Miracle-dz/UniFAR-FTUs huggingface dataset:
The Safe Start Initiative: Building and Disseminating Knowledge to Support Children Exposed to Violence

ABSTRACT The Safe Start Initiative promotes community investment in evidence-based strategies for preventing and reducing children's exposure to violence in the home and the community. This article describes the implementation of practice innovation in 26 communities across the United States and provides information on the national research, evaluation, training, and technical assistance, resource development, and broad dissemination components of the initiative. Evaluation of the initiative is expanding the knowledge of the elements needed to implement comprehensive service delivery systems and improve access to, delivery of, and quality of services both for children at high risk of being exposed to violence and for those who have already been exposed.
A Feasibility Study of Women's Confidence and Comfort in Use of a Kit to Monitor Ovulation.

INTRODUCTION The focus of this study was to examine whether low-income adult women will use ovulation test strips, a menstrual calendar chart, thermometer, temperature graph, and cervical mucus assessment to monitor their ovulation time and other menstrual changes. Women's confidence in their ability to detect ovulation time and understand the menstrual cycle changes were also examined. METHODS This is a descriptive study. Twenty-two low-income women aged 18 to 39 years living in medically underserved neighborhoods participated in this study. The women were introduced to and taught how to use a knowing your body (KB) kit, which consisted of ovulation test strips, monthly calendars for menstrual logs, digital thermometer for basal body temperature, and graphs to chart temperature. The women were interviewed 6 to 8 weeks later to confirm their experiences with the use of the KB kit. RESULTS Ninety-one percent of the women used the ovulation test strips (mean, 3.8 strips); 77.3% were very to extremely confident that they could properly use the ovulation strip, 54.6% knew when they ovulated, and 31.8% could use the thermometer to confirm when they were ovulating. Seventy-three percent of the women were very to extremely comfortable using the ovulation test strips, 81.8% using the thermometer, 45.5% using the temperature graph, and 31.8% using the TwoDay Method (cervical mucus observation). DISCUSSION The use of the ovulation test strip and other content of the KB kit provides a new opportunity for low-income women to learn about their bodies by monitoring their ovulation time and other menstrual changes as a pregnancy planning and early pregnancy recognition tool.
Systematic Outcomes Research for Corrections-Based Treatment: Implications from the Criminal Justice Kentucky Treatment Outcome Study

Over the last four years, the Kentucky correctional system has expanded corrections-based modified therapeutic community treatment from 6 programs to 24 programs. To examine the effectiveness of these programs, the state initiated a systematic treatment outcome study known as the Criminal Justice Kentucky Treatment Outcome Study (CJKTOS). The approach involves corrections-based counselors using personal digital assistants (PDAs) to collect and enter clinical assessment data for the baseline. Follow-up interviews 12 months postrelease from incarceration are conducted by a university research team with a stratified random sample of treatment program participants. This article describes the innovative systematic data collection approach for evaluating corrections-based substance abuse treatment currently being used in Kentucky, as well as treatment outcome data for 700 offenders who completed prison or jail-based treatment one year after release using this data collection approach. Findings indicate that the percentage of jail and prison treatment participants reporting any substance use following release from custody was significantly lower at follow-up (43.9%) compared to baseline (94.1%). In addition, there were few differences in substance use at follow-up between offenders who participated in community aftercare compared to those who did not, but those offenders who participated in treatment had reduced rates of recidivism at one-year postrelease. These data suggest positive outcomes from Kentucky corrections-based substance abuse treatment, and provide implications for the importance of a systematic data collection approach to evaluate correctional treatment programs.
Importance of cholesterol in dopamine transporter function

The conformation and function of the dopamine transporter (DAT) can be affected by manipulating membrane cholesterol, yet there is no agreement as to the impact of cholesterol on the activity of lipid‐raft localized DATs compared with non‐raft DATs. Given the paucity of information regarding the impact of cholesterol on substrate efflux by the DAT, this study explores its influence on the kinetics of DAT‐mediated DA efflux induced by dextroamphetamine, as measured by rotating disk electrode voltammetry (RDEV). Treatment with methyl‐β‐cyclodextrin (mβCD), which effectively depletes total membrane cholesterol––uniformly affecting cholesterol–DAT interactions in both raft and non‐raft membrane domains––reduced both DA uptake and efflux rate. In contrast, disruption of raft‐localized DAT by cholesterol chelation with nystatin had no effect, arguing against a vital role for raft‐localized DAT in substrate uptake or efflux. Supranormal repletion of cholesterol‐depleted cells with the analog desmosterol, a non‐raft promoting sterol, was as effective as cholesterol itself in restoring transport rates. Further studies with Zn2+ and the conformationally biased W84L DAT mutant supported the idea that cholesterol is important for maintaining the outward‐facing DAT with normal rates of conformational interconversions. Collectively, these results point to a role for direct cholesterol–DAT interactions in regulating DAT function.
Development of NMR spectroscopic methods for dynamic detection of acetylcholine synthesis by choline acetyltransferase in hippocampal tissue

Choline acetyltransferase (ChAT) is the key enzyme for acetylcholine (ACh) synthesis and constitutes a reliable marker for the integrity of cholinergic neurons. Cortical ChAT activity is decreased in the brain of patients suffering from Alzheimer's and Parkinson's diseases. The standard method used to measure the activity of ChAT enzyme relies on a very sensitive radiometric assay, but can only be performed on post‐mortem tissue samples. Here, we demonstrate the possibility to monitor ACh synthesis in rat brain homogenates in real time using NMR spectroscopy. First, the experimental conditions of the radiometric assay were carefully adjusted to produce maximum ACh levels. This was important for translating the assay to NMR, which has a low intrinsic sensitivity. We then used 15N‐choline and a pulse sequence designed to filter proton polarization by nitrogen coupling before 1H‐NMR detection. ACh signal was resolved from choline signal and therefore it was possible to monitor ChAT‐mediated ACh synthesis selectively over time. We propose that the present approach using a labeled precursor to monitor the enzymatic synthesis of ACh in rat brain homogenates through real‐time NMR represents a useful tool to detect neurotransmitter synthesis. This method may be adapted to assess the state of the cholinergic system in the brain in vivo in a non‐invasive manner using NMR spectroscopic techniques.
Involvement of gangliosides in the process of Cbp/PAG phosphorylation by Lyn in developing cerebellar growth cones

The association of gangliosides with specific proteins in the central nervous system was examined by coimmunoprecipitation with an anti‐ganglioside antibody. The monoclonal antibody to the ganglioside GD3 (R24) immunoprecipitated the Csk (C‐terminal src kinase)‐binding protein (Cbp). Sucrose density gradient analysis showed that Cbp of rat cerebellum was detected in detergent‐resistant membrane (DRM) raft fractions. R24 treatment of the rat primary cerebellar cultures induced Lyn activation and tyrosine phosphorylation of Cbp. Treatment with anti‐ganglioside GD1b antibody also induced tyrosine phosphorylation. Furthermore, over‐expressions of Lyn and Cbp in Chinese hamster ovary (CHO) cells resulted in tyrosine 314 phosphorylation of Cbp, which indicates that Cbp is a substrate for Lyn. Immunoblotting analysis showed that the active form of Lyn and the Tyr314‐phosphorylated form of Cbp were highly accumulated in the DRM raft fraction prepared from the developing cerebellum compared with the DRM raft fraction of the adult one. In addition, Lyn and the Tyr314‐phosphorylated Cbp were highly concentrated in the growth cone fraction prepared from the developing cerebellum. Immunoelectron microscopy showed that Cbp and GAP‐43, a growth cone marker, are localized in the same vesicles of the growth cone fraction. These results suggest that Cbp functionally associates with gangliosides on growth cone rafts in developing cerebella.
Profiling two indole‐2‐carboxamides for allosteric modulation of the CB1 receptor

Allosteric modulation of G‐protein coupled receptors (GPCRs) represents a novel approach for fine‐tuning GPCR functions. The cannabinoid CB1 receptor, a GPCR associated with the CNS, has been implicated in the treatment of drug addiction, pain, and appetite disorders. We report here the synthesis and pharmacological characterization of two indole‐2‐carboxamides:5‐chloro‐3‐ethyl‐1‐methyl‐N‐(4‐(piperidin‐1‐yl)phenethyl)‐1H‐indole‐2‐carboxamide (ICAM‐a) and 5‐chloro‐3‐pentyl‐N‐(4‐(piperidin‐1‐yl)phenethyl)‐1H‐indole‐2‐carboxamide (ICAM‐b). Although both ICAM‐a and ICAM‐b enhanced CP55, 940 binding, ICAM‐b exhibited the strongest positive cooperativity thus far demonstrated for enhancing agonist binding to the CB1 receptor. Although it displayed negative modulatory effects on G‐protein coupling to CB1, ICAM‐b induced β‐arrestin‐mediated downstream activation of extracellular signal‐regulated kinase (ERK) signaling. These results indicate that this compound represents a novel class of CB1 ligands that produce biased signaling via CB1.
Utility of Intraoperative Cystoscopy in Detecting Ureteral Injury During Vaginal Hysterectomy

Objectives The aim of this study was to determine the utility of intraoperative cystoscopy in detecting and managing ureteral injury among women undergoing vaginal hysterectomy. Methods We performed a secondary analysis of a retrospective cohort study of 593 patients who underwent vaginal hysterectomy for benign indications, with or without additional pelvic floor reconstructive surgery, from January 2, 2004, through December 30, 2005. A logistic regression model determining the propensity to undergo intraoperative cystoscopy was constructed. Comparisons of ureteral injury and cost between patients with and without cystoscopy were adjusted for the cystoscopy propensity score. We further explored the feasibility of using perioperative change in creatinine level to detect ureteral injury. Results In total, 230 (38.8%) of 593 patients underwent cystoscopy. Six patients (2.6%) in the cystoscopy group and 5 (1.4%) in the no-cystoscopy group had ureteral injuries (odds ratio, 1.92; 95% confidence interval [CI], 0.58–6.36). This association was further attenuated after adjusting for the propensity to undergo cystoscopy (odds ratio, 1.31; 95% CI, 0.19–9.09). Four injuries detected cystoscopically were managed intraoperatively. Adjusted mean-predicted costs for patients undergoing cystoscopy were $10,686 (95% CI, $7500–$13,872) versus $10,217 (95% CI, $6894–$13,540). In the no-cystoscopy group, patients with ureteral injury had a median increase in creatinine level of 0.2 mg/dL, whereas patients without injury had a median decrease of 0.1 mg/dL (P < 0.001). Conclusions The level of selection for cystoscopy did not significantly increase the mean predicted costs for patients. Reliance on postoperative creatinine level to detect ureteral injury, while highly sensitive, is limited by a low positive predictive value and variable range.
The α‐subunit of the trimeric GTPase Go2 regulates axonal growth

The Goα splice variants Go1α and Go2α are subunits of the most abundant G‐proteins in brain, Go1 and Go2. Only a few interacting partners binding to Go1α have been described so far and splice variant‐specific differences are not known. Using a yeast two‐hybrid screen with constitutively active Go2α as bait, we identified Rap1GTPase activating protein (Rap1GAP) and Girdin as interacting partners of Go2α, which was confirmed by co‐immunoprecipitation. Comparison of subcellular fractions from brains of wild type and Go2α−/− mice revealed no differences in the overall expression level of Girdin or Rap1GAP. However, we found higher amounts of active Rap1‐GTP in brains of Go2α deficient mutants, indicating that Go2α may increase Rap1GAP activity, thereby effecting the Rap1 activation/deactivation cycle. Rap1 has been shown to be involved in neurite outgrowth and given a Rap1GAP‐Go2α interaction, we found that the loss of Go2α affected axonal outgrowth. Axons of cultured cortical and hippocampal neurons prepared from embryonic Go2α−/− mice grew longer and developed more branches than those from wild‐type mice. Taken together, we provide evidence that Go2α regulates axonal outgrowth and branching.
Exploring the radiosynthesis and in vitro characteristics of [68 Ga]Ga-DOTA-Siglec-9.

Vascular adhesion protein 1 is a leukocyte homing-associated glycoprotein, which upon inflammation rapidly translocates from intracellular sources to the endothelial cell surface. It has been discovered that the cyclic peptide residues 283-297 of sialic acid-binding IgG-like lectin 9 (Siglec-9) "CARLSLSWRGLTLCPSK" bind to vascular adhesion protein 1 and hence makes the radioactive analogues of this compound ([68 Ga]Ga-DOTA-Siglec-9) interesting as a noninvasive visualizing marker of inflammation. Three different approaches to the radiosynthesis of [68 Ga]Ga-DOTA-Siglec-9 are presented and compared with previously published methods. A simple, robust radiosynthesis of [68 Ga]Ga-DOTA-Siglec-9 with a yield of 62% (non decay-corrected) was identified, and it had a radiochemical purity >98% and a specific radioactivity of 35 MBq/nmol. Furthermore, the protein binding and stability of [68 Ga]Ga-DOTA-Siglec-9 were analyzed in vitro in mouse, rat, rabbit, pig, and human plasma and compared with in vivo pig results. The plasma in vitro protein binding of [68 Ga]Ga-DOTA-Siglec-9 was the lowest in the pig followed by rabbit, human, rat, and mouse. It was considerably higher in the in vivo pig experiments. The in vivo stability in pigs was lower than the in vitro stability. Despite considerable species differences, the observed characteristics of [68 Ga]Ga-DOTA-Siglec-9 are suitable as a positron emission tomography tracer.
Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia‐induced oxidative stress and cognitive deficits in mouse

Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI‐34 attenuates IH‐induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8‐hydroxydeoxyguanosine, and increases in hypoxia inducible factor‐1α DNA binding and up‐regulation of insulin growth factor‐1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA‐602) during intermittent hypoxia did not affect any of the IH‐induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH‐vulnerable brain regions from OSA‐associated neurocognitive dysfunction.
Estrogen receptor‐β regulates human tryptophan hydroxylase‐2 through an estrogen response element in the 5′ untranslated region

In the dorsal raphe nucleus, 17β‐estradiol (E2) increases the expression of the brain‐specific, rate‐limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase‐2 (Tph2). Although estrogen receptor beta (ERβ) has been localized to Tph2 neurons, little is known about the transcriptional regulation of the Tph2 gene by estrogen. Since the ERβ agonist, diarylpropionitrile (DPN) also increases Tph2 expression, we tested the hypothesis that E2 regulates the Tph2 promoter through direct interactions with ERβ. A serotonergic cell line, B14, which endogenously expresses ERβ was transiently transfected with a fragment of the human TPH2 5′‐untranslated region (5′‐UTR) cloned into a luciferase reporter vector (TPH2‐luc). Treatment with E2 or DPN caused a dose‐dependent increase of TPH2‐luc activity. In contrast, E2 conjugated to bovine serum albumin, which is cell membrane impermeable, had no effect on TPH2‐luc activity. An estrogen receptor (ER) antagonist blocked E2 or DPN‐induced TPH2‐luc activity suggesting a classical ER mechanism. In silico analysis revealed an estrogen‐response element (ERE) half‐site located within the TPH2 5′‐UTR. Deletion and site‐directed mutation of this site abolished ligand‐induced TPH2‐luc activity. These results support the concept that there is a direct and functional interaction between E2:ERβ and the ERE half‐site of the TPH2 promoter to regulate Tph2 expression.
Metabolic products of [2‐13C]ethanol in the rat brain after chronic ethanol exposure

Most ingested ethanol is metabolized in the liver to acetaldehyde and then to acetate, which can be oxidized by the brain. This project assessed whether chronic exposure to alcohol can increase cerebral oxidation of acetate. Through metabolism, acetate may contribute to long‐term adaptation to drinking. Two groups of adult male Sprague–Dawley rats were studied, one treated with ethanol vapor and the other given room air. After 3 weeks the rats received an intravenous infusion of [2‐13C]ethanol via a lateral tail vein for 2 h. As the liver converts ethanol to [2‐13C]acetate, some of the acetate enters the brain. Through oxidation the 13C is incorporated into the metabolic intermediate α‐ketoglutarate, which is converted to glutamate (Glu), glutamine (Gln), and GABA. These were observed by magnetic resonance spectroscopy and found to be 13C‐labeled primarily through the consumption of ethanol‐derived acetate. Brain Gln, Glu, and, GABA 13C enrichments, normalized to 13C‐acetate enrichments in the plasma, were higher in the chronically treated rats than in the ethanol‐naïve rats, suggesting increased cerebral uptake and oxidation of circulating acetate. Chronic ethanol exposure increased incorporation of systemically derived acetate into brain Gln, Glu, and GABA, key neurochemicals linked to brain energy metabolism and neurotransmission.
HIV increases the release of dickkopf‐1 protein from human astrocytes by a Cx43 hemichannel‐dependent mechanism

Human immunodeficiency virus‐1 (HIV) is a public health issue and a major complication of the disease is NeuroAIDS. In vivo, microglia/macrophages are the main cells infected. However, a low but significant number of HIV‐infected astrocytes has also been detected, but their role in the pathogenesis of NeuroAIDS is not well understood. Our previous data indicate that gap junction channels amplify toxicity from few HIV‐infected into uninfected astrocytes. Now, we demonstrated that HIV infection of astrocytes results in the opening of connexin43 hemichannels (HCs). HIV‐induced opening of connexin43 HCs resulted in dysregulated secretion of dickkopf‐1 protein (DKK1, a soluble wnt pathway inhibitor). Treatment of mixed cultures of neurons and astrocytes with DKK1, in the absence of HIV infection, resulted in the collapse of neuronal processes. HIV infection of mixed cultures of human neurons and astrocytes also resulted in the collapse of neuronal processes through a DKK1‐dependent mechanism. In addition, dysregulated DKK1 expression in astrocytes was observed in human brain tissue sections of individuals with HIV encephalitis as compared to tissue sections from uninfected individuals. Thus, we demonstrated that HIV infection of astrocytes induces dysregulation of DKK1 by a HC‐dependent mechanism that contributes to the brain pathogenesis observed in HIV‐infected individuals.
Rac1‐mediated indentation of resting neurons promotes the chain migration of new neurons in the rostral migratory stream of post‐natal mouse brain

New neurons generated in the ventricular‐subventricular zone in the post‐natal brain travel toward the olfactory bulb by using a collective cell migration process called ‘chain migration. ’ These new neurons show a saltatory movement of their soma, suggesting that each neuron cycles through periods of ‘rest’ during migration. Here, we investigated the role of the resting neurons in chain migration using post‐natal mouse brain, and found that they undergo a dynamic morphological change, in which a deep indentation forms in the cell body. Inhibition of Rac1 activity resulted in less indentation of the new neurons in vivo. Live cell imaging using a Förster resonance energy transfer biosensor revealed that Rac1 was activated at the sites of contact between actively migrating and resting new neurons. On the cell surface of resting neurons, Rac1 activation coincided with the formation of the indentation. Furthermore, Rac1 knockdown prevented the indentation from forming and impaired migration along the resting neurons. These results suggest that Rac1 regulates a morphological change in the resting neurons, which allows them to serve as a migratory scaffold, and thereby non‐cell‐autonomously promotes chain migration.
Neuroprotective and symptomatic effects of targeting group III mGlu receptors in neurodegenerative disease

Neurodegenerative disorders possess common pathological mechanisms, such as protein aggregation, inflammation, oxidative stress (OS) and excitotoxicity, raising the possibility of shared therapeutic targets. As a result of the selective cellular and regional expression of group III metabotropic glutamate (mGlu) receptors, drugs targeting such receptors have demonstrated both neuroprotective properties and symptomatic improvements in several models of neurodegeneration. In recent years, the discovery and development of subtype‐selective ligands for the group III mGlu receptors has gained pace, allowing further research into the functions of these receptors and revealing their roles in health and disease. Activation of this class of receptors results in neuroprotection, with a variety of underlying mechanisms implicated. Group III mGlu receptor stimulation prevents excitotoxicity by inhibiting glutamate release from neurons and microglia and increasing glutamate uptake by astrocytes. It also attenuates the neuroinflammatory response by reducing glial reactivity and encourages neurotrophic phenotypes. This article will review the current literature with regard to the neuroprotective and symptomatic effects of group III mGlu receptor activation and discuss their promise as therapeutic targets in neurodegenerative disease.