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Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 ( 59 ). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.

Objective: Previous research has demonstrated different cannabis-related outcomes depending on the goal of cannabis use (i.e., recreational, medical, a hybrid of both), underscoring the need to identify variables associated with specific goals of use, particularly in understudied populations., Method: This report used data from a national survey of menopausal individuals using nonprobability sampling. Respondents reporting current regular (≥1x/month) cannabis use (medical n = 35; recreational n = 61; and hybrid n = 102) were included in multivariate logistic regression analyses examining demographic, clinical (e.g., menopause-related symptomatology), and cannabis-related variables associated with the goal of cannabis use., Results: Overall, an increased number of medical conditions was associated with medical and hybrid use relative to recreational use ( p s ≤ .047), and greater menopause-related symptomatology was associated with medical relative to hybrid use ( p = .001). Lower education level was associated with hybrid relative to recreational use ( p = .010). Lastly, more varied modes of use was associated with hybrid use relative to medical and recreational use ( p s ≤ .001)., Conclusions: Results suggest that medical and hybrid consumers with more medical conditions and more severe clinical symptoms that are not sufficiently alleviated by conventional treatments may be more open to cannabinoid-based therapies. In addition, because a lower education level is often associated with recreational cannabis use, results suggest that hybrid consumers may begin as recreational consumers who then expand their use for medical purposes. Further, more varied modes of use for hybrid consumers may reflect different product selections based on the goal of use. Future research should investigate the etiology of hybrid cannabis use and predictors of long-term outcomes associated with goals of use.

Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2- b ]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S. During profiling of imidazo[3.2- b ]pyrazoles, we elucidated the bioactivation mechanism causing CYP3A4/5 time-dependent inhibition (TDI) and found key modifications to mitigate the TDI. Compound 31 inhibited EGFR L858R/T790M/C797S in biochemical assays with a K i = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC 50 = 56.9 nM. The deuterated analogue of 31 ( 38 ) demonstrated dose-dependent tumor growth inhibition in a Ba/F3 EGFR del19/T790M/C797S CDX model by 47% at 50 mg/kg BID and 92% at 100 mg/kg BID.

Background: Despite the significance of menopause as a natural biological milestone experienced by approximately half the population, few studies have evaluated factors associated with menopause-related shame and stigma. Given previous research indicating increased shame and stigma are associated with negative outcomes that directly impact health ( e.g., reduced access to health care), it is critical to identify variables associated with menopause-related shame and stigma. Materials and Methods: As part of a larger, national survey, 214 perimenopausal ( n  = 111) and postmenopausal ( n  = 103) individuals completed self-report questionnaires assessing demographics and menopause-related symptoms, shame, and stigma. Regression analyses examined variables associated with shame and stigma. Results: Over a third of respondents reported feeling shame related to their menopause-related symptoms (37.4%), while the majority of respondents reported feeling stigma associated with symptoms (82.7%). In addition, most respondents endorsed talking about their symptoms with friends, family, partners, or doctors (80.8%), and felt that their peers might experience the same symptoms (93.9%). Regression analyses identified several significant predictor variables; in particular, more severe psychosocial and urogenital symptoms, higher education level, and younger age were significantly associated with greater odds of reporting shame and stigma. Conclusions: Overall, findings suggest that even though menopausal individuals report feeling their symptoms are similar to their peers, shame and stigma are significantly associated with these symptoms, which may be impacted by symptom severity and socioeconomic factors. Results suggest that younger individuals ( i.e., those just entering perimenopause) with more education may be more likely to feel shame and stigma, which could inform interventional strategies and improve clinical outcomes.

Increasing numbers of individuals have access to cannabinoid-based products containing various amounts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids. Exposure to specific cannabinoids likely influences outcomes; however, current methods for quantifying cannabis exposure do not account for the cannabinoid concentrations of the products used. We developed CannaCount, an examiner-driven metric that quantifies estimated maximum possible cannabinoid exposure by accounting for variables related to cannabinoid concentration, duration, frequency, and quantity of use. To demonstrate feasibility and applicability, CannaCount was used to quantify estimated maximum THC and CBD exposure in 60 medical cannabis patients enrolled in a two-year, longitudinal, observational study. Medical cannabis patients reported using a variety of product types and routes of administration. Calculating estimated exposure to THC and CBD was possible for the majority of study visits, and the ability to generate estimated cannabinoid exposure improved over time, likely a function of improved product labeling, laboratory testing, and more informed consumers. CannaCount is the first metric to provide estimated maximum possible exposure to individual cannabinoids based on actual cannabinoid concentrations. This metric will ultimately facilitate cross-study comparisons and can provide researchers and clinicians with detailed information regarding exposure to specific cannabinoids, which will likely have significant clinical impact., (© 2023. The Author(s).)

Background: Suicide is a leading cause of death, and rates of attempted suicide have increased during the COVID-19 pandemic. The under-diagnosed psychiatric phenotype of dissociation is associated with elevated suicidal self-injury; however, it has largely been left out of attempts to predict and prevent suicide. Objective: We designed an artificial intelligence approach to identify dissociative patients and predict prior suicide attempts in an unbiased, data-driven manner. Method: Participants were 30 controls and 93 treatment-seeking female patients with posttraumatic stress disorder (PTSD) and various levels of dissociation, including some with the PTSD dissociative subtype and some with dissociative identity disorder (DID). Results: Unsupervised learning models identified patients along a spectrum of dissociation. Moreover, supervised learning models accurately predicted prior suicide attempts with an F 1 score up to 0.83. DID had the highest risk of prior suicide attempts, and distinct subtypes of dissociation predicted suicide attempts in PTSD and DID. Conclusions: These findings expand our understanding of the dissociative phenotype and underscore the urgent need to assess for dissociation to identify individuals at high-risk of suicidal self-injury.

Background: Previous studies have demonstrated abnormal white matter (WM) microstructure in recreational cannabis consumers; however, the long-term impact of medical cannabis (MC) use on WM coherence is unknown. Accordingly, this study assessed the longitudinal impact of MC treatment on WM coherence. Given results from preclinical studies, we hypothesized that MC treatment would be associated with increased fractional anisotropy (FA) and reduced mean diffusivity (MD). Methods: As part of a larger, longitudinal investigation, patients interested in treating at least one medical condition with commercially available MC products of their choosing were assessed before initiating MC use (baseline n =37; female=25, male=12) and following three ( n =31) and six ( n =22) months of treatment. WM coherence was assessed via diffusion tensor imaging for bilateral regions of interest including the genu of the corpus callosum, anterior limb of the internal capsule, external capsule, and anterior corona radiata, as well as an occipital control region not expected to change over time. Results: In MC patients, FA values significantly increased bilaterally in several callosal regions relative to baseline following both 3 and 6 months of treatment; MD values significantly decreased in all callosal regions but only following 6 months of treatment. No significant changes in WM coherence were observed in the control region or in a pilot sample of treatment-as-usual patients (baseline n =14), suggesting that increased WM coherence observed in MC patients may be attributed to MC treatment as opposed to confounding factors. Interestingly, significant reductions in MD values correlated with higher cannabidiol (CBD) exposure but not Δ-9-tetrahydrocannabinol exposure. Conclusions: Overall, MC treatment was associated with increased WM coherence, which contrasts with prior research examining recreational cannabis consumers, likely related to inherent differences between recreational consumers and MC patients (e.g., product choice, age of onset). In addition, increased CBD exposure was associated with reduced MD following 6 months of treatment, extending evidence from preclinical research indicating that CBD may be neuroprotective against demyelination. However, additional research is needed to elucidate the clinical efficacy of MC treatment and the risks and benefits of long-term MC use.

Background: Evidence suggests cannabidiol (CBD) has anxiolytic properties, indicating potential for novel treatment strategies. However, few clinical trials of CBD-based products have been conducted, and none thus far have examined the impact of these products on cognition., Methods: For the open-label stage of clinical trial NCT02548559, autoregressive linear modeling assessed efficacy and tolerability of four-weeks of 1 mL t.i.d. treatment with a full-spectrum, high-CBD sublingual solution (9.97 mg/mL CBD, 0.23 mg/mL Δ-9-tetrahydrocannabinol) in 14 outpatients with moderate-to-severe anxiety, defined as ≥16 on the Beck Anxiety Inventory (BAI) or ≥11 on the Overall Anxiety Severity and Impairment Scale (OASIS)., Results: Findings suggest significant improvement on primary outcomes measuring anxiety and secondary outcomes assessing mood, sleep, quality of life, and cognition (specifically executive function) following treatment. Anxiety is significantly reduced at week 4 relative to baseline (BAI: 95% CI = [-21.03, -11.40], p < 0.001, OASIS: 95% CI = [-9.79, -6.07], p < 0.001). Clinically significant treatment response (≥15% symptom reduction) is achieved and maintained as early as week 1 in most patients (BAI = 78.6%, OASIS = 92.7%); cumulative frequency of treatment responders reached 100% by week 3. The study drug is well-tolerated, with high adherence/patient retention and no reported intoxication or serious adverse events. Minor side effects, including sleepiness/fatigue, increased energy, and dry mouth are infrequently endorsed., Conclusions: Results provide preliminary evidence supporting efficacy and tolerability of a full-spectrum, high-CBD product for anxiety. Patients quickly achieve and maintain symptom reduction with few side effects. A definitive assessment of the impact of this novel treatment on clinical symptoms and cognition will be ascertained in the ongoing double-blind, placebo-controlled stage., (© 2022. The Author(s).)

Objective: Expanding access to legal cannabis has dovetailed with increased interest in medical cannabis (MC) use; however, there is a paucity of research examining MC use to alleviate menopause-related symptoms. This survey study assessed patterns of MC use in perimenopausal and postmenopausal individuals., Methods: Participants (perimenopausal, n = 131; postmenopausal, n = 127) completed assessments of menopause-related symptomatology and cannabis use, including modes of use, type of use, and menopause-related symptoms addressed by MC use., Results: Most participants reported current cannabis use (86.1%) and endorsed using MC for menopause-related symptoms (78.7%). The most common modes of use were smoking (84.3%) and edibles (78.3%), and the top menopause-related symptoms for MC use were sleep disturbance (67.4%) and mood/anxiety (46.1%). Relative to postmenopausal participants, perimenopausal participants reported significantly worse menopause-related symptomatology on the vasomotor and psychosocial subscales of the Menopause-Specific Quality of Life Questionnaire ( P s ≤ 0.04), including greater burden of anxiety ( P = 0.01) and hot flash ( P = 0.04) symptoms. In addition, perimenopausal participants reported higher incidence of depression ( P = 0.03) and anxiety diagnoses ( P < 0.01), as well as increased use of MC to treat menopause-related mood/anxiety symptoms relative to postmenopausal participants ( P = 0.01)., Conclusions: Results suggest that many individuals are currently using MC as an adjunctive treatment for menopause-related symptoms, particularly sleep disturbance and mood/anxiety. Future research should examine the impact of different MC use characteristics (e.g., cannabinoid profiles) on the efficacy of MC use for menopause-related symptoms. Increased severity and prevalence of mood and anxiety symptoms in perimenopausal participants suggest promising targets for clinical trials of cannabinoid-based therapies., Competing Interests: Financial disclosures/conflicts of interest: S.A.G. reported grants from the National Institute on Drug Abuse, Foria/Praxis Ventures, and Charlotte's Web outside the submitted work. S.A.G. also reported personal fees from the Coalition for Cannabis Policy, Education, and Regulation; Beth Israel Deaconess; Fenway Health; Greenwich Biosciences Cannabis Education Working Group; and National Academy of Neuropsychology outside the submitted work. M.K.D. reported receiving the McLean Hospital Jonathan Edward Brooking Mental Health Research Fellowship outside the submitted work. K.A.S. received the McLean Hospital Eleanor and Miles Shore Fellowship and the Charles Robert Broderick III Phytocannabinoid Research Fellowship, and reported personal fees from the Coalition for Cannabis Policy, Education, and Regulation outside the submitted work. All authors report no biomedical financial interests or potential conflicts of interest. No other disclosures were reported., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

d-Serine is a coagonist of the N -methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.

Cannabis withdrawal symptoms contribute to relapse, but the underlying mechanism remains unclear. We hypothesize that cannabis withdrawal may be associated with a reset of regional γ-amino butyric acid (GABA) and glutamate concentrations secondary to changes in the endocannabinoid system during abstinence and conducted a study on this issue. We used magnetic resonance spectroscopy (MRS) to detect the associated changes of these neurochemicals in twenty-six frequent, recreational cannabis users and eleven age-matched non-using controls. Twenty users (8F/12M) and ten control (5F/5M) participants completed a verified 21-day abstinence period. Striatal GABA and glutamine concentrations were measured at baseline and on abstinence days 7 and 21 in conjunction with measures of cannabis withdrawal symptoms and mood state. Cannabis users reported increased self-reported ratings of cannabis-withdrawal-symptoms on abstinence day 7 relative to controls. Striatal glutamate + glutamine (Glx) group concentrations were elevated in cannabis users at baseline and abstinence days 7 and 21 (F = 7.16, p = 0.012), and changes in GABA concentration and withdrawal symptoms between baseline and abstinence day 7 were positively correlated (r = 0.550, p = 0.010). In addition, baseline striatal GABA concentrations were negatively correlated with withdrawal symptoms on abstinence day 7 (r = -0.680, p = 0.003). Our data demonstrate that striatal Glx was elevated in cannabis users and baseline striatal GABA correlated with withdrawal during the abstinence. In addition, striatal GABA may temporally correlate with self-reported withdrawal symptoms during the initial days of abrupt cannabis abstinence. These findings provide preliminary evidence that striatal GABA and Glx are associated with the severity of cannabis withdrawal., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: To date, no studies have directly assessed potential cannabis use disorder (CUD) in medical cannabis (MC) patients pre- vs post-MC treatment. Given that MC patients use cannabis for symptom alleviation rather than intoxication, we hypothesized that MC patients would exhibit few symptoms of CUD after initiating MC treatment., Methods: As part of an ongoing observational, longitudinal study, 54 MC patients completed baseline assessments prior to initiating MC use and returned for at least one follow-up assessment after three, six, and/or twelve months of a self-selected MC treatment regimen; detailed MC treatment information was collected and quantified. All patients completed the Cannabis Use Disorder Identification Test - Revised (CUDIT-R) at each visit. Changes in individual items scores and total scores were assessed over time, and we examined whether total CUDIT-R scores correlated with frequency of MC use, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) exposure. Further, Cronbach's alpha analyses were conducted to provide preliminary data regarding the psychometric properties of the CUDIT-R when used among MC patients., Results: Although total CUDIT-R scores increased relative to baseline, on average, ratings fell below the 'hazardous use' threshold at each visit. Analyses of individual items revealed that increases in total scores were primarily attributable to increases in frequency of use and not necessarily other aspects of problematic use. Total CUDIT-R scores were not associated with number of MC uses or CBD exposure, but a significant relationship was detected between increased THC exposure and higher CUDIT-R scores. Importantly however, analyses revealed that the CUDIT-R does not appear to be an appropriate tool for identifying CUD in MC patients., Conclusions: Screening tools specifically designed to assess CUD in MC patients are needed and should distinguish between frequent use and problematic use; exposure to individual cannabinoids must also be considered., Competing Interests: All authors declare no conflicts of interest., (© 2021 Authors et al.)

We report on the development and validation of the OPLS4 force field. OPLS4 builds upon our previous work with OPLS3e to improve model accuracy on challenging regimes of drug-like chemical space that includes molecular ions and sulfur-containing moieties. A novel parametrization strategy for charged species, which can be extended to other systems, is introduced. OPLS4 leads to improved accuracy on benchmarks that assess small-molecule solvation and protein-ligand binding.

Objective: Cannabis use has increased dramatically across the country; however, few studies have assessed the long-term impact of medical cannabis (MC) use on cognition. Studies examining recreational cannabis users generally report cognitive decrements, particularly in those with adolescent onset. As MC patients differ from recreational consumers in motives for use, product selection, and age of onset, we assessed cognitive and clinical measures in well-characterized MC patients over 1 year. Based on previous findings, we hypothesized MC patients would not show decrements and might instead demonstrate improvements in executive function over time., Method: As part of an ongoing study, MC patients completed a baseline visit prior to initiating MC and evaluations following 3, 6, and 12 months of treatment. At each visit, patients completed a neurocognitive battery assessing executive function, verbal learning/memory, and clinical scales assessing mood, anxiety, and sleep. Exposure to delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) was also quantified., Results: Relative to baseline, MC patients demonstrated significant improvements on measures of executive function and clinical state over the course of 12 months; verbal learning/memory performance generally remained stable. Improved cognitive performance was not correlated with MC use; however, clinical improvement was associated with higher CBD use. Analyses suggest cognitive improvements were associated with clinical improvement., Conclusions: Study results extend previous pilot findings, indicating that MC patients may exhibit enhanced rather than impaired executive function over time. Future studies should examine distinctions between recreational and MC use to identify potential mechanisms related to cognitive changes and the role of clinical improvement.

Previous studies have demonstrated improvements in pain following short-term medical cannabis (MC) use, suggesting long-term MC treatment may alleviate symptoms associated with chronic pain. The goal of this observational and longitudinal study was to examine patients using MC to treat chronic pain pre versus post MC treatment. These interim analyses included 37 patients with chronic pain evaluated prior to initiation of MC treatment and following 3 and 6 months of MC use; pain, clinical state, sleep, quality of life, and conventional medication use were assessed. Correlation analyses examined the relationship between changes in pain and other clinical measures, assessed the impact of cannabinoid exposure on pain and clinical ratings, and assessed whether baseline cannabis expectancies influenced outcome variables. Additionally, a pilot group of treatment-as-usual patients (n = 9) who did not use MC were examined at baseline and 3 months later. Relative to baseline, following 3 and 6 months of treatment, MC patients exhibited improvements in pain which were accompanied by improved sleep, mood, anxiety, and quality of life, and stable conventional medication use. Reduced pain was associated with improvements in aspects of mood and anxiety. The results generally suggest increased THC exposure was related to pain-related improvement, while increased CBD exposure was related to improved mood. Cannabis expectancies were not related to observed improvements. Pilot analyses revealed that treatment-as-usual patients do not demonstrate the same pattern of improvement. Findings highlight the potential efficacy of MC treatment for pain and underscore the unique impact of individual cannabinoids on specific aspects of pain and comorbid symptoms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Brain development continues throughout childhood and requires micronutrients for optimal maturation, but studies have typically examined only a limited number of micronutrients and there has been inconsistent use of validated cognitive measures. This study evaluated the impact of providing low-income children with a daily fortified meal (570 kcal) in the form of a bar and shake containing >75% of the FDA Daily Values for all essential vitamins and minerals, as well as macronutrients (e.g., omega-3 and omega-6 fatty acids and protein), in an afterschool care setting (instead of the usual meal provided) on cognitive functioning. Students aged 8-12 were randomly assigned to intervention ( n = 19) or control ( n = 16) meals. Students completed the Stroop Color Word Task, Trail Making Test, and Conner's Continuous Performance Task (CPT) at baseline and 3 months post-intervention. Differences in cognitive scores were examined using 2 × 2 mixed model ANOVAs (Stroop and CPT) and ANCOVAs (Trail Making Test). Significant main effects of time indicated improvements in both intervention and control groups, but there were no significant main effects of group or group*time interactions. When the amount of meal consumed was examined, most results became non-significant, suggesting that overall meal consumption significantly impacted the observed results. Overall, this pilot study suggests that there may be limited additional benefits to short-term consumption of micronutrient fortified meals among low-income children in an afterschool care setting, and potential benefits observed may be directly related to the amount of food consumed.

In healthy individuals, stimuli associated with injury (such as those depicting blood or wounds) tend to evoke negative responses on both self-report and psychophysiological measures. Such an instinctive aversion makes sense from an evolutionary perspective. However, to engage in nonsuicidal self-injury (NSSI), this natural barrier must be overcome. The Benefits and Barriers model of NSSI predicts that people who engage in NSSI will show diminished aversion to NSSI-related stimuli compared to controls who do not engage in NSSI. We tested this hypothesis in a pilot study assessing 30 adults, 15 of whom reported current skin cutting and 15 of whom had no history of NSSI. Functional magnetic resonance imaging (fMRI) data were collected while participants viewed neutral, positive, and negative images selected from the International Affective Picture System. Participants also viewed NSSI images depicting razors, scalpels, or wounds caused by cutting. Compared to healthy control (HC) participants, the NSSI group showed decreased amygdala and increased cingulate cortex (CC) and orbitofrontal cortex (OFC) activation to NSSI and negative images. They also showed increased amygdalar and OFC activation to positive images. Neither the control group nor the NSSI group demonstrated significant activation within regions more typically associated with reward during any of the conditions; however, positive and negative affect ratings collected throughout the course of the task suggested that none of the affective conditions were viewed as rewarding. Although preliminary, these findings are suggestive of reduced limbic and greater cortical processing of NSSI stimuli in those with a history of this behavior. This has potentially important implications for current models of NSSI as well as for its treatment., (Copyright © 2020 Hooley, Dahlgren, Best, Gonenc and Gruber.)

Background: Across the nation, growing numbers of individuals are exploring the use of cannabis for medical or recreational purposes, and the proportion of cannabis-positive drivers involved in fatal crashes increased from 8 percent in 2013 to 17 percent in 2014, raising concerns about the impact of cannabis use on driving. Previous studies have demonstrated that cannabis use is associated with impaired driving performance, but thus far, research has primarily focused on the effects of acute intoxication., Methods: The current study assessed the potential impact of cannabis use on driving performance using a customized driving simulator in non-intoxicated, heavy, recreational cannabis users and healthy controls (HCs) without a history of cannabis use., Results: Overall, cannabis users demonstrated impaired driving relative to HC participants with increased accidents, speed, and lateral movement, and reduced rule-following. Interestingly, however, when cannabis users were divided into groups based on age of onset of regular cannabis use, significant driving impairment was detected and completely localized to those with early onset (onset before age 16) relative to the late onset group (onset ≥16 years old). Further, covariate analyses suggest that impulsivity had a significant impact on performance differences., Conclusions: Chronic, heavy, recreational cannabis use was associated with worse driving performance in non-intoxicated drivers, and earlier onset of use was associated with greater impairment. These results may be related to other factors associated with early exposure such as increased impulsivity., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

The hit-to-lead and lead optimization processes usually involve the design, synthesis, and profiling of thousands of analogs prior to clinical candidate nomination. A hit finding campaign may begin with a virtual screen that explores millions of compounds, if not more. However, this scale of computational profiling is not frequently performed in the hit-to-lead or lead optimization phases of drug discovery. This is likely due to the lack of appropriate computational tools to generate synthetically tractable lead-like compounds in silico, and a lack of computational methods to accurately profile compounds prospectively on a large scale. Recent advances in computational power and methods provide the ability to profile much larger libraries of ligands than previously possible. Herein, we report a new computational technique, referred to as "PathFinder", that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. In this work, the integration of PathFinder-driven compound generation, cloud-based FEP simulations, and active learning are used to rapidly optimize R-groups, and generate new cores for inhibitors of cyclin-dependent kinase 2 (CDK2). Using this approach, we explored >300 000 ideas, performed >5000 FEP simulations, and identified >100 ligands with a predicted IC 50 < 100 nM, including four unique cores. To our knowledge, this is the largest set of FEP calculations disclosed in the literature to date. The rapid turnaround time, and scale of chemical exploration, suggests that this is a useful approach to accelerate the discovery of novel chemical matter in drug discovery campaigns.

Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chemical space by addressing limitations in chemotype transferability. OPLS3e accomplishes this by incorporating new parameter types that recognize moieties with greater chemical specificity and integrating an on-the-fly parametrization approach to the assignment of partial charges. As a consequence, OPLS3e leads to greater accuracy against performance benchmarks that assess small molecule conformational propensities, solvation, and protein-ligand binding.

Background: Cannabis concentrates, including dabs, contain extremely high levels of Δ 9 -tetrahydrocannabinol (THC). Although these products appear to be gaining popularity among recreational cannabis consumers, little data exists regarding concentrate use in the US. We conducted a national web-based survey to examine patterns of concentrate use, specifically dabbing., Methods: 4077 respondents completed a survey designed to assess the use of conventional flower cannabis relative to dabs. Individuals provided information about frequency and magnitude of use, and also completed the Marijuana Motives Measure and Severity of Dependence Scale to examine whether dab users have different motives for use and/or demonstrate more severe consequences of use compared to those who only use conventional flower products., Results: 58% of respondents reported they had tried dabs at least once and 36.5% endorsed regular use (once a month or more). Those who use regularly use dabs were significantly more likely to report using for experimentation (feeling "curious") relative to reasons for using conventional flower products. Interestingly, motives reflecting positive effects (i.e., coping, sleep problems, relieving social anxiety) were endorsed more highly for flower use. In addition, regular dab users reported being more worried about their use of cannabis products relative to those who had tried dabs but did not use regularly., Conclusions: Results indicate that cannabis consumers do not necessarily choose dabs over flower products for positive effects, but rather appear to choose these highly potent products for experimentation. As concentrate use may lead to increased cannabis-related problems, studies directly assessing concentrate users are needed., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Nonsuicidal self-injury (NSSI), deliberate behavior resulting in self-inflicted damage to oneself, is common, particularly among female adolescents, and may be a form of maladaptive emotion regulation. Cognitive interference, a specific type of processing associated with inhibiting prepotent responses in favor of less automatic ones, is utilized in treatment strategies to shift patients' thoughts and behaviors away from maladaptive responses and replace them with more adaptive ones. We examined cognitive interference processing using the Multi-Source Interference Task (MSIT) in females with NSSI behavior (n=15) and healthy control females (n=15). Functional magnetic resonance imaging (fMRI) data were collected concurrently. Results revealed similar between-group performance on the MSIT; however, women with NSSI behavior exhibited altered patterns of neural activation during the MSIT. Specifically, the NSSI group demonstrated increased cingulate cortex (CC) and decreased dorsolateral prefrontal cortex (DLPFC) activation compared to the control group. Further, within the NSSI group, DLPFC activation inversely correlated with emotional reactivity and self-reported impulsivity, suggesting that decreased DLPFC activation is associated with poorer emotional control and increased impulsivity. Taken together, these results indicate that women with NSSI behavior utilize different cortical areas during cognitive interference processing, which may have broader implications regarding the treatment efficacy of cognitive-based therapies., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Previous research has shown relatively diminished medial prefrontal cortex activation and heightened psychophysiological responses during the recollection of personal events in post-traumatic stress disorder (PTSD), but the origin of these abnormalities is unknown. Twin studies provide the opportunity to determine whether such abnormalities reflect familial vulnerabilities, result from trauma exposure, or are acquired characteristics of PTSD., Methods: In this case-control twin study, 26 male identical twin pairs (12 PTSD; 14 non-PTSD) discordant for PTSD and combat exposure recalled and imagined trauma-unrelated stressful and neutral life events using a standard script-driven imagery paradigm during functional magnetic resonance imaging and concurrent skin conductance measurement., Results: Diminished activation in the medial prefrontal cortex during Stressful v. Neutral script-driven imagery was observed in the individuals with PTSD, relative to other groups., Conclusions: Diminished medial prefrontal cortex activation during Stressful v. Neutral script-driven imagery may be an acquired characteristic of PTSD. If replicated, this finding could be used prospectively to inform diagnosis and the assessment of treatment response.

The vast majority of states have enacted full or partial medical marijuana (MMJ) programs, causing the number of patients seeking certification for MMJ use to increase dramatically in recent years. Despite increased use of MMJ across the nation, no studies thus far have examined the specific impact of MMJ on cognitive function and related brain activation. In the present study, MMJ patients seeking treatment for a variety of documented medical conditions were assessed prior to initiating MMJ treatment and after 3 months of treatment as part of a larger longitudinal study. In order to examine the effect of MMJ treatment on task-related brain activation, MMJ patients completed the Multi-Source Interference Test (MSIT) while undergoing functional magnetic resonance imaging (fMRI). We also collected data regarding conventional medication use, clinical state, and health-related measures at each visit. Following 3 months of treatment, MMJ patients demonstrated improved task performance accompanied by changes in brain activation patterns within the cingulate cortex and frontal regions. Interestingly, after MMJ treatment, brain activation patterns appeared more similar to those exhibited by healthy controls from previous studies than at pre-treatment, suggestive of a potential normalization of brain function relative to baseline. These findings suggest that MMJ use may result in different effects relative to recreational marijuana (MJ) use, as recreational consumers have been shown to exhibit decrements in task performance accompanied by altered brain activation. Moreover, patients in the current study also reported improvements in clinical state and health-related measures as well as notable decreases in prescription medication use, particularly opioids and benzodiapezines after 3 months of treatment. Further research is needed to clarify the specific neurobiologic impact, clinical efficacy, and unique effects of MMJ for a range of indications and how it compares to recreational MJ use.

Background: Cognitive deficits are well-documented in patients with bipolar disorder (BPD) and may impact the efficacy of psychotherapy. Cognitive control, a form of executive functioning, is often used therapeutically to shift patients' thoughts and behaviors from automatic, maladaptive responses to adaptive coping strategies. This study examined cognitive control processing in patients with BPD using the Multi-Source Interference Task (MSIT)., Method: Twenty-nine patients diagnosed with BPD and 21 healthy control (HC) subjects completed the MSIT with concurrent functional magnetic resonance imaging (fMRI)., Results: Patients with BPD generally performed worse on the MSIT relative to HC participants; the BPD group had significantly lower performance accuracy and made more omission errors. Further, fMRI analyses revealed differential patterns of activation between the groups during the MSIT. Region of interest (ROI) analyses revealed that relative to HC participants, patients with BPD activated significantly fewer voxels within the cingulate cortex (CC) and more voxels within prefrontal cortex (PFC), although the PFC findings did not survive more stringent significance thresholds., Limitations: Patients and HCs were not matched for age, sex, and premorbid verbal IQ, however, these variables were controlled for statistically. Medication usage in the BPD group may have possibly impacted the results. Given a priori hypotheses, ROI analyses were utilized., Conclusions: Decreased CC activation and increased PFC activation may be associated with impaired cognitive control, demonstrated by BPD patients when completing the MSIT. Identifying the neural mechanisms which underlie key cognitive abnormalities in BPD may aid in clarifying the pathophysiology of this disorder and inform selection of potential targets for cognition remediation in BPD., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Currently, 25 states and Washington DC have enacted full medical marijuana (MMJ) programs while 18 states allow limited access to MMJ products. Limited access states permit low (or zero) tetrahydrocannabinol (THC) and high cannabidiol (CBD) products to treat specified conditions such as uncontrolled epilepsy. Although MMJ products are derived from the same plant species as recreational MJ, they are often selected for their unique cannabinoid constituents and ratios, not typically sought by recreational users, which may impact neurocognitive outcomes. To date, few studies have investigated the potential impact of MMJ use on cognitive performance, despite a well-documented association between recreational marijuana (MJ) use and executive dysfunction. The current study assessed the impact of 3 months of MMJ treatment on executive function, exploring whether MMJ patients would experience improvement in cognitive functioning, perhaps related to primary symptom alleviation. As part of a larger longitudinal study, 24 patients certified for MMJ use completed baseline executive function assessments and 11 of these so far have returned for their first follow-up visit 3 months after initiating treatment. Results suggest that in general, MMJ patients experienced some improvement on measures of executive functioning, including the Stroop Color Word Test and Trail Making Test, mostly reflected as increased speed in completing tasks without a loss of accuracy. On self-report questionnaires, patients also indicated moderate improvements in clinical state, including reduced sleep disturbance, decreased symptoms of depression, attenuated impulsivity, and positive changes in some aspects of quality of life. Additionally, patients reported a notable decrease in their use of conventional pharmaceutical agents from baseline, with opiate use declining more than 42%. While intriguing, these findings are preliminary and warrant further investigation at additional time points and in larger sample sizes. Given the likelihood of increased MMJ use across the country, it is imperative to determine the potential impact of short- and long-term treatment on cognitive performance as well as the efficacy of MMJ treatment itself.

Marijuana is the most widely used illicit substance in those diagnosed with bipolar I disorder. However, there is conflicting evidence as to whether marijuana may alleviate or exacerbate mood symptomatology. As bipolar disorder and marijuana use are individually associated with cognitive impairment, it also remains unclear whether there is an additive effect on cognition when bipolar patients use marijuana. The current study aimed to determine the impact of marijuana on mood in bipolar patients and to examine whether marijuana confers an additional negative impact on cognitive function. Twelve patients with bipolar disorder who smoke marijuana (MJBP), 18 bipolar patients who do not smoke (BP), 23 marijuana smokers without other Axis 1 pathology (MJ), and 21 healthy controls (HC) completed a neuropsychological battery. Further, using ecological momentary assessment, participants rated their mood three times daily as well as after each instance of marijuana use over a four-week period. Results revealed that although the MJ, BP, and MJBP groups each exhibited some degree of cognitive impairment relative to HCs, no significant differences between the BP and MJBP groups were apparent, providing no evidence of an additive negative impact of BPD and MJ use on cognition. Additionally, ecological momentary assessment analyses indicated alleviation of mood symptoms in the MJBP group after marijuana use; MJBP participants experienced a substantial decrease in a composite measure of mood symptoms. Findings suggest that for some bipolar patients, marijuana may result in partial alleviation of clinical symptoms. Moreover, this improvement is not at the expense of additional cognitive impairment.

Objective: Despite growing evidence that chronic marijuana use is associated with cognitive impairment, particularly when use is initiated at an early age, national trends demonstrate significant decreases in the perceived risk of marijuana corresponding with increased use, especially among youth. The current study assessed the impact of marijuana use on executive function and whether patterns of marijuana use, including earlier age at onset, higher frequency, and increased magnitude of use, predict impairment., Method: Forty-four chronic, heavy marijuana smokers (37 male, 7 female) and 32 healthy, nonsmoking control participants (20 male, 12 female) recruited from the Greater Boston area completed two assessments of executive function: the Stroop Color Word Test and Wisconsin Card Sorting Test (WCST)., Results: Marijuana smokers had poorer executive function relative to control participants, a between-group difference that was primarily driven by individuals with early onset of marijuana use (before age 16; n = 21); significance remained even when controlling for frequency and magnitude of use. Further, earlier age at marijuana onset and increased marijuana use predicted poorer neurocognitive performance, and perseverative errors on the WCST significantly predicted marijuana group membership., Conclusions: These findings underscore the impact of early onset of marijuana use on executive function impairment independent of increased frequency and magnitude of use. In addition, poorer performance on the WCST may serve as a neuropsychological marker for heavy marijuana users. These results highlight the need for additional research to identify predictors associated with early marijuana use, as exposure to marijuana during a period of developmental vulnerability may result in negative cognitive consequences.

The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS&#95;2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.

Background: Emotion dysregulation is central to the clinical conceptualization of borderline personality disorder (BPD), with individuals often displaying instability in mood and intense feelings of negative affect. Although existing data suggest important neural and behavioral differences in the emotion processing of individuals with BPD, studies thus far have only explored reactions to overt emotional information. Therefore, it is unclear if BPD-related emotional hypersensitivity extends to stimuli presented below the level of conscious awareness (preattentively)., Methods: Functional magnetic resonance imaging (fMRI) was used to measure neural responses to happy, angry, fearful, and neutral faces presented preattentively, using a backward masked affect paradigm. Given their tendency toward emotional hyperreactivity and altered amygdala and frontal activation, we hypothesized that individuals with BPD would demonstrate a distinct pattern of fMRI responses relative to those without BPD during the viewing of masked affective versus neutral faces in specific regions of interests (ROIs)., Results: RESULTS indicated that individuals with BPD demonstrated increases in frontal, cingulate, and amygdalar activation represented by number of voxels activated and demonstrated a different pattern of activity within the ROIs relative to those without BPD while viewing masked affective versus neutral faces., Conclusion: These findings suggest that in addition to the previously documented heightened responses to overt displays of emotion, individuals with BPD also demonstrate differential responses to positive and negative emotions, early in the processing stream, even before conscious awareness.

Marijuana (MJ) use is on the rise, particularly among teens and emerging adults. This poses serious public health concern, given the potential deleterious effects of MJ on the developing brain. We examined 50 chronic MJ smokers divided into early onset (regular MJ use prior to age 16; n=24) and late onset (age 16 or later; n=26), and 34 healthy control participants (HCs). All completed a modified Stroop Color Word Test during fMRI. Results demonstrated that MJ smokers exhibited significantly poorer performance on the Interference subtest of the Stroop, as well as altered patterns of activation in the cingulate cortex relative to HCs. Further, early onset MJ smokers exhibited significantly poorer performance relative to both HCs and late onset smokers. Additionally, earlier age of MJ onset as well as increased frequency and magnitude (grams/week) of MJ use were predictive of poorer Stroop performance. fMRI results revealed that while late onset smokers demonstrated a more similar pattern of activation to the control group, a different pattern was evident in the early onset group. These findings underscore the importance of assessing age of onset and patterns of MJ use and support the need for widespread education and intervention efforts among youth., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Citicoline is an endogenous nucleotide that has historically been used to treat stroke, traumatic brain injury, and cognitive dysfunction. Research has also shown that citicoline treatment is associated with improved cognitive performance in substance-abusing populations. We hypothesized that marijuana (MJ) smokers who received citicoline would demonstrate improvement in cognitive performance as well as increased neural efficiency during tasks of cognitive control relative to those who received placebo., Method: The current study tested this hypothesis by examining the effects of citicoline in treatment-seeking chronic MJ smokers. In an 8-week double-blind, placebo-controlled study, 19 MJ smokers were randomly assigned via a double-blind procedure to the citicoline (8 Males, 2 Females) or placebo group (9 Males, 0 Females). All participants completed fMRI scanning at baseline and after 8 weeks of treatment during two cognitive measures of inhibitory processing, the Multi Source Interference Test (MSIT) and Stroop Color Word Test, and also completed the Barratt Impulsiveness Scale (BIS-11), a self-report measure of impulsivity., Results: Following the 8 week trial, MJ smokers treated with citicoline demonstrated significantly lower levels of behavioral impulsivity, improved task accuracy on both the MSIT and Stroop tasks, and exhibited significantly different patterns of brain activation relative to baseline levels and relative to those who received placebo., Conclusions: Findings suggest that citicoline may facilitate the treatment of MJ use disorders by improving the cognitive skills necessary to fully engage in comprehensive treatment programs.

Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.

Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Here we report on the structure-based optimization of antibody-recruiting molecules targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chemistry, biochemical and cellular assay analysis, and computation. Our findings have afforded an optimized analog of ARM-H, which is ~1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported derivative. Furthermore, computational analysis, taken together with experimental data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple unique binding modes in interacting with gp120. These results are likely to prove highly enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.

Rationale: Marijuana (MJ) use continues to rise, and as the perceived risk of using MJ approaches an all-time historic low, initiation of MJ use is occurring at even younger ages. As adolescence is a critical period of neuromaturation, teens and emerging adults are at greater risk for experiencing the negative effects of MJ on the brain. In particular, MJ use has been shown to be associated with alterations in frontal white matter microstructure, which may be related to reports of increased levels of impulsivity in this population., Objectives: The aim of this study was to examine the relationship between age of onset of MJ use, white matter microstructure, and reported impulsivity in chronic, heavy MJ smokers., Methods: Twenty-five MJ smokers and 18 healthy controls underwent diffusion tensor imaging and completed the Barratt Impulsiveness Scale. MJ smokers were also divided into early onset (regular use prior to age 16) and late onset (age 16 or later) groups in order to clarify the impact of age of onset of MJ use on these variables., Results: MJ smokers exhibited significantly reduced fractional anisotropy (FA) relative to controls, as well as higher levels of impulsivity. Earlier MJ onset was also associated with lower levels of FA. Interestingly, within the early onset group, higher impulsivity scores were correlated with lower FA, a relationship that was not observed in the late onset smokers., Conclusions: MJ use is associated with white matter development and reported impulsivity, particularly in early onset smokers.

The parasite Toxoplasma gondii can lead to toxoplasmosis in those who are immunocompromised. To combat the infection, the enzyme responsible for nucleotide synthesis thymidylate synthase-dihydrofolate reductase (TS-DHFR) is a suitable drug target. We have used virtual screening to determine novel allosteric inhibitors at the interface between the two TS domains. Selected compounds from virtual screening inhibited TS activity. Thus, these results show that allosteric inhibition by small drug-like molecules can occur in T. gondii TS-DHFR and pave the way for new and potent species-specific inhibitors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Previous studies have reported that patients with bipolar disorder (BPD) exhibit altered emotional processing and regulation. However, results remain largely inconsistent across studies. The aim of the current study was to further examine affective processing in patients with bipolar disorder., Methods: Twenty-three patients diagnosed with BPD (Type I) and 18 healthy matched controls completed a backward-masked affect paradigm while undergoing functional magnetic resonance imaging. Participants also completed a computerized, overt task of facial emotional discrimination after scanning., Results: Results demonstrated altered affective processing of happy and fearful stimuli in bipolar participants in the amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) relative to controls. BPD participants also displayed significant deficits in identifying fearful facial affect., Limitations: This study has a moderate sample size, and the patients with BPD were significantly older than the healthy control participants; this did not appear to impact results, and although statistically significant, it is not likely biologically significant., Conclusions: These findings may have implications for patients with BPD, as altered affective processing could result in deficits in reading social cues., (© 2013 Elsevier B.V. All rights reserved.)

Although several psychological and pharmacological treatment options are available for anxiety disorders, not all patients respond well to each option. Furthermore, given the relatively long duration of adequate treatment trials, finding a good treatment fit can take many months or longer. Thus, both clinicians and patients would benefit from the identification of objective pre-treatment measures that predict which patients will best respond to a given treatment. Recent studies have begun to use biological measures to help predict symptomatic change after treatment in anxiety disorders. In this review, we summarize studies that have used structural and functional neuroimaging measures to predict treatment response in obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and social anxiety disorder (SAD). We note the limitations of the current studies and offer suggestions for future research. Although the literature is currently small, we conclude that pre-treatment neuroimaging measures do appear to predict treatment response in anxiety disorders, and future research will be needed to determine the relative predictive power of neuroimaging measures as compared to clinical and demographic measures.

The frequency of biaryl substructures in a database of approved oral drugs has been analyzed. This led to designation of 20 prototypical biaryls plus 10 arylpyridinones for parametrization in the OPLS all-atom force fields. Bond stretching, angle-bending, and torsional parameters were developed to reproduce the MP2 geometries and torsional energy profiles. The transferability of the new parameters was tested through their application to three additional biaryls. The torsional energetics for the 33 biaryl molecules are analyzed and factors leading to preferences for planar and nonplanar geometries are identified. For liquid biphenyl, the computed density and heat of vaporization at the boiling point (255 °C) are also reported.

The Plasmodium falciparum orthologue of the human cytokine, macrophage migratory inhibitory factor (PfMIF), is produced by the parasite during malaria infection and modulates the host's immune response. As for other MIF orthologues, PfMIF has tautomerase activity, whose inhibition may influence the cytokine activity. To identify small-molecule inhibitors of the tautomerase activity of PfMIF, virtual screening has been performed by docking 2.1 million compounds into the enzymatic site. Assaying of 17 compounds identified four as active. Substructure search for the most potent of these compounds, a 4-phenoxypyridine analogue, identified four additional compounds that were purchased and also shown to be active. Thirty-one additional analogues were then designed, synthesized, and assayed. Three were found to be potent PfMIF tautomerase inhibitors with K(i) of ∼40 nM; they are also highly selective with K(i) &gt; 100 μM for human MIF.

Marijuana (MJ) remains the most widely abused illicit substance in the United States, and in recent years, a decline in perceived risk of MJ use has been accompanied by a simultaneous increase in rates of use among adolescents. In this study, the authors hypothesized that chronic MJ smokers would perform cognitive tasks, specifically those that require executive function, more poorly than control subjects and that individuals who started smoking MJ regularly prior to age 16 (early onset) would have more difficulty than those who started after age 16 (late onset). Thirty-four chronic, heavy MJ smokers separated into early and late onset groups, and 28 non-MJ smoking controls completed a battery of neurocognitive measures. As hypothesized, MJ smokers performed more poorly than controls on several measures of executive function. Age of onset analyses revealed that these between-group differences were largely attributed to the early onset group, who were also shown to smoke twice as often and nearly 3 times as much MJ per week relative to the late onset smokers. Age of onset, frequency, and magnitude of MJ use were all shown to impact cognitive performance. Findings suggest that earlier MJ onset is related to poorer cognitive function and increased frequency and magnitude of MJ use relative to later MJ onset. Exposure to MJ during a period of neurodevelopmental vulnerability, such as adolescence, may result in altered brain development and enduring neuropsychological changes., (PsycINFO Database Record (c) 2012 APA, all rights reserved.)

Salicylidene acylhydrazides belong to a class of compounds shown to inhibit bacterial type III secretion (T3S) in pathogenic Gram-negative bacteria. This class of compounds also inhibits growth and replication of Chlamydiae, strict intracellular bacteria that possess a T3S system. In this study a library of 58 salicylidene acylhydrazides was screened to identify inhibitors of Chlamydia growth. Compounds inhibiting growth of both Chlamydia trachomatis and Chlamydophila pneumoniae were tested for cell toxicity and seven compounds were selected for preliminary pharmacokinetic analysis in mice using cassette dosing. Two compounds, ME0177 and ME0192, were further investigated by individual pharmacokinetic analysis. Compound ME0177 had a relatively high peak plasma concentration (C(max)) and area under curve and therefore may be considered for systemic treatment of Chlamydia infections. The other compound, ME0192, had poor pharmacokinetic properties but the highest anti-chlamydial activity in vitro and therefore was tested for topical treatment in a mouse vaginal infection model. ME0192 administered vaginally significantly reduced the infectious burden of C. trachomatis and the number of infected mice.

Difficulties in the ability to successfully inhibit impulsive behaviors have been reported in marijuana (MJ) smokers, yet few studies have made direct comparisons between early (prior to age 16) and late (age 16 or later) onset MJ smokers, specifically during behavioral inhibition tasks. The current study utilized the Multi-Source Interference Task (MSIT) during functional magnetic resonance imaging (fMRI) in chronic, heavy MJ smokers and healthy non-MJ smoking controls which revealed a more focal pattern of anterior cingulate activity in controls relative to smokers. Early onset smokers had more focal activation but tended to make more errors of commission relative to late onset smokers, suggesting a possible neural adaptation despite difficulty with behavioral inhibition. Further investigation is warranted, as early exposure to MJ may result in reorganization of critical brain regions., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Patients with bipolar disorder (BP) often report subjective mood improvements after smoking marijuana (MJ); however, empirical studies supporting this claim have not been conducted. We conducted this study to determine if marijuana has an impact on mood in bipolar patients who smoke marijuana (MJBP), hypothesizing MJBP participants would experience improved mood after smoking MJ. All participants completed electronic mood ratings three times daily and recorded episodes of MJ use using Palm Pilot devices in their own environments in order to examine the impact of MJ use on mood in MJ-smoking bipolar patients ( n = 12) and pure MJ smokers (MJ; n = 20). Difference scores were calculated between pre and post-MJ scales. Patients with BP ( n = 11) who did not smoke MJ were also included as a comparison group. Significant mood improvement was observed in the MJBP group on a range of clinical scales after smoking MJ, while the MJ group reported a slight worsening of symptoms. Notably, total mood disturbance, a composite of the Profile of Mood States, was significantly reduced in the MJBP group, but increased in the MJ group after smoking. Further, while the MJBP group reported generally worse mood ratings than the BP group prior to smoking MJ, they demonstrated improvement on several scales post-MJ use as compared to BP participants. These data provide empirical support for anecdotal reports that MJ acts to alleviate mood-related symptoms in at least a subset of bipolar patients and underscore the importance of examining MJ use in this population.

Difficulty monitoring and inhibiting impulsive behaviors has been reported in marijuana (MJ) smokers; neuroimaging studies, which examined frontal systems in chronic MJ smokers, have reported alterations during inhibitory tasks. Diffusion tensor imaging (DTI) provides a quantitative estimate of white matter integrity at the microstructural level. We applied DTI, clinical ratings, and impulsivity measures to explore the hypotheses that chronic, heavy MJ smokers would demonstrate alterations in white matter microstructure and a different association between white matter measures and impulsivity relative to nonsmoking control subjects (NS). Fractional anisotropy (FA), a measure of directional coherence, and trace, a measure of overall diffusivity, were calculated for 6 locations including bilateral frontal regions in 15 chronic MJ smokers and 15 NS. Subjects completed clinical rating scales, including the Barratt Impulsivity Scale (BIS). Analyses revealed significant reductions in left frontal FA in MJ smokers relative to NS and significantly higher levels of trace in the right genu. MJ smokers also had significantly higher BIS total and motor subscale scores relative to NS, which were positively correlated with left frontal FA values. Finally, age of onset of MJ use was positively correlated with frontal FA values and inversely related to trace. These data represent the first report of significant alterations in frontal white matter tracts associated with measures of impulsivity in chronic MJ smokers. Early MJ use may result in reduced FA and increased diffusivity, which may be associated with increased impulsivity, and ultimately contribute to the initiation of MJ use or the inability to discontinue use., ((PsycINFO Database Record (c) 2011 APA, all rights reserved).)

A focused library of [4-(2-hydroxyphenyl)thiazol-2-yl]methanones was prepared in a four-step synthesis with the aim to obtain potent inhibitors of type III secretion in Gram-negative bacteria. The compounds are potential bioisosteres of salicylidene acylhydrazides that are a known class of type III secretion inhibitors.

Salicylidene acylhydrazides are inhibitors of type III secretion in several gram-negative pathogens. To further develop the salicylidene acylhydrazides, scaffold hopping was applied to replace the core fragment of the compounds. The novel 2-(2-amino-pyrimidine)-2,2-difluoroethanol scaffold was identified as a possible analog to the salicylidene acylhydrazide core structure. The synthesis of a library of 2-(2-amino-pyrimidine)-2,2-difluoro-ethanols is described in this paper.

A combined application of statistical molecular design (SMD), quantitative structure-activity relationship (QSAR) modeling and prediction of new active compounds was effectively used to develop salicylidene acylhydrazides as inhibitors of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. SMD and subsequent synthesis furnished 50 salicylidene acylhydrazides in high purity. Based on data from biological evaluation in T3S linked assays 18 compounds were classified as active and 25 compounds showed a dose-dependent inhibition. The 25 compounds were used to compute two multivariate QSAR models and two multivariate discriminant analysis models were computed from both active and inactive compounds. Three of the models were used to predict 4416 virtual compounds in consensus and eight new compounds were selected as an external test set. Synthesis and biological evaluation of the test set in Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis validated the models. Y. pseudotuberculosis and C. trachomatis cell-based infection models showed that compounds identified in this study are selective and non-toxic inhibitors of T3S dependent virulence., (Copyright 2010 Elsevier Ltd. All rights reserved.)