A modern scleractinian coral with a two-component calcite-aragonite skeleton.

One of the most conserved traits in the evolution of biomineralizing organisms is the taxon-specific selection of skeletal minerals. All modern scleractinian corals are thought to produce skeletons exclusively of the calcium-carbonate polymorph aragonite. Despite strong fluctuations in ocean chemistry (notably the Mg/Ca ratio), this feature is believed to be conserved throughout the coral fossil record, spanning more than 240 million years. Only one example, the Cretaceous scleractinian coral Coelosmilia (ca. 70 to 65 Ma), is thought to have produced a calcitic skeleton. Here, we report that the modern asymbiotic scleractinian coral Paraconotrochus antarcticus living in the Southern Ocean forms a two-component carbonate skeleton, with an inner structure made of high-Mg calcite and an outer structure composed of aragonite. P. antarcticus and Cretaceous Coelosmilia skeletons share a unique microstructure indicating a close phylogenetic relationship, consistent with the early divergence of P. antarcticus within the Vacatina (i.e., Robusta) clade, estimated to have occurred in the Mesozoic (ca. 116 Mya). Scleractinian corals thus join the group of marine organisms capable of forming bimineralic structures, which requires a highly controlled biomineralization mechanism; this capability dates back at least 100 My. Due to its relatively prolonged isolation, the Southern Ocean stands out as a repository for extant marine organisms with ancient traits.

Bamboozled! Resolving deep evolutionary nodes within the phylogeny of bamboo corals (Octocorallia: Scleralcyonacea: Keratoisididae).

Keratoisididae is a globally distributed, and exclusively deep-sea, family of octocorals that contains species and genera that are polyphyletic. An alphanumeric system, based on a three-gene-region phylogeny, is widely used to describe the biodiversity within this family. That phylogeny identified 12 major groups although it did not have enough signal to explore the relationships among groups. Using increased phylogenomic resolution generated from Ultraconserved Elements and exons (i.e. conserved elements), we aim to resolve deeper nodes within the family and investigate the relationships among those predefined groups. In total, 109 libraries of conserved elements were generated from individuals representing both the genetic and morphological diversity of our keratoisidids. In addition, the conserved element data of 12 individuals from previous studies were included. Our taxon sampling included 11 of the 12 keratoisidid groups. We present two phylogenies, constructed from a 75% (231 loci) and 50% (1729 loci) taxon occupancy matrix respectively, using both Maximum Likelihood and Multiple Species Coalescence methods. These trees were congruent at deep nodes. As expected, S1 keratoisidids were recovered as a well-supported sister clade to the rest of the bamboo corals. S1 corals do not share the same mitochondrial gene arrangement found in other members of Keratoisididae. All other bamboo corals were recovered within two major clades. Clade I comprises individuals assigned to alphanumeric groups B1, C1, D1&D2, F1, H1, I4, and J3 while Clade II contains representatives from A1, I1, and M1. By combining genomics with already published morphological data, we provide evidence that group H1 is not monophyletic, and that the division between other groups - D1 and D2, and A1 and M1 - needs to be reconsidered. Overall, there is a lack of robust morphological markers within Keratoisididae, but subtle characters such as sclerite microstructure and ornamentation seem to be shared within groups and warrant further investigation as taxonomically diagnostic characters.

Preparation and Activity of Hemostatic and Antibacterial Dressings with Greige Cotton/Zeolite Formularies Having Silver and Ascorbic Acid Finishes.

The need for prehospital hemostatic dressings that exert an antibacterial effect is of interest for prolonged field care. Here, we consider a series of antibacterial and zeolite formulary treatment approaches applied to a cotton-based dressing. The design of the fabric formulations was based on the hemostatic dressing TACGauze with zeolite Y incorporated as a procoagulant with calcium and pectin to facilitate fiber adherence utilizing silver nanoparticles, and cellulose-crosslinked ascorbic acid to confer antibacterial activity. Infra-red spectra were employed to characterize the chemical modifications on the dressings. Contact angle measurements were employed to document the surface hydrophobicity of the cotton fabric which plays a role in the contact activation of the coagulation cascade. Ammonium Y zeolite-treated dressings initiated fibrin equal to the accepted standard hemorrhage control dressing and showed similar improvement with antibacterial finishes. The antibacterial activity of cotton-based technology utilizing both citrate-linked ascorbate-cellulose conjugate analogs and silver nanoparticle-embedded cotton fibers was observed against Staphylococcus aureus and Klebsiella pneumoniae at a level of 99.99 percent in the AATCC 100 assay. The hydrogen peroxide levels of the ascorbic acid-based fabrics, measured over a time period from zero up to forty-eight hours, were in line with the antibacterial activities.

Design and Synthesis of D3R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies.

A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D3R-selective compound. The effect of the flexible linker ((R,S)-trans-2a-d), SBFs ((R,S)-trans-2h-j), and the chirality of orthosteric binding fragments (OBFs) ((S,R)-trans-d, (S,R)-trans-i, (S,S)-trans-d, (S,S)-trans-i, (R,R)-trans-d, and (R,R)-trans-i) were evaluated in in vitro binding assays. Computational chemistry studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP1103.32 of the D3R, thereby reducing the D3R affinity to a suboptimal level.

Avian behaviour changes in response to human activity during the COVID-19 lockdown in the United Kingdom.

Human activities may impact animal habitat and resource use, potentially influencing contemporary evolution in animals. In the United Kingdom, COVID-19 lockdown restrictions resulted in sudden, drastic alterations to human activity. We hypothesized that short-term daily and long-term seasonal changes in human mobility might result in changes in bird habitat use, depending on the mobility type (home, parks and grocery) and extent of change. Using Google human mobility data and 872 850 bird observations, we determined that during lockdown, human mobility changes resulted in altered habitat use in 80% (20/25) of our focal bird species. When humans spent more time at home, over half of affected species had lower counts, perhaps resulting from the disturbance of birds in garden habitats. Bird counts of some species (e.g. rooks and gulls) increased over the short term as humans spent more time at parks, possibly due to human-sourced food resources (e.g. picnic refuse), while counts of other species (e.g. tits and sparrows) decreased. All affected species increased counts when humans spent less time at grocery services. Avian species rapidly adjusted to the novel environmental conditions and demonstrated behavioural plasticity, but with diverse responses, reflecting the different interactions and pressures caused by human activity.

An assessment of people living by coral reefs over space and time.

Human populations near ecosystems are used as both a proxy for dependency on ecosystems, and conversely to estimate threats. Consequently, the number of people living near coral reefs is often used in regional coral reef management, evaluation of risk at regional and global scales, and even considerations of funding needs. Human populations and their statistics, are ever-changing and data relating to coral reefs have not been updated regularly. Here, we present an up-to-date analysis of the abundance, and density of people living within 5-100 km of coral reef ecosystems along with population proportion, using freely available data sets and replicable methods. We present trends of changes in human populations living near coral reefs over a 20-year time period (2000-2020), divided by region and country, along with socio-economic denominations such as country income category and Small Island Developing States (SIDS). We find that across 117 coral reef countries there are currently close to a billion people living within 100 km of a coral reef (~13% of the global population) compared with 762 million people in 2000. Population growth by coral reefs is higher than global averages. The Indian Ocean saw a 33% increase in populations within 100 km of a coral reef and 71% at 5 km. There are 60 countries with 100% of their population within 100 km of coral reefs. In SIDS, the proportion of the total population within 100 km of a coral reef is extremely high: 94% in 2020. Population density 5-10 km from coral reefs is 4× the global average. From 5 to 100 km, more people from lower-middle-income countries live by coral reefs than any other income category. Our findings provide the most up-to-date and extensive statistics on the regional and nation-level differences in population trends that play a large role in coral reef health and survival.

Design of an individualised questionnaire to measure the impact of cancer on quality of life: The cancer dependent quality of life (CancerDQoL) questionnaire.

AIM: To design an individualised questionnaire to measure the impact of cancer and its treatments on quality of life (QoL). MATERIALS & METHODS: Design of the Cancer-Dependent Quality of Life (CancerDQoL) questionnaire was based on the Audit of Diabetes Dependent QoL (ADDQoL) questionnaire and related -DQoLs for other conditions. Item selection, face validity and content validity were established through clinician and patient ratings of the importance and relevance of 60 domains from the -DQoL Item Library, and semi-structured interviews with 25 English-speaking participants with a range of cancers attending a cancer centre in Zimbabwe (age range: 25-78 years; 16 women, 9 men). Ten interviews were subsequently conducted with UK English-speaking participants with a range of cancers attending Maggie's Centres in London and Dundee (age range: 40-76; 5 women, 5 men) to adapt the CancerDQoL for UK use. RESULTS: The first draft of the CancerDQoL contained 25 domain-specific items from the -DQoL Item Library plus four overview items. Zimbabwean participants indicated that cancer negatively impacted on all life domains included, except 'having children'. Weighted impact (impact ratings multiplied by importance) was most negative for 'sex life', 'depend on others' and 'physical capability'. The least negative weighted impact was found for 'having children', 'spiritual/religious life' and 'past medical/self-care'. UK interviews confirmed no new items were required. CONCLUSIONS: Face and content validity of the CancerDQoL is established for an adult sample of English-speaking cancer patients in Zimbabwe and confirmed in an adaptation following UK interviews.

Impact of the naloxone standing order on trends in opioid fatal overdose: an ecological analysis.

Background: Maryland expanded its "Statewide Naloxone Standing Order" (NSO) in 2017 to eliminate training and prescription requirements for obtaining naloxone, improve naloxone access, help reverse opioid overdose, and reduce overdose fatality rates.Objectives: To assess the change in the trends of fatal opioid overdose rates following the expansion of the Naloxone Standing Order (eNSO) and its association with the social determinants of health (SDoH).Methods: Data on overdose deaths and SDoH from 2015-2019 was collected and analyzed using interrupted time series and multivariate Poisson regression models to study the change in trends and the associations.Results: There was a significant decrease in the rate of fatal overdoses after the intervention: prescription opioid estimate number of deaths declined by .25 per 100,000 (p = .02), heroin estimate number of deaths declined by 1.83 per 100,000 (p < .001), fentanyl estimate number of deaths declined by 2.54 per 100,000 (p < .001). After controlling for eNOS implementation in Maryland, state-level estimates with high proportions of female residents and those with bachelor's degree or higher were associated with reduction in overdose, while state-level estimates with high proportions of African Americans and higher employment rates were associated with an increase in overdose.Conclusions: Our analysis shows that the expanded naloxone standing order is associated with reducing opioid-related overdose death rates. Even though we observed a significant reduction in overdose death rate in fentanyl-related deaths, the rate of deaths post-eNSO was still increasing, suggesting the need for additional measures to impact the rates of fentanyl.

Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D3-Selective Antagonists.

Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3 receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3 receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D2 receptor ranging from 22- to 180-fold. The ß-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50 = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D3 receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3 receptors and TSPO. The results of this study revealed that a new class of selective D3 receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.

Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration. Herein, we examined post-mortem MS retinas, and then used a mouse model, experimental autoimmune encephalomyelitis (EAE), to examine the role of C3 in the pathogenesis of RGC loss associated with optic neuritis. First, we show extensive C3 expression in astrocytes (C3+/GFAP+ cells) and significant RGC loss (RBPMS+ cells) in post-mortem retinas from people with MS compared to retinas from non-MS individuals. A patient with progressive MS with a remote history of optic neuritis showed marked reactive astrogliosis with C3 expression in the inner retina extending into deeper layers in the affected eye more than the unaffected eye. To study whether C3 mediates retinal degeneration, we utilized global C3-/- EAE mice and found that they had less RGC loss and partially preserved neurites in the retina compared with C3+/+ EAE mice. C3-/- EAE mice had fewer axonal swellings in the optic nerve, reflecting reduced axonal injury, but had no changes in demyelination or T cell infiltration into the CNS. Using a C3-tdTomato reporter mouse line, we show definitive evidence of C3 expression in astrocytes in the retina and optic nerves of EAE mice. Conditional deletion of C3 in astrocytes showed RGC protection replicating the effects seen in the global knockouts. These data implicate astrocyte C3 expression as a critical mediator of retinal neuronal pathology in EAE and MS, and are consistent with recent studies showing C3 gene variants are associated with faster rates of retinal neurodegeneration in human disease.

Factors Governing Selectivity of Dopamine Receptor Binding Compounds for D2R and D3R Subtypes.

Targeting the D3 dopamine receptor (D3R) is a promising pharmacotherapeutic strategy for the treatment of many disorders. The structure of the D3R is similar to the D2 dopamine receptor (D2R), especially in the transmembrane spanning regions that form the orthosteric binding site, making it difficult to identify D3R selective pharmacotherapeutic agents. Here, we examine the molecular basis for the high affinity D3R binding and D3R vs D2R binding selectivity of substituted phenylpiperazine thiopheneamides. We show that removing the thiophenearylamide portion of the ligand consistently decreases the affinity of these ligands at D3R, while not affecting their affinity at the D2R. Our long (>10 µs) molecular dynamics simulations demonstrated that both dopamine receptor subtypes adopt two major conformations that we refer to as closed or open conformations, with D3R sampling the open conformation more frequently than D2R. The binding of ligands with conjoined orthosteric-allosteric binding moieties causes the closed conformation to populate more often in the trajectories. Also, significant differences were observed in the extracellular loops (ECL) of these two receptor subtypes leading to the identification of several residues that contribute differently to the ligand binding for the two receptors that could potentially contribute to ligand binding selectivity. Our observations also suggest that the displacement of ordered water in the binding pocket of D3R contributes to the affinity of the compounds containing an allosteric binding motif. These studies provide a better understanding of how a bitopic mode of engagement can determine ligands that bind selectively to D2 and D3 dopamine receptor subtypes.

Young adults with epilepsy: Relationships between psychosocial variables and anxiety, depression, and suicidality.

BACKGROUND: People with epilepsy (PWE) are at an increased risk of anxiety, depression, and suicidality. Young adulthood is a critical developmental period which can be complicated by the unique challenges of having epilepsy. The risk factors of mental health difficulties in young adults with epilepsy (YAWE) have not been investigated. AIMS: To examine the relationships between psychosocial variables (coping strategies and sources of social support) and mental health outcomes in YAWE, and determine whether these psychosocial variables independently predict mental health outcomes after controlling for sociodemographic and epilepsy-related factors. METHOD: An online survey was completed by 144 YAWE (18-25-year-olds), which measured sociodemographic and epilepsy-related factors, coping strategies, sources of social support, and current mental health symptoms (anxiety, depression, and suicidality). RESULTS: Avoidant-focused coping was positively correlated, and problem-focused coping and meaning-focused coping were negatively correlated, with symptoms of anxiety, depression, and suicidality. Social support from family, friends, and a special person all negatively correlated with mental health outcomes. Using multiple regression analyses, greater use of avoidant-focused coping strategies independently predicted higher symptoms of anxiety, depression, and suicidality. Greater support from friends independently predicted significantly lower anxiety and depression, whereas greater support from family independently predicted significantly lower suicidality. CLINICAL IMPLICATIONS: These findings have implications for clinical practice in YAWE and suggest that screening for mental health symptoms and psychosocial variables to identify those at risk would be beneficial. Access to tailored psychological support is also needed.

Low Back Pain and Substance Use: Diagnostic and Administrative Coding for Opioid Use and Dependence Increased in U.S. Older Adults with Low Back Pain.

OBJECTIVE: Low back pain (LBP) is a leading cause of pain and disability. Substance use complicates the management of LBP, and potential risks increase with aging. Despite implications for an aging, diverse U.S. population, substance use and LBP comorbidity remain poorly defined. The objective of this study was to characterize LBP and substance use diagnoses in older U.S. adults by age, gender, and race. DESIGN: Cross-sectional study of a random national sample. SUBJECTS: Older adults including 1,477,594 U.S. Medicare Part B beneficiaries. METHODS: Bayesian analysis of 37,634,210 claims, with 10,775,869 administrative and 92,903,649 diagnostic code assignments. RESULTS: LBP was diagnosed in 14.8±0.06% of those more than 65 years of age, more in females than in males (15.8±0.08% vs. 13.4±0.09%), and slightly less in those more than 85 years of age (13.3±0.2%). Substance use diagnosis varied by substance: nicotine, 9.6±0.02%; opioid, 2.8±0.01%; and alcohol, 1.3±0.01%. Substance use diagnosis declined with advancing age cohort. Opioid use diagnosis was markedly higher for those in whom LBP was diagnosed (10.5%) than for those not diagnosed with LBP (1.5%). Most older adults (54.9%) with an opioid diagnosis were diagnosed with LBP. Gender differences were modest. Relative rates of substance use diagnoses in LBP were modest for nicotine and alcohol. CONCLUSIONS: Older adults with LBP have high relative rates of opioid diagnoses, irrespective of gender or age. Most older adults with opioid-related diagnoses have LBP, compared with a minority of those not opioid diagnosed. In caring for older adults with LBP or opioid-related diagnoses, health systems must anticipate complexity and support clinicians, patients, and caregivers in managing pain comorbidities. Older adults may benefit from proactive incorporation of non-opioid pain treatments. Further study is needed.

Substances and your senses: The sensory patterns of young people within an alcohol and drug treatment service.

Background: Substance use disorders (SUD) and trauma histories in adults have been linked with sensory processing patterns that are significantly different from the general population. Nevertheless, no studies have investigated sensory patterns, or the variables with which they are related, in youth with SUD. This study aimed to compare sensory patterns of this sample with normative data and consider associations between sensory patterns and: substance use, trauma, quality-of-life, mental and physical health. Methods: A cross-sectional quantitative research design was employed with a sample of 87 young people (mean age = 20.8 years) with SUD voluntarily attending a specialist youth outpatient alcohol and other drug (AOD) service. For participants, the Adolescent Adult Sensory Profile was added to measures routinely collected at the service. Results: Participants' sensory processing patterns for low registration, sensory sensitivity, and sensation avoiding were significantly higher than the normative population, while sensation seeking was both lower and higher. Ninety-one percent reported atypical scores on one or more sensory patterns. High rates of probable Post-Traumatic-Stress-Disorder (PTSD), psychological distress, and low quality-of-life were also reported, which were meaningfully related with sensory patterns. Conclusion: Young people reported complex combinations of sensory processing patterns, with comorbid probable PTSD, psychological distress, and low quality-of-life. Findings reflect studies with adult AOD, trauma, and other clinical conditions, and highlight the potential value of screening for sensory patterns and applying transdiagnostic approaches which simultaneously address substance use, mental health, trauma and sensory needs to optimize outcomes for young people with SUD.

Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands.

N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound 6a was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease.

Longitudinal evaluation of a programme for safety culture change in a mental health service.

AIM: To evaluate whether a two-part culture improvement programme aimed at nurses in clinical and managerial positions in an inpatient mental health service was associated with culture change, and safety-related behaviour and knowledge improvements. BACKGROUND: Due to serious failings in the delivery of physiological care to mentally disordered inpatients, it was deemed important that interventions be applied to improve service culture. METHODS: A pre-test and post-test study was conducted to evaluate change associated with a mandated intervention aimed at culture change. Nurses in clinical and managerial positions at all levels attended relevant sessions. All were invited to participate in evaluation measures. RESULTS: N = 241 nurses participated in the evaluation (n = 137 and n = 104, pre-test and post-test, respectively). There was a small but significant change in organisational culture indicating greater adhocracy and less clan culture in the second survey period and a small decline in reported safety behaviour. Measures of safety culture, knowledge and emergency-related educational satisfaction were unchanged. CONCLUSION: Only a small change in measured culture was associated with the programme. IMPLICATIONS FOR NURSING MANAGEMENT: Attempts to evaluate culture change need to align anticipated outcomes with appropriate outcome measures. A mandated programme of culture change had little tangible effect on the outcomes measured.

Biosecurity Dogs Detect Live Insects after Training with Odor-Proxy Training Aids: Scent Extract and Dead Specimens.

Detector dogs could be trained to find invasive insect pests at borders before they establish in new areas. However, without access to the live insects themselves, odor training aids are needed to condition dogs to their scent. This proof-of-concept study assessed 2 potential training aids for insect detection: a scent extract and dead specimens of the target species. Using Musgraveia sulciventris (Hemiptera: Tessaratomidae) as an experimental model, gas chromatography-mass spectrometry (GC-MS) analyses were carried out to compare the chemical headspaces that make up the odors of live specimens and these 2 training aids. This was then followed by canine scent-detection testing to investigate biosecurity detector dogs' (n = 4) responses to training in an ecologically valid context. Both the scent extract and the dead specimens shared the majority of their volatile organic compounds (VOCs) with live insects. Of the dogs trained with scent extract (n = 2), both were able to detect the live insects accurately, and of those trained with dead specimens (n = 2), one detected the live insects accurately. These findings lend support for these training aids as odor-proxies for live insects-particularly scent extract, which is a relatively novel product with the potential for broad application to facilitate and improve insect-detection training.

Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes.

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands.

As part of our on-going effort to explore the role of dopamine receptors in drug addiction and identify potential novel therapies for this condition, we have a identified a series of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide D3 ligands. Members of this class are highly selective for D3 versus D2, and we have identified two compounds (13g and 13r) whose rat in vivo IV pharmacokinetic properties that indicate that they are suitable for assessment in in vivo efficacy models of substance use disorders.