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We investigated efficacy of in ovo application of epidermal growth factor (EGF) on intestinal expression of EGF receptor (EGFR) during embryogenesis (experiment 1) and posthatch growth performance and gastrointestinal development in broiler chickens (experiment 2). In experiment 1, 450 fertile Ross 708 eggs were allocated to 3 groups (150 eggs/group): 1) control, 2) 160 μg EGF/kg of egg, and 3) 640 μg of EGF/kg of egg. Eggs were candled for live embryos on day 16 and injected with the respective treatment solutions on day 17 and sampled for jejunal tissue from day 17 to hatch for EGFR analyses. There was no effect of EGF (P > 0.05) on EGFR expression on day 17 to 20; however, on day 21, EGF increased (P < 0.05) EGFR expression in EGF birds relative to control birds. In experiment 2, 600 fertile Ross 708 eggs were allocated to 5 treatments: 1) intact, no puncture or injection, 2) punched but not injected, 3) control, no EGF, 4) 80 μg of EGF/kg of egg, and 5) 160 μg of EGF/kg of egg. The eggs were incubated and candled for live embryos on D 19, treated, and subsequently transferred to the hatcher. Upon hatching, chicks were weighed, and 90 chicks per treatment placed in cages (15 birds/cage) and allowed free access to a standard antibiotic-free corn-soybean diet for 21 D. Feed intake and body weight were monitored on a weekly basis. Samples of birds were necropsied on D 0, 7, 14, and 21 for measurements of intestinal weight and jejunal histomorphology and excreta samples taken on D 3 to 5 and 17 to 19 for apparent retention of dry matter. There was no EGF effect (P > 0.05) on any posthatch response criteria. In conclusion, in ovo application of EGF increased EGFR expression but had no effect on posthatch growth performance, DM retention, and intestinal development. The lack of EGF effect on posthatch response was surprising but suggested in ovo application of EGF may not be a viable approach.

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.

Lung cancer mortality can be reduced by 20% via low dose CT lung cancer screening (LCS) and treatment of early-stage disease. Providing tobacco use treatment to high risk cigarette smokers in the LCS setting may result in health benefits beyond the impact of LCS. As one of the nine trials in the National Cancer Institute's Smoking Cessation at Lung Examination (SCALE) collaboration, the goal of the Lung Screening, Tobacco, and Health (LSTH) trial is to develop a scalable and cost-effective cessation intervention for subsequent implementation by LCS programs. Guided by the RE-AIM Framework, the LSTH trial is a two-arm RCT ( N = 1330) enrolling English- and Spanish-speaking smokers registered for LCS at one of seven collaborating sites. Participants are randomly assigned to Usual Care (UC; three proactive telephone counseling sessions/two weeks of nicotine patches) vs. Intensive Telephone Counseling (ITC; eight proactive sessions/eight weeks of nicotine patches, plus discussion of the LCS results to increase motivation to quit). Telephone counseling is provided by tobacco treatment specialists. To increase continuity of care, referring physicians are notified of participant enrollment and smoking status following the intervention. Outcomes include: 1) self-reported 7-day, 30-day, and sustained abstinence, and biochemically-verified at 3-, 6-, and 12-months post-randomization, 2) reach and engagement of the interventions, and 3) cost-effectiveness of the interventions. The Cancer Intervention and Surveillance Modeling Network (CISNET) will model long-term impacts of six SCALE trials on the cost per life year saved, quality-adjusted life years saved, lung cancer mortality reduction, and population mortality. Clinical trials registration The trial is registered at clinical trials.gov : NCT03200236 .

Prior research documents that analyst revisions are important information events and that some investors trade ahead of them. However, prior studies have been unable to show which investors trade ahead of analyst revisions, the aggregate benefits to trading ahead, and the costs borne by various investors from trading against investors that anticipate revisions. To address these questions, we exploit high-frequency trading information from the Korea Exchange (KRX) that characterizes all purchase and sale transactions of twenty different investor groups. We first validate that analyst revisions contain valuable private information: upgrades increase prices by 2.5% and downgrades decrease prices by 2.9%. We next document that asset managers who are geographically and socially close to analysts anticipate recommendations up to two days before they are released, while other institutions do not. Lastly, we show that this ability to anticipate analyst revisions enables these investors to trade profitably against domestic retail investors and foreign professional investors. Local hedge funds earn $2.5 million more than normal when trading against foreign professionals ahead of analyst revisions, which is more than all other investor groups combined. Notably, local asset managers typically lose money when trading against foreign professionals, who seem to earn profits by engaging in high-frequency market making. In sum, asset managers in Korea appear to receive tips from brokerages about upcoming revisions, which shifts the competitive balance between domestic institutions and skilled foreign market makers, and aggregate profits around revisions depend on investor sophistication, geographic proximity, and cultural affinity.

In July 2019, the Trump administration began implementing its domestic gag rule to ban discussion of abortion in pregnancy options counseling and ensure physical separation of contraceptive and abortion services at clinical sites funded by the federal government's Title X Family Planning program. In this paper, we examine how organizational policy utilization correlated with organization-level protocols for discussing abortion in options counseling interactions while the domestic gag rule policy was under legal contest. From April 2018 to July 2019, we conducted in-depth interviews with 50 administrators in charge of setting clinical protocols regarding options counseling after a positive pregnancy test at 20 Title X-covered and 14 non-Title X-covered safety-net healthcare organizations in Ohio. We found that organizational characteristics and Title X policy utilization did not explain the heterogeneity in approaches to abortion referral that administrators reported. Administrators from 2 of 20 organizations covered by Title X policy requirements pre-emptively restricted discussion of abortion in their facilities in advance of policy enactment. Meanwhile, administrators from 10 of 14 non-Title X-covered organizations did not restrict discussion of abortion. Our analysis demonstrates how safety-net healthcare organizations' response to federal policy is shaped by administrators' institutional entrepreneurship within the abortion aversion complex: a pattern of policy miscomprehension and endorsed abortion stigma that facilitates the structural stigmatization of abortion within safety-net healthcare organizations. We conclude that current efforts to reverse the domestic gag rule will fail unless local abortion aversion complexes are targeted with intervention.

Significance Although it is a requirement that tobacco treatment is offered to cigarette smokers undergoing low-dose computed tomographic lung cancer screening (LCS), not all smokers engage in treatment. To understand the barriers to tobacco treatment in this setting, we evaluated predictors of attrition in a smoking cessation trial among individuals undergoing LCS. Methods Prior to LCS, 926 participants, 50–80 years old, completed the baseline (T0) phone assessment, including demographic, clinical, tobacco, and psychological characteristics. Following LCS and receipt of the results, participants completed the pre-randomization (T1) assessment. Results At the T1 assessment, 735 (79%) participants were retained and 191 (21%) dropped out. In multivariable analyses, attrition was higher among those who: smoked >1 pack per day (OR = 1.44, CI 1.01, 2.06) or had undergone their first (vs. annual) LCS scan (OR = 1.70, CI 1.20, 2.42). Attrition was lower among those with: more education (associates (OR = 0.67, CI = 0.46, 0.98) or bachelor's degree (OR = 0.56, CI 0.35, 0.91) vs. high school/GED), some (vs. none/a little) worry about lung cancer (OR = 0.60, CI 0.39, 0.92), or a screening result that was benign (OR = 0.57, CI 0.39, 0.82) or probably benign (OR = 0.38, CI 0.16, 0.90) vs. negative. Conclusions This study illuminated several LCS-related factors that contributed to trial attrition. Increasing tobacco treatment in this setting will require targeted strategies for those who. report little lung cancer worry, are undergoing their first LCS exam, and/or who have a negative LCS result. Addressing attrition and reducing barriers to tobacco treatment will increase. the likelihood of cessation, thereby reducing the risk of developing lung cancer.

Study objective Cervical spine injuries in children are rare. However, immobilization and imaging for potential cervical spine injury after trauma are common and are associated with adverse effects. Risk factors for cervical spine injury have been developed to safely limit immobilization and radiography in adults, but not in children. The purpose of our study is to identify risk factors associated with cervical spine injury in children after blunt trauma. Methods We conducted a case-control study of children younger than 16 years, presenting after blunt trauma, and who received cervical spine radiographs at 17 hospitals in the Pediatric Emergency Care Applied Research Network (PECARN) between January 2000 and December 2004. Cases were children with cervical spine injury. We created 3 control groups of children free of cervical spine injury: (1) random controls, (2) age and mechanism of injury-matched controls, and (3) for cases receiving out-of-hospital emergency medical services (EMS), age-matched controls who also received EMS care. We abstracted data from 3 sources: PECARN hospital, referring hospital, and out-of-hospital patient records. We performed multiple logistic regression analyses to identify predictors of cervical spine injury and calculated the model's sensitivity and specificity. Results We reviewed 540 records of children with cervical spine injury and 1,060, 1,012, and 702 random, mechanism of injury, and EMS controls, respectively. In the analysis using random controls, we identified 8 factors associated with cervical spine injury: altered mental status, focal neurologic findings, neck pain, torticollis, substantial torso injury, conditions predisposing to cervical spine injury, diving, and high-risk motor vehicle crash. Having 1 or more factors was 98% (95% confidence interval 96% to 99%) sensitive and 26% (95% confidence interval 23% to 29%) specific for cervical spine injury. We identified similar risk factors in the other analyses. Conclusion We identified an 8-variable model for cervical spine injury in children after blunt trauma that warrants prospective refinement and validation.

The aim of the current study was to examine the association between psychopathic features and various forms of relationship aggression in a non-clinical population. Additionally, exposure to media aggression was examined as a potential mediator of the relationship between psychopathy and aggression. Participants consisted of a total of 337 individuals who either reported on their current or most recent relationship. Results revealed that secondary psychopathy traits were related to both types of aggression measured in the current study (physical aggression and romantic relational aggression). Additionally, primary psychopathy traits were related to romantic relational aggression. Though exposure to media aggression (both physical and relational forms) was related to perpetration of relationship aggression, such exposure did not mediate the relationship between psychopathy and aggression.

Regulators of G protein signaling (RGS) constitute a family of proteins with a conserved RGS domain of approximately 120 amino acids that accelerate the intrinsic GTP hydrolysis of activated Galpha(i) and Galpha(q) subunits. The phosphorylation-dependent interaction of 14-3-3 proteins with a subset of RGS proteins inhibits their GTPase-accelerating activity in vitro. The inhibitory interaction between 14-3-3 and RGS7 requires phosphorylation of serine 434 of RGS7. We now show that phosphorylation of serine 434 is dynamically regulated by TNF-alpha. Cellular stimulation by TNF-alpha transiently decreased the phosphorylation of serine 434 of RGS7, abrogating the inhibitory interaction with 14-3-3. We examined the effect of 14-3-3 on RGS-mediated deactivation kinetics of G protein-coupled inwardly rectifying K(+) channels (GIRKs) in Xenopus oocytes. 14-3-3 inhibited the function of wild-type RGS7, but not that of either RSG7(P436R) or RGS4, two proteins that do not bind 14-3-3. Our findings are the first evidence that extracellular signals can modulate the activity of RGS proteins by regulating their interaction with 14-3-3.

Two distinct signaling pathways, involving Wnt signaling and polycystin, have been found to be critical for normal kidney development. Renal tubulogenesis requires the presence of certain Wnt proteins, whereas mutations in polycystin impede the terminal differentiation of renal tubular epithelial cells, causing the development of large cystic kidneys that characterize autosomal dominant polycystic kidney disease. Polycystin is an integral membrane protein, consisting of several extracellular motifs indicative of cell-cell and cell-matrix interactions, coupled through multiple transmembrane domains to a functionally active cytoplasmic domain. We report here that expression of the C-terminal cytoplasmic domain of polycystin stabilizes soluble endogenous β-catenin and stimulates TCF- dependent gene transcription in human embryonic kidney cells. Microinjection of the polycystin C-terminal cytoplasmic domain induces dorsalization in zebrafish. Our findings suggest that polycystin has the capacity to modulate Wnt signaling during renal development.

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder that accounts for 8-10% of end stage renal disease. PKD1, one of two recently isolated ADPKD gene products, has been implicated in cell-cell and cell-matrix interactions. However, the signaling pathway of PKD1 remains undefined. We found that the C-terminal 226 amino acids of PKD1 transactivate an AP-1 promoter construct in human embryonic kidney cells (293T). PKD1-induced transcription is specific for AP-1; promoter constructs containing cAMP response element-binding protein, c-Fos, c-Myc, or NFkappaB-binding sites are unaffected by PKD1. In vitro kinase assays revealed that PKD1 triggers the activation of c-Jun N-terminal kinase (JNK), but not of mitogen-activated protein kinases p38 or p44. Dominant-negative Rac-1 and Cdc42 mutations abrogated PKD1-mediated JNK and AP-1 activation, suggesting a critical role for small GTP-binding proteins in PKD1-mediated signaling. Several protein kinase C (PKC) inhibitors decreased PKD1-mediated AP-1 activation. Conversely, expression of the C-terminal domain of PKD1 increased PKC activity in 293T cells. A dominant-negative PKC alpha, but not a dominant-negative PKC beta or delta, abrogated PKD1-mediated AP-1 activation. These findings indicate that small GTP-binding proteins and PKC alpha mediate PKD1-induced JNK/AP-1 activation, together comprising a signaling cascade that may regulate renal tubulogenesis.