Borylation via iridium catalysed C-H activation: a new concise route to duocarmycin derivatives.

The synthesis of the ethyl ester analogue of the ultrapotent antitumour antibiotic seco-duocarmycin SA has been achieved in eleven linear steps from commercially available starting materials. The DSA alkylation subunit can be made in ten linear steps from the same precursor. The route involves C-H activation at the equivalent of the C7 position on indole leading to a borylated intermediate 9 that is stable enough for peptide coupling reactions but can be easily converted to the free hydroxyl analogue.

Care integration goes Beyond Co-Location: Creating a Medical Home.

How to successfully integrate mental health and primary care remains a critically important question given the continued morbidity and early mortality of people with serious mental illness. This study investigated integration in a community mental health center (MHC) primarily treating people with SMI in a large, urban northeastern city where an on-site primary care center (PCC) was opened resulting in co-located mental health and primary care services being provided. Using focus groups and online surveys this study asked participants about their thoughts and interactions with the on-site PCC. Participants included staff from clinical, non-clinical, and leadership roles in the mental health center (MHC; PCC staff; and MHC clients who did not use the on-site PCC). MHC staff also offered their thoughts about and experiences with the on-site PCC one year and two years after the on-site PCC opened through an on-line survey. In both methods, staff reported limited awareness and expectations of the PCC in the first year. Staff indicated that successful care integration goes beyond co-location and peer health navigation can enhance integration. Finally, staff discussed desires for enhancing care integration and co-located services into a medical home that included communicating across medical records and providers at different agencies. Our results suggest that, in addition to the previously researched three C's of care integration (consultation, coordination, and collaboration), two more C's were essential to successful care integration: co-location and communication. Communication across medical records and providers at different agencies was an essential component of care integration, and co-location added increased ability to communicate across providers.

Diverse elements comprising studies of peer support complicate evidence synthesis.

BACKGROUND: Innovative approaches to care, such as peer support, are needed to address the substantial and frequently unmet needs of people with serious mental illnesses such as schizophrenia. Although peer support services continue to expand in mental healthcare, findings of effectiveness from systematic reviews are mixed. However, the studies evaluated in these reviews consisted of diverse elements which the review methods neglected to consider. AIMS: This review aims to demonstrate the substantial diversity in intervention components and measured outcomes among studies of peer support and lay the groundwork for more focused reviews of individual intervention components. METHODS: As part of a realist review of the literature, here we synthesize evidence in a way that examines the substantial diversity in intervention components and measured outcomes comprising studies of peer support. RESULTS: Seven categories of outcomes were represented, including recovery, symptoms and functioning, and care utilization. Importantly, seven distinct intervention components were represented in 26 studies: "being there," assistance in self-management, linkage to clinical care and community resources, social and emotional support, ongoing support, explicit utilization of shared lived experience or peer support values, and systems advocacy. Reflecting diversity in approaches, no study reported all intervention components, and no component was found among all studies. IMPLICATIONS: Peer support services constitute a category of intervention approaches far too varied to evaluate as a single entity. Results suggest intervention components deserving more focused research, including assistance in self-management, "being there," and explicit utilization of shared lived experience or peer support values. PRISMA/PROSPERO: As this article reports results from a realist review of the literature, we did not follow the PRISMA guidance which is suitable for systematic reviews. We did follow the Realist and Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) guidelines.This review was not registered on PROSPERO as it is not a systematic review.

Detection of endometrial cancer using tampon-based collection and methylated DNA markers.

OBJECTIVE: Alterations in DNA methylation are early events in endometrial cancer (EC) development and may have utility in EC detection via tampon-collected vaginal fluid. METHODS: For discovery, DNA from frozen EC, benign endometrium (BE), and benign cervicovaginal (BCV) tissues underwent reduced representation bisulfite sequencing (RRBS) to identify differentially methylated regions (DMRs). Candidate DMRs were selected based on receiver operating characteristic (ROC) discrimination, methylation level fold-change between cancers and controls, and absence of background CpG methylation. Methylated DNA marker (MDM) validation was performed using qMSP on DNA from independent EC and BE FFPE tissue sets. Women ≥45 years of age with abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB) or any age with biopsy-proven EC self-collected vaginal fluid using a tampon prior to clinically indicated endometrial sampling or hysterectomy. Vaginal fluid DNA was assayed by qMSP for EC-associated MDMs. Random forest modeling analysis was performed to generate predictive probability of underlying disease; results were 500-fold in-silico cross-validated. RESULTS: Thirty-three candidate MDMs met performance criteria in tissue. For the tampon pilot, 100 EC cases were frequency matched by menopausal status and tampon collection date to 92 BE controls. A 28-MDM panel highly discriminated between EC and BE (96% (95%CI 89-99%) specificity; 76% (66-84%) sensitivity (AUC 0.88). In PBS/EDTA tampon buffer, the panel yielded 96% (95% CI 87-99%) specificity and 82% (70-91%) sensitivity (AUC 0.91). CONCLUSION: Next generation methylome sequencing, stringent filtering criteria, and independent validation yielded excellent candidate MDMs for EC. EC-associated MDMs performed with promisingly high sensitivity and specificity in tampon-collected vaginal fluid; PBS-based tampon buffer with added EDTA improved sensitivity. Larger tampon-based EC MDM testing studies are warranted.

Beyond Supported Housing: Correlates of Improvements in Quality of Life Among Homeless Adults with Mental Illness.

BACKGROUND: The goal of supported housing, aside from exiting homelessness, is to improve overall quality of life. The contribution of factors that enhance quality of life in supported housing programs, beyond housing itself, have not been empirically identified. METHODS: Five-year follow-up data from two arms of a randomized trial comparing case management with and without housing vouchers (n = 278) were examined to identify correlates of improved quality of life, beyond housing resources. RESULTS: Access to a housing contributed to 4% of the variance in improved quality of life. Improvement in psychiatric symptoms, alcohol and drug use, employment, total income, and social support were associated with an additional 34-43% of variance in improved quality of life above and beyond housing. CONCLUSION: Improvements in quality of life were more strongly associated with improvements in mental health and other aspects of social well-being than housing alone.

Training Male Sexual Abuse Survivors as Peer Leaders to Deliver Motivational Interviewing and Trauma-Informed Affirmative Care.

This paper provides a description and evaluation of training male sexual abuse survivors to deliver Motivational Interviewing (MI) and Motivational Interviewing with Trauma-Informed Affirmative Care (MI-AC) online to sexual and gender minority (SGM) men with sexual assault histories and depression. After a search and selection process, 26 men with lived experience of sexual abuse received MI training that included the use of role-playing, video demonstrations, and practice followed by weekly supervision while co-leading groups. Peer leaders completed several measures pre and post training, including beliefs about MI and self-reported learning of MI and satisfaction with the training. A sample of MI and MI-AC audio sessions were independently rated for adherence and competence. Peer leaders' beliefs about MI changed over time, while self-rated skill level stayed consistent. Peer leaders demonstrated good adherence to the MI and MI-AC conditions. Results suggest that men with lived experience of sexual trauma effectively learned to deliver MI and/or MI-AC to SGM male survivors in online groups. These interventions have the potential to expand the reach of limited services for this population as well as reduce their depression and assist in SGM men with histories of sexual abuse entering into formal mental health services.

Methylated DNA markers for plasma detection of ovarian cancer: Discovery, validation, and clinical feasibility.

OBJECTIVE: Aberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma. METHODS: DNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma from women newly diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. RESULTS: Thirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (HGS)) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95% CI, 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86-0.96)). Among the 5 stage I/II HGS OCs included, all were correctly identified. CONCLUSIONS: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted.

Euglenatides, Potent Antiproliferative Cyclic Peptides Isolated from the Freshwater Photosynthetic Microalga Euglena gracilis.

By limiting the nitrogen source to glutamic acid, we isolated cyclic peptides from Euglena gracilis containing asparagine and non-proteinogenic amino acids. Structure elucidation was accomplished through spectroscopic methods, mass spectrometry and chemical degradation. The euglenatides potently inhibit pathogenic fungi and cancer cell lines e.g., euglenatide B exhibiting IC50 values of 4.3 µM in Aspergillus fumigatus and 0.29 µM in MCF-7 breast cancer cells. In an unprecedented convergence of non-ribosomal peptide synthetase and polyketide synthase assembly-line biosynthesis between unicellular species and the metazoan kingdom, euglenatides bear resemblance to nemamides from Caenorhabditis elegans and inhibited both producing organisms E. gracilis and C. elegans. By molecular network analysis, we detected over forty euglenatide-like metabolites in E. gracilis, E. sanguinea and E. mutabilis, suggesting an important biological role for these natural products.

Enhancing outcomes for persons with co-occurring disorders through skills training and peer recovery support.

Background: "Recovery supports", often provided by persons in recovery themselves, have emerged over the last decade as important components of recovery-oriented systems of care for persons with substance use disorders.Aims: This study assesses the benefit of adding peer recovery supports to the care of adults with co-occurring psychosis and substance use.Method: 137 adults with both disorders who had at least one prior admission within the past year were recruited during an index hospitalization into a randomized trial of standard care vs skills training with and without a peer-led social engagement program. Participants were assessed at admission and at three and nine months post-discharge on symptoms, functioning, substance use, and other factors.Results: At three months, skills training was effective in reducing alcohol use and symptoms, with the addition of peer-led support resulting in higher levels of relatedness, self-criticism, and outpatient service use. At nine months, skills training was effective in decreasing symptoms and inpatient readmissions and increasing functioning, with the addition of peer support resulting in reduced alcohol use.Conclusions: Adding peer-led support may increase engagement in care over the short term and reduce substance use over the longer-term for adults with co-occurring disorders.

"If You Want to Know About the Book, Ask the Author": Enhancing Community Engagement Through Participatory Research in Clinical Mental Health Settings.

Participatory research, in which people with lived experience of the study phenomenon are involved as collaborators, has been conducted for decades; however, these innovations have struggled to take hold in mental health settings-until recently. The slow uptake of community partnered research in mental health has been unfortunate, especially because this field already suffers from poor community relations, pervasive community mistrust, and racial and ethnic disparities. But now, people with lived experience of severe mental illness-long considered to be "incapable" of functioning as co-researchers-are beginning to be included on research teams. However, training and opportunities for conducting such work are still lacking. This report describes a two-year initiative to improve the quality and quantity of participatory research being conducted in a department of psychiatry at a large medical school, which culminated in an innovative training program for both researchers and patients, developed in direct collaboration with stakeholders. In addition to detailing this program, we also discuss the deep legacy of mental health mistrust and our own efforts to address issues of social justice and health equity.

Missing Ingredients in Shared Decision-Making?

Shared decision-making (SDM) is a collaborative approach to making decisions in health care, and is a cornerstone of person-centered care. While providers are increasingly expected to utilize SDM in routine practice, widespread and sustainable implementation has proven difficult, especially in the care of individuals diagnosed with serious mental illnesses, and physicians and patients continue to identify barriers to effective collaboration. To date, SDM research has largely focused on the provision of high-quality clinical information from doctors to patients to the neglect of what may be the most important, and transformative, aspect of SDM-the relationship itself. In this forum, the lack of attention to the relationship in SDM research and practice will be explored, along with the relational qualities that need to be in place to implement SDM in the care of persons with serious mental illness based on the findings from a mixed-methods, participatory research project.

A Gold(III) Pincer Ligand Scaffold for the Synthesis of Binuclear and Bioconjugated Complexes: Synthesis and Anticancer Potential.

Cyclometalated (C^N^C)AuIII complexes bearing functionalized N-heterocyclic carbene (NHC) ligands provide a high-yielding, modular route to bioconjugated and binuclear complexes. This methodology has been applied to the synthesis of bioconjugated complexes presenting biotin and 17α-ethynylestradiol vectors, as well as to the synthesis of bimetallic AuIII /AuI complexes. The in vitro antiproliferative activities of these compounds against various cancer cells lines depend on the linker length, with the longer linker being the most potent. The estradiol conjugate AuC6 Estra proved to be more toxic against the estrogen receptor positive (ER+) cancer cells than against the ER- cancer cells and non-cancer cells. The bimetallic complex AuC6 Au was more selective for breast cancer cells with respect to a healthy cell standard than the monometallic complex AuNHC. The metal uptake study on cells expressing or not biotin and estrogen receptors revealed an improved and targeted delivery of gold for both the bioconjugated complexes AuC6 Biot and AuC6 Estra compared to the non-vectorised analogue AuNHC. The investigations of the interaction of the bioconjugates and bimetallic complexes with human telomeric G-quadruplex DNA using FRET-melting techniques revealed a reduced ability to stabilize this DNA structure with respect to the non-vectorised analogue AuNHC.

Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction.

The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the ß-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl-bridging group to constrain the peptides, coupled with a glutamic acid to proline replacement leads to a new peptide with a Ki of 6.1 nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity.

Cardiovascular Mechanisms of Action of Anthocyanins May Be Associated with the Impact of Microbial Metabolites on Heme Oxygenase-1 in Vascular Smooth Muscle Cells.

Anthocyanins are reported to have cardio-protective effects, although their mechanisms of action remain elusive. We aimed to explore the effects of microbial metabolites common to anthocyanins and other flavonoids on vascular smooth muscle heme oxygenase-1 (HO-1) expression. Thirteen phenolic metabolites identified by previous anthocyanin human feeding studies, as well as 28 unique mixtures of metabolites and their known precursor structures were explored for their activity on HO-1 protein expression in rat aortic smooth muscle cells (RASMCs). No phenolic metabolites were active when treated in isolation; however, five mixtures of phenolic metabolites significantly increased HO-1 protein expression (127.4-116.6%, p ≤ 0.03). The present study demonstrates that phenolic metabolites of anthocyanins differentially affect HO-1 activity, often having additive, synergistic or nullifying effects.

How do Housing Subsidies Improve Quality of Life Among Homeless Adults? A Mediation Analysis.

Supported housing, combining rent subsidies with intensive case management, is associated with improvements in quality of life of homeless adults, but factors mediating their impact on quality of life have not been studied. Twelve-month outcome data from a randomized trial of the Housing and Urban Development- Veterans Affairs Supported Housing program (HUD-VASH) showed that access to a housing rent subsidy plus intensive case management (ICM) was associated with greater improvement in subjective quality of life than ICM alone. Multiple mediation analyses were applied to identify variables that significantly mediated the relationship between receipt of housing voucher and improvements in quality of life. Significant mediating covariates were those whose 95% bias-corrected confidence intervals, when added to the model predicting improvement in quality of life, did not overlap zero. Increases in the number of days housed, size of social network, and availability of emotional support appear to mediate improvement in quality of life and account for 71% of the benefit attributable to having a rent subsidy. Improvement in subjective quality of life though housing subsidies is mediated by gains in both material and psychosocial factors. Mediating factors deserve special attention in supported housing services.

Improved Sleep, Diet, and Exercise in Adults with Serious Mental Illness: Results from a Pilot Self-Management Intervention.

Compared to the general population, adults with serious mental illnesses have elevated rates of medical morbidity resulting in a reduced life expectancy of approximately 15 years. Chronic disease self-management programs for adults with serious mental and chronic medical illnesses show some promise in improving physical health-related outcomes, yet none of them address sleep quality. Poor sleep affects a majority of adults with serious mental illness and is robust risk factor for physical morbidity and premature mortality. This pilot project examined the impact of a 14-week educational and support group that included sleep quality as a cornerstone in promoting wellness and self-management in 78 adults with serious mental illness and poor health. Results provide preliminary data that the self-management program was associated with significant improvements in self-reported sleep quality at post-intervention. At 3-month follow-up, participants reported additional increases in sleep quality as well as in healthy diet and exercise frequency. Addressing sleep quality as part of self-management and wellness programs may be a viable approach to assist adults with chronic mental and physical illnesses to adopt health-promoting changes.

A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules.

Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken >150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products. Using pathway engineering and improved agro-infiltration methodology we are able to generate gram-scale quantities of purified triterpene in just a few weeks. In contrast to heterologous expression in microbes, this system does not depend on re-engineering of the host. We next exploit agro-infection for quick and easy combinatorial biosynthesis without the need for generation of multi-gene constructs, so affording an easy entrée to suites of molecules, some new-to-nature, that are recalcitrant to chemical synthesis. We use this platform to purify a suite of bespoke triterpene analogs and demonstrate differences in anti-proliferative and anti-inflammatory activity in bioassays, providing proof of concept of this system for accessing and evaluating medicinally important bioactives. Together with new genome mining algorithms for plant pathway discovery and advances in plant synthetic biology, this advance provides new routes to synthesize and access previously inaccessible natural products and analogs and has the potential to reinvigorate drug discovery pipelines.

Formal Total Synthesis of (+)-C9-Deoxyomuralide from l-Leucine Using a Double Sacrificial Chirality Transfer Approach.

Formal stereocontrolled syntheses of (±)- and (+)-C9-deoxyomuralide is reported, constituting one of the shortest routes to the full carbon skeleton reported to date.

Cytotoxicity of Pyrazine-Based Cyclometalated (C

The synthesis of a series of cyclometalated gold(III) complexes supported by pyrazine-based (C^N^C)-type pincer ligands is reported, including the crystal structure of a cationic example. The compounds provide a new platform for the study of antiproliferative properties of gold(III) complexes. Seven complexes were tested: the neutral series (C^Npz^C)AuX [X = Cl (1), 6-thioguanine (4), C≡CPh (5), SPh (6)] and an ionic series that included the N-methyl complex [(C^NpzMe^C)AuCl]BF4 (7) and the N-heterocyclic carbene complexes [(C^Npz^C)AuL]+ with L = 1,3-dimethylbenzimidazol-2-ylidene (2) or 1,3,7,9-tetramethylxanthin-8-ylidene (3). Tests against human leukemia cells identified 1, 2, 3, and 4 as particularly promising, whereas protecting the noncoordinated N atom on the pyrazine ring by methylation (as in 7) reduced the cytotoxicity. Complex 2 proved to be the most effective of the entire series against the HL60 leukemia, MCF-7 breast cancer, and A549 lung cancer cell lines, with IC50 values down to submicromolar levels, associated with a lower toxicity toward healthy human lung fibroblast cells. The benzimidazolylidene complex 2 accumulated more effectively in human lung cancer cells than its caffeine-based analogue 3 and the gold(III) chloride 1. Compound 2 proved to be unaffected by glutathione under physiological conditions for periods of up to 6 days and stabilizes the DNA G-quadruplex and i-motif structures; the latter is the first such report for gold compounds. We also show the first evidence of inhibition of MDM2-p53 protein-protein interactions by a gold-based compound and identified the binding mode of the compound with MDM2 using saturation transfer difference NMR spectroscopy combined with docking calculations.

Reliability and Validity of a Newly Developed Measure of Citizenship Among Persons with Mental Illnesses.

Following development of a 46-item of measure citizenship, a framework for supporting the full membership in society of persons with mental illness, this study tested the measure's reliability and validity. 110 persons from a mental health center completed a questionnaire packet containing the citizenship measure and other measures to assess internal consistency and validity of the citizenship instrument. Correlation matrices were examined for associations between the citizenship instrument and other measures. Stepwise regression examines demographic factors, sense of community, and social capital as predictors of citizenship, recovery, and well-being. Analyses revealed that the measure is psychometrically sound. The measure captures subjective information about the degree to which individuals experience rights, sense of belonging, and other factors associated with community membership that have been previously difficult to assess. The measure establishes a platform for interventions to support the full participation in society of persons with mental illnesses.