Exosomes originating from infection with the cytoplasmic single-stranded RNA virus Rift Valley fever virus (RVFV) protect recipient cells by inducing RIG-I mediated IFN-B response that leads to activation of autophagy.

BACKGROUND: Although multiple studies have demonstrated a role for exosomes during virus infections, our understanding of the mechanisms by which exosome exchange regulates immune response during viral infections and affects viral pathogenesis is still in its infancy. In particular, very little is known for cytoplasmic single-stranded RNA viruses such as SARS-CoV-2 and Rift Valley fever virus (RVFV). We have used RVFV infection as a model for cytoplasmic single-stranded RNA viruses to address this gap in knowledge. RVFV is a highly pathogenic agent that causes RVF, a zoonotic disease for which no effective therapeutic or approved human vaccine exist. RESULTS: We show here that exosomes released from cells infected with RVFV (designated as EXi-RVFV) serve a protective role for the host and provide a mechanistic model for these effects. Our results show that treatment of both naïve immune cells (U937 monocytes) and naïve non-immune cells (HSAECs) with EXi-RVFV induces a strong RIG-I dependent activation of IFN-B. We also demonstrate that this strong anti-viral response leads to activation of autophagy in treated cells and correlates with resistance to subsequent viral infection. Since we have shown that viral RNA genome is associated with EXi-RVFV, RIG-I activation might be mediated by the presence of packaged viral RNA sequences. CONCLUSIONS: Using RVFV infection as a model for cytoplasmic single-stranded RNA viruses, our results show a novel mechanism of host protection by exosomes released from infected cells (EXi) whereby the EXi activate RIG-I to induce IFN-dependent activation of autophagy in naïve recipient cells including monocytes. Because monocytes serve as reservoirs for RVFV replication, this EXi-RVFV-induced activation of autophagy in monocytes may work to slow down or halt viral dissemination in the infected organism. These findings offer novel mechanistic insights that may aid in future development of effective vaccines or therapeutics, and that may be applicable for a better molecular understanding of how exosome release regulates innate immune response to other cytoplasmic single-stranded RNA viruses.

A knowledge-based, structural-aided discovery of a novel class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors.

Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.

Impact of overdose prevention sites during a public health emergency in Victoria, Canada.

The primary objective of this study was to examine the impacts associated with implementation of overdose preventions sites (OPSs) in Victoria, Canada during a declared provincial public health overdose emergency. A rapid case study design was employed with three OPSs constituting the cases. Data were collected through semi-structured interviews with 15 staff, including experiential staff, and 12 service users. Theoretically, we were informed by the Consolidated Framework for Implementation Research. This framework, combined with a case study design, is well suited for generating insight into the impacts of an intervention. Zero deaths were identified as a key impact and indicator of success. The implementation of OPSs increased opportunities for early intervention in the event of an overdose, reducing trauma for staff and service users, and facilitated organizational transitions from provision of safer supplies to safer spaces. Providing a safer space meant drug use no longer needed to be concealed, with the effect of mitigating drug related stigma and facilitating a shift from shame and blame to increasing trust and development of relationships with increased opportunities to provide connections to other services. These impacts were achieved with few new resources highlighting the commitment of agencies and harm reduction workers, particularly those with lived experience, in achieving beneficial impacts. Although mitigating harms of overdose, OPSs do not address the root problem of an unsafe drug supply. OPSs are important life-saving interventions, but more is needed to address the current contamination of the illicit drug supply including provision of a safer supply.

Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway.

4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.

Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.

4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy.

The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.

One-pot synthesis of chiral nonracemic amines.

One-pot five-component reactions of oxathiazolidine-S-oxides with mesitylmagnesium bromide, lithium bis(trimethylsilyl)amide, aldehydes and Grignard reagents afford chiral nonracemic amines or sulfinamides in good yields and high stereoselectivities.

On the utility of S-mesitylsulfinimines for the stereoselective synthesis of chiral amines and aziridines.

The synthetic utility of S-mesitylsulfinimines for the synthesis of chiral amines and aziridines was examined through their reactions with Grignard reagents, with the ylides derived from trimethylsulfonium iodide and S-allyl-tetrahydrothiophenium bromide and through an aza-Darzens manifold, affording convenient access to a diverse range of highly substituted chiral amines and aziridines in high yields and excellent stereoselectivities.

Multicomponent synthesis of chiral sulfinimines.

Two oxathiozolidine-S-oxide templates have been developed and used in a four-component coupling protocol for the synthesis of a wide range of chiral sulfinimines in high enantiomeric excesses. The templates can be synthesized from cheap commodity chemicals in three steps in high yields. Furthermore the template is easily recovered in high yields for recycling.

4-Phenyl-7-azaindoles as potent and selective IKK2 inhibitors.

The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.

Synthesis of the non-adjacent bis-THF core of cis-sylvaticin using a double oxidative cyclisation.

A short synthesis of the non-adjacent bis-THF core of the Annonaceous acetogenin cis-sylvaticin (1) is described. C(2) Symmetrical (Z,E,E,Z)- and (E,E,E,E)-tetraenes and were synthesised in six and three steps respectively from (1E,5E,9E)-cyclododeca-1,5,9-triene. Subsequent permanganate promoted asymmetric bi-directional oxidative cyclisation of tetraene was used to create the non-adjacent bis-THF core of 1, installing seven of the nine stereogenic centres present in the natural product in a single step. Desymmetrization of the oxidative cyclisation product by mono-tosylation gave access to a C11-C32 fragment of cis-sylvaticin.

The right stuff for early intervention in psychosis: time, attitude, place, intensity, treatment, & cost.

This article shares information about an exciting new approach in psychiatry. During the past 12 years, the authors have worked with young people experiencing their first episode of psychosis. It is clear that intervention at the earliest stages of psychotic illness allows clinicians to make a significant difference in the lives of young people and their families. This article summarizes current intervention strategies, which are considered best practice guidelines for early treatment.

Psychotic disorders clinic and first-episode psychosis: a program evaluation.

BACKGROUND: There is growing recognition that people presenting with psychotic symptoms for the first time need specialized treatment. The Hamilton Health Sciences Corporation, McMaster Hospital, offers one such program, the Psychotic Disorders Clinic (PDC); it addresses some of the problems posed by long waiting lists, lack of family interventions, and long-term hospitalizations. The PDC is affiliated with the Department of Psychiatry and Behavioural Neurosciences at McMaster University. The program's goals are to provide comprehensive outpatient care and early interventions for persons in the early stages of illness and, consequently, to improve symptom control and functioning and reduce hospitalizations. Key service components include providing low dosages of antipsychotics, offering specialized family education, and supporting return to school and work settings. OBJECTIVES: This study compared outcomes before and after enrolment in the PDC to determine whether first-episode patients achieved improved symptom control and functioning and fewer hospitalizations. METHOD: For a 12-month period, we followed 40 patients, aged between 16 and 45 years, who experienced their first episode of psychotic illness between 1997 and 2000. Prospective longitudinal data were collected at baseline, 3, 6, and 12 months. Outcome measures included symptoms, global functioning, employment rates, duration of untreated psychosis, and number of bed-days. RESULTS: Of the patients, 37 completed the study at 6 months, and 31 at 12 months. Over the 12 months, significant improvements occurred in psychiatric symptoms (P < 0.001), global functioning (P < 0.001), and the mean number of hospital bed-days (P < 0.001). CONCLUSIONS: It is feasible for small outpatient services to provide early intervention strategies and obtain good outcomes among first-episode patients.

Evaluation of the Alumni Program. A shared-care model for psychosis.

This article describes the results of a prospective, naturalistic evaluation of the Alumni Program, conducted by the Psychotic Disorders Clinic at the McMaster Site of Hamilton Health Sciences, Hamilton, Ontario, Canada. The Alumni Program is a form of continuing psychiatric support offered to individuals with psychosis. The program involves providing shared care by both the specialist psychiatric team and the family practitioner. This model has been in operation for more than 8 years. The clinical data have been reviewed to determine whether the program is beneficial in supporting clients with their health maintenance goals, thus reducing occurrences of relapse, hospital readmission, and crisis or emergency room visits. The results appear favorable and affirm the Alumni Program is one viable method of follow up within a comprehensive range of psychiatric services.

Pilot study: access to fitness facility and exercise levels in olanzapine-treated patients.

BACKGROUND: Increasingly alarmed by the health risks (that is, weight gain, elevated lipids, and poor glucose tolerance) posed by novel antipsychotic medications, clinicians who treat schizophrenia are attempting to help patients improve lifestyle factors. Unfortunately, schizophrenia research has neglected exercise as a legitimate adjunctive treatment for schizophrenia. OBJECTIVE: To assess the extent to which stable patients with schizophrenia would adhere to an exercise program if offered access to a fitness facility. METHODS: Ten of 20 stable patients with schizophrenia or schizoaffective disorder who were treated with olanzapine for at least 4 weeks had the opportunity to receive access to a Young Men's Christian Association (YMCA) fitness facility, based on random allocation. The intervention included a free membership to the YMCA for 6 months, with access to all the fitness amenities and equipment. The mean dosage of olanzapine was 11.5 mg daily for the YMCA group. RESULTS: Of the 10 subjects, 2 did not attend at all. One subject met criteria for full attendance for each of the 6 months and lost 15 Kg. Dropout rates were as follows: 90% at 6 months, 70% at 5 months, and 40% at 4 months. The main reason they gave for poor attendance was lack of motivation. The mean weight gain was 2 kg in the YMCA group. CONCLUSION: Most subjects did not regularly exercise or attend. They cited poor motivation as the main reason. The subject who exercised regularly lost a significant amount of weight.