to radiation-induced DNA damage. Conclusions These data demonstrate a clear role for WDR5 in colon cancer and future studies should examine its potential to serve as a therapeutic target in cancer. Additional studies are needed to fully elucidate if the requirement for WDR5 is independent of or consistent with its role within the COMPASS complex. OICR-9429 treatment was particularly toxic to SW620 and T84 colon cancer cells, two cell lines without mutations in WDR5 and KMT2/MLL proteins suggesting COMPASS complex inhibition may be particularly effective in tumors lacking KMT2 mutations. Additionally, the ability of WDR5 depletion to amplify the toxic effects of radiation presents the possibility of targeting WDR5 to sensitize cells to DNA-damaging therapies.