Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

Comparative Transcriptome Profiling Unfolds a Complex Defense and Secondary Metabolite Networks Imparting Corynespora cassiicola Resistance in Soybean (Glycine max (L.) Merrill).

Target spot is caused by Corynespora cassiicola, which heavily affects soybean production areas that are hot and humid. Resistant soybean genotypes have been identified; however, the molecular mechanisms governing resistance to infection are unknown. Comparative transcriptomic profiling using two known resistant genotypes and two susceptible genotypes was performed under infected and control conditions to understand the regulatory network operating between soybean and C. cassiicola. RNA-Seq analysis identified a total of 2571 differentially expressed genes (DEGs) which were shared by all four genotypes. These DEGs are related to secondary metabolites, immune response, defense response, phenylpropanoid, and flavonoid/isoflavonoid pathways in all four genotypes after C. cassiicola infection. In the two resistant genotypes, additional upregulated DEGs were identified affiliated with the defense network: flavonoids, jasmonic acid, salicylic acid, and brassinosteroids. Further analysis led to the identification of differentially expressed transcription factors, immune receptors, and defense genes with a leucine-rich repeat domain, dirigent proteins, and cysteine (C)-rich receptor-like kinases. These results will provide insight into molecular mechanisms of soybean resistance to C. cassiicola infection and valuable resources to potentially pyramid quantitative resistance loci for improving soybean germplasm.

Design, synthesis, characterization and anticancer activity evaluation of deoxycholic acid-chalcone conjugates.

A series of deoxycholic acid-chalcone amides were synthesised and tested against the human lung cancer cell line, A549 and the cervical cancer cell line, SiHa. Among the synthesised deoxycholic acid-chalcone conjugates, some conjugates showed encouraging results as anticancer agents with good in vitro activity. More precisely, deoxycholic acid-chalcone conjugates 4b (IC50: 0.51 µM) and 4e (IC50: 0.84 µM) having 2­nitrophenyl and 3,4,5­trimethoxyphenyl groups exhibited a good activity against human cancer cell-line SiHa and while 4d (IC50: 0.25 µM) and 4b (IC50: 1.71 µM) showed better activity against A549 lung cancer cell line with respect to deoxycholic acid and chalcones. The anticancer activity of the bile acid conjugated chalcones was more than the activity of chalcone and deoxycholic acid alone. The results indicate that a bile acid conjugate strategy may be beneficial in improving the biological activity of chalcone derivatives. The enhanced activity of certain compounds may be due to their increased bioavailability.

Assessing Psychosocial Distress in Cystic Fibrosis: Validation of the 'Distress in Cystic Fibrosis Scale'.

Experiences of anxiety and depression are common in adults with Cystic Fibrosis (AwCF) (e.g. Quittner in Thorax 69:1090-1097, 2014) and may impact on a wide range of important health-related behaviours, such as adherence to medication and timely attendance for medical review when experiencing pulmonary exacerbation. Common screening measures used in CF such as the PHQ-9 and GAD-7 may reflect an absence of anxiety or depression when clinically significant emotional difficulties are apparent on further assessment. This study preliminarily validated the previously developed Distress in Cystic Fibrosis Scale (DCFS) (Patel in Journal of Cystic Fibrosis 15:S26, 2016); a 23-item questionnaire to assess psychosocial distress in AwCF. Inpatient and outpatient participants with CF (N = 119) completed a battery of questionnaires, including the DCFS. PCA results supported a single component model. The DCFS showed high internal consistency and correlated significantly with measures of mood and quality of life. The DCFS shows promise as a screening tool to assess clinically significant psychosocial distress in an adult CF population.

Safety and Inner City Neighborhood Change: Student and Teacher Perspectives.

The introduction of mixed-income communities in public housing neighborhoods is a common revitalization strategy in metropolitan areas in North America. This study investigates student and teacher perspectives on safety in a Canadian inner city and marginalized neighborhood undergoing revitalization, alongside the redesign of a local school. The displacement of families and students, tied to housing relocation and student school mobility, resulted in increased concern around bullying, school safety, and displacement of place-based familiarity and social bonds. While most students felt safe at school, they were acutely aware of community level violence, criminal and gang activity in the neighborhood, and racial stereotyping. Students were also generally skeptical that revitalization would address the root causes of violence. The findings support the importance of including children's voices when planning, implementing, and evaluating policy initiatives that directly affect their lives.

Deriving within-person estimates of delta-beta coupling: A novel measure for identifying individual differences in emotion and neural function in childhood.

Delta-beta coupling is increasingly used to understand early emotional development. However, little is known about the development of the coupling, limiting its utility for identifying normative or aberrant functioning. We used a prospective longitudinal sample (N = 122) to compare measures of within-person and between-person coupling between ages 3 and 5, track the developmental trajectory of coupling, identify individual differences in patterns of development, and explore emotion-related predictors and outcomes of discrete developmental patterns. Within-person measures, limited in overall utility, were most useful when (1) statistical approaches produced more homogenous groups within the overall sample (extreme groups or latent classes) or (2) the full developmental course was considered. We found two trajectories of change in frontal coupling and three trajectories of change in parietal coupling. Coupling trajectories were predicted by observed fear and approach/avoidance at age 3. In addition, high levels of frontal coupling at age 3 that declined and then levelled out through age 5 were associated with lower levels of internalizing by age 5. This work provides a foundation for understanding normative change in delta-beta coupling across the preschool years and useful insight for the use of this metric in future work.

American Psychiatric Association's Leadership Fellowship Program: Short-term and Longer-term Outcomes.

OBJECTIVE: This study assessed the impact of a Leadership Fellowship, sponsored by the American Psychiatric Association (APA) and APA Foundation, on the careers of psychiatry residents and examined the influence of gender and year of Fellowship completion. This 2-year program for residents offered multiple opportunities to interact with professional leaders at various levels. METHODS: A retrospective online survey of alumni of the APA Leadership Fellowship, who had completed this Fellowship between 2003 and 2019, was conducted. RESULTS: Out of the 93 psychiatrists who were sent the survey, 59 alumni responded (60.8% response rate). Most respondents had remained involved with organized psychiatry groups and 80% held leadership positions. Respondents reported high levels of satisfaction with the APA Fellowship experience, noting the importance of peer networking. Overall, male and female respondents were similar in their subsequent leadership positions and satisfaction with the survey. Similarly, Fellows who completed the Fellowship in 2003-2015 had responses about the experience that were largely similar to those in the 2016-2019 cohort that had not yet completed their residency. CONCLUSION: A vast majority of alumni of the APA Leadership Fellowship had become leaders in their workplace or organized psychiatry groups. The leadership-focused career development programs for psychiatry trainees are important avenues to develop a diverse cohort of future leaders in psychiatry.

Investigating microstructural variation in the human hippocampus using non-negative matrix factorization.

In this work we use non-negative matrix factorization to identify patterns of microstructural variance in the human hippocampus. We utilize high-resolution structural and diffusion magnetic resonance imaging data from the Human Connectome Project to query hippocampus microstructure on a multivariate, voxelwise basis. Application of non-negative matrix factorization identifies spatial components (clusters of voxels sharing similar covariance patterns), as well as subject weightings (individual variance across hippocampus microstructure). By assessing the stability of spatial components as well as the accuracy of factorization, we identified 4 distinct microstructural components. Furthermore, we quantified the benefit of using multiple microstructural metrics by demonstrating that using three microstructural metrics (T1-weighted/T2-weighted signal, mean diffusivity and fractional anisotropy) produced more stable spatial components than when assessing metrics individually. Finally, we related individual subject weightings to demographic and behavioural measures using a partial least squares analysis. Through this approach we identified interpretable relationships between hippocampus microstructure and demographic and behavioural measures. Taken together, our work suggests non-negative matrix factorization as a spatially specific analytical approach for neuroimaging studies and advocates for the use of multiple metrics for data-driven component analyses.

Primary Care Providers' Acceptance of Pharmacists' Recommendations to Support Optimal Medication Management for Patients with Diabetic Kidney Disease.

BACKGROUND: Patients with diabetic kidney disease (DKD) often struggle with blood pressure control. In team-based models of care, pharmacists and primary care providers (PCPs) play important roles in supporting patients' blood pressure management. OBJECTIVE: To describe whether PCPs' acceptance of pharmacists' recommendations impacts systolic blood pressure (SBP) at 36 months. DESIGN: An observational analysis of a subset of participants randomized to the intervention arm of the Simultaneous risk factor control using Telehealth to slOw Progression of Diabetic Kidney Disease (STOP-DKD) study. PARTICIPANTS: STOP-DKD participants for whom (1) the pharmacist made at least one recommendation to the PCP; (2) there were available data regarding the PCP's corresponding action; and (3) there were SBP measurements at baseline and 36 months. INTERVENTION: Participants received monthly telephone calls with a pharmacist addressing health behaviors and medication management. Pharmacists made medication-related recommendations to PCPs. MAIN MEASURES: We fit an unadjusted generalized linear mixed model to assess the association between the number of pharmacists' recommendations for DKD and blood pressure management and PCPs' acceptance of such recommendations. We used a linear regression model to evaluate the association between PCP acceptance and SBP at 36 months, adjusted for baseline SBP. KEY RESULTS: Pharmacists made 176 treatment recommendations (among 59 participants), of which 107 (61%) were accepted by PCPs. SBP significantly declined by an average of 10.5 mmHg (p < 0.01) among 47 of 59 participants who had valid measurements at baseline and 36 months. There was a significant association between the number of pharmacist recommendations and the odds of PCP acceptance (OR 1.19; 95%CI 1.00, 1.42; p < 0.05), but no association between the number of accepted recommendations and SBP. CONCLUSIONS: Pharmacists provided actionable medication-related recommendations. We identified a significant decline in SBP at 36 months, but this reduction was not associated with recommendation acceptance. TRIAL REGISTRATION: NCT01829256.

The role of perioperative nonsteroidal anti-inflammatory drugs use in cataract surgery.

PURPOSE OF REVIEW: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used and studied by cataract surgeons for varied benefits in the perioperative period, but optimal medication formulae and dosing have yet to be established. In this article, we perform a literature review of articles published between 1 January 2016 and 30 June 2018 concerning perioperative NSAID use for patients undergoing cataract surgery. RECENT FINDINGS: Literature review revealed five areas of recent study including preoperative NSAID use for iatrogenic inflammation, intraoperative NSAID use for pupillary mydriasis, postoperative NSAID use for prevention of cystoid macular edema (CME), for prevention of pain/inflammation, and for improvement in patient quality of life. SUMMARY: Recent literature establishes the efficacy of a newly available intracameral phenylephrine-NSAID combination for pupillary mydriasis, postoperative NSAID use for preventing CME in certain high-risk populations, and postoperative NSAIDs for controlling pain and inflammation. However, further high-quality studies are required to determine the long-term effects of perioperative NSAIDs on visual acuity and CME rates.

Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application.

Curcumin is an admired, plant-derived compound that has been extensively investigated for diverse range of biological activities, but the use of this polyphenol is limited due to its instability. Chemical modifications in curcumin are reported to seize this limitation; such efforts are intensively performed to discover molecules with similar but improved stability and better properties. Focal points of these reviews are synthesis of stable pyrazole and isoxazole analogs of curcumin and application in various biological systems. This review aims to emphasize the latest evidence of curcumin pyrazole analogs as a privileged scaffold in medicinal chemistry. Manifold features of curcumin pyrazole analogs will be summarized herein, including the synthesis of novel curcumin pyrazole analogs and the evaluation of their biological properties. This review is expected to be a complete, trustworthy and critical review of the curcumin pyrazole analogs template to the medicinal chemistry community.

Heritability estimates of cortical anatomy: The influence and reliability of different estimation strategies.

Twin study designs have been previously used to investigate the heritability of neuroanatomical measures, such as regional cortical volumes. Volume can be fractionated into surface area and cortical thickness, where both measures are considered to have independent genetic and environmental bases. Region of interest (ROI) and vertex-wise approaches have been used to calculate heritability of cortical thickness and surface area in twin studies. In our study, we estimate heritability using the Human Connectome Project magnetic resonance imaging dataset composed of healthy young twin and non-twin siblings (mean age of 29, sample size of 757). Both ROI and vertex-wise methods were used to compare regional heritability of cortical thickness and surface area. Heritability estimates were controlled for age, sex, and total ipsilateral surface area or mean cortical thickness. In both approaches, heritability estimates of cortical thickness and surface area were lower when accounting for average ipsilateral cortical thickness and total surface area respectively. When comparing both approaches at a regional level, the vertex-wise approach showed higher surface area and lower cortical thickness heritability estimates compared to the ROI approach. The calcarine fissure had the highest surface area heritability estimate (ROI: 44%, vertex-wise: 50%) and posterior cingulate gyrus had the highest cortical thickness heritability (ROI: 50%, vertex-wise 40%). We also observed that limitations in image processing and variability in spatial averaging errors based on regional size may make obtaining true estimates of cortical thickness and surface area challenging in smaller regions. It is important to identify which approach is best suited to estimate heritability based on the research hypothesis and the size of the regions being investigated.

Small-molecule WNK inhibition regulates cardiovascular and renal function.

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

Utilization of multiple SAVI SCOUT surgical guidance system reflectors in the same breast: A single-institution feasibility study.

SAVI SCOUT Surgical Guidance System has been shown to be a reliable and safe alternative to wire localization in breast surgery. This study evaluated the feasibility of using multiple reflectors in the same breast. We performed an IRB-approved, HIPAA-compliant, single-institution retrospective review of 183 patients who underwent breast lesion localization and excision using SAVI SCOUT Surgical Guidance System (Cianna Medical) between June 2015 and January 2017. We performed a subset analysis in 42 patients in whom more than one reflector was placed. Specimen radiography, pathology, distance between reflectors, target removal, margin positivity, and complications were evaluated. Among 183 patients, 42 patients had more than one reflector placed in the same breast to localize 68 lesions. Benign (n = 6, 8.8%), high-risk (n = 23, 33.8%), and malignant (n = 39, 57.4%) lesions were included. Thirty-six patients (85.7%) had a total of 2 reflectors placed and 6 patients had a total of 3 reflectors placed (14.3%). The indications for multiple reflector placement in the same breast included multiple separate lesions (n = 23) and bracketing of large lesions (n = 19). The mean distance between the reflectors was 42 mm (22-93 mm). All lesions were successfully targeted and retrieved. Of 39 malignant lesions, 10.3% (n = 4) had positive margins and 10.3% (n = 4) had close (<1 mm) margins at surgery. All patients with positive margins underwent re-excision. No complications occurred preoperatively, intra-operatively, or postoperatively. The use of multiple SAVI SCOUT reflectors for localizing multiple lesions in the same breast or bracketing large lesions is feasible and safe.

Heritability of hippocampal subfield volumes using a twin and non-twin siblings design.

The hippocampus is composed of distinct subfields linked to diverse functions and disorders. The subfields can be mapped using high-resolution magnetic resonance images, and their volumes can potentially be used as quantitative phenotypes for genetic investigation of hippocampal function. We estimated the heritability of hippocampus subfield volumes of 465 subjects from the Human Connectome Project (twins and non-twin siblings) using two methods. The first used a univariate model to estimate heritability with and without adjustment for total brain volume (TBV) and ipsilateral hippocampal volume to determine if heritability was uniquely attributable to subfield volume rather than confounds that attributed to global volumes. We observed the right: subiculum, cornu ammonis 2/3, and cornu ammonis 4/dentate gyrus subfields had the highest significant heritability estimates after adjusting for ipsilateral hippocampal volume. In the second analysis, we used a bivariate model to investigate the shared heritability and genetic correlation of the subfield volumes with TBV and ipsilateral hippocampal volume. Genetic correlation demonstrates shared genetic architecture between phenotypes and shared heritability is what proportion of the genetic architecture of one trait is shared by the other. Highest genetic correlations were between subfield volumes and ipsilateral hippocampal volume than with TBV. The pattern was opposite for shared heritability suggesting that subfields share greater proportion of the genetic architecture with TBV than with ipsilateral hippocampal volume. The relationship between the genetic architecture of TBV, hippocampal volume, and of individual subfields should be accounted for when using hippocampal subfield volumes as quantitative phenotypes for imaging genetics studies. Hum Brain Mapp 38:4337-4352, 2017. © 2017 Wiley Periodicals, Inc.

Beyond Wires and Seeds: Reflector-guided Breast Lesion Localization and Excision.

Purpose To evaluate outcomes of Savi Scout (Cianna Medical, Aliso Viejo, Calif) reflector-guided localization and excision of breast lesions by analyzing reflector placement, localization, and removal, along with target excision and rates of repeat excision (referred to as re-excision). Materials and Methods A single-institution retrospective review of 100 women who underwent breast lesion localization and excision by using the Savi Scout surgical guidance system from June 2015 to May 2016 was performed. By using image guidance 0-8 days before surgery, 123 nonradioactive, infrared-activated, electromagnetic wave reflectors were percutaneously inserted adjacent to or within 111 breast targets. Twenty patients had two or three reflectors placed for bracketing or for localizing multiple lesions, and when ipsilateral, they were placed as close as 2.6 cm apart. Target and reflector were localized intraoperatively by one of two breast surgeons who used a handpiece that emitted infrared light and electromagnetic waves. Radiographs of the specimen and pathologic analysis helped verify target and reflector removal. Target to reflector distance was measured on the mammogram and radiograph of the specimen, and reflector depth was measured on the mammogram. Pathologic analysis was reviewed. Re-excision rates and complications were recorded. By using statistics software, descriptive statistics were generated with 95% confidence intervals (CIs) calculated. Results By using sonographic (40 of 123; 32.5%; 95% CI: 24.9%, 41.2%) or mammographic (83 of 123; 67.5%; 95% CI: 58.8% 75.1%) guidance, 123 (100%; 95% CI: 96.4%, 100%) reflectors were placed. Mean mammographic target to reflector distance was 0.3 cm. All 123 (100%; 95% CI: 96.4%, 100%) targets and reflectors were excised. Pathologic analysis yielded 54 of 110 malignancies (49.1%; 95% CI: 39.9%, 58.3%; average, 1.0 cm; range, 0.1-5 cm), 32 high-risk lesions (29.1%; 95% CI: 21.4%, 38.2%), and 24 benign lesions (21.8%; 95% CI: 115.1%, 30.4%). Four of 54 malignant cases (7.4%; 95% CI: 2.4%, 18.1%) demonstrated margins positive for cancer that required re-excision. Five of 110 radiographs of the specimen (4.5%; 95% CI: 1.7%, 10.4%) demonstrated increased distance between the target and reflector distance of greater than 1.0 cm (range, 1.1-2.6 cm) compared with postprocedure mammogram the day of placement, three of five were associated with hematomas, two of five migrated without identifiable cause. No related postoperative complications were identified. Conclusion Savi Scout is an accurate, reliable method to localize and excise breast lesions with acceptable margin positivity and re-excision rates. Bracketing is possible with reflectors as close as 2.6 cm. Savi Scout overcomes many limitations of other localization methods, which warrants further study. © RSNA, 2017.

Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism.

BACKGROUND: People with an autistic spectrum disorder (ASD) display a variety of characteristic behavioral traits, including impaired social interaction, communication difficulties and repetitive behavior. This complex neurodevelopment disorder is known to be associated with a combination of genetic and environmental factors. Neurexins and neuroligins play a key role in synaptogenesis and neurexin-neuroligin adhesion is one of several processes that have been implicated in autism spectrum disorders. RESULTS: In this report we describe the manual annotation of a selection of gene products known to be associated with autism and/or the neurexin-neuroligin-SHANK complex and demonstrate how a focused annotation approach leads to the creation of more descriptive Gene Ontology (GO) terms, as well as an increase in both the number of gene product annotations and their granularity, thus improving the data available in the GO database. CONCLUSIONS: The manual annotations we describe will impact on the functional analysis of a variety of future autism-relevant datasets. Comprehensive gene annotation is an essential aspect of genomic and proteomic studies, as the quality of gene annotations incorporated into statistical analysis tools affects the effective interpretation of data obtained through genome wide association studies, next generation sequencing, proteomic and transcriptomic datasets.

Letting youths choose for themselves: concept mapping as a participatory approach for program and service planning.

Ensuring that the voices of youths are heard is key in creating services that align with the needs and goals of youths. Concept mapping, a participatory mixed-methods approach, was used to engage youths, families, and service providers in an assessment of service gaps facing youth in an underserviced neighborhood in Toronto, Canada. We describe 6 phases of concept mapping: preparation, brainstorming, sorting and rating, analysis, interpretation, and utilization. Results demonstrate that youths and service providers vary in their conceptualizations of youth service needs and priorities. Implications for service planning and for youth engagement in research are discussed.

Folate conjugated albumin as a targeted nanocarrier for the delivery of fisetin: in silico and in vitro biological studies.

Fisetin (FST), a natural flavonoid compound derived from various fruits and vegetables, including apple, strawberry, and onion, demonstrates potential for a wide range of pharmaceutical applications, including potential anticancer properties. However, challenges such as low bioavailability, poor aqueous solubility, and limited permeability restrict the use of FST in the pharmaceutical sector. Nowadays, targeted nanomedicines have garnered attention to overcome limitations associated with phytochemicals, including FST. In the present study, we have designed and successfully prepared folate-targeted FST nanoparticles (FFNPs). Characterization through DLS and FE-SEM revealed the successful preparation of monodisperse (PDI: 0.117), nanoscale-sized (150 nm), and spherical nanoparticles. Physicochemical characterization including FTIR, XRD, DSC, and TGA analysis, confirmed the encapsulation of the FST within the Folic acid (FA) - conjugated nanoparticles (CNPs) and revealed its amorphous nature. Molecular docking analysis revealed the strong binding affinity and specific amino acid interactions involved in the BSA-FST-FA complex, suggesting the potential synergistic effect of FST and FA in enhancing the therapeutic activity of the FFANPs. Cytotoxic assessments by the MTT assay, migration assay, AO-EtBr staining assay, colony formation assay, and cellular uptake study demonstrated enhanced anticancer efficacy, apoptosis induction, and enhanced uptake of FFNPs compared to pure FST. These findings propose prepared FFNPs as a promising targeted drug delivery nanocarrier for effective FST delivery in cancer therapy.