Sleep difficulties related to psychopathology and neurocognition in people with 22q11.2 deletion syndrome.

The 22q11.2 Deletion Syndrome (22q11.2DS) is a multisystem genetic disorder with prominent sleep disturbances, neuropsychiatric conditions and neurocognitive challenges.

Structure-Activity Relationships and Discovery of ()-5-(-Butyl)-11-(difluoromethoxy)-9-methoxy-2-oxo-1,2,5,6-tetrahydropyrido[2',1':2,3]imidazo[4,5-]quinoline-3-carboxylic Acid (AB-161), a Novel Orally Available and Liver-Centric HBV RNA Destabilizer.

Lowering hepatitis B surface antigen (HBsAg) levels from covalently closed circular DNA (cccDNA) and the integrated genome could reduce the persistence of hepatitis B virus (HBV) infection. Since HBV replication occurs in the liver and to ameliorate the peripheral neuropathy observed with a first-generation tricyclic 4-pyridone PAPD5/7 inhibitor () having high systemic exposure, we focused on increasing the hepatocyte concentration and reducing plasma levels. Optimization of a novel series of PAPD5/7 inhibitors that decrease HBsAg levels led to the tetracyclic 2-pyridone , which was similarly potent to and but showed dramatically higher rodent liver-to-plasma ratios.

Conformationally Constrained Isoquinolinones as Orally Efficacious Hepatitis B Capsid Assembly Modulators.

Isoquinolinone-based HBV capsid assembly modulators that bind at the dimer:dimer interface of HBV core protein have been shown to suppress viral replication in chronic hepatitis B patients. Analysis of their binding mode by protein X-ray crystallography has identified a region of the small molecule where the application of a constraint can lock the preferred binding conformation and has allowed for further optimization of this class of compounds. Key analogues demonstrated single digit nM EC values in reducing HBV DNA in a HepDE19 cellular assay in addition to favorable ADME and pharmacokinetic properties, leading to a high degree of oral efficacy in a relevant hydrodynamic injection mouse model of HBV infection, with effecting a 3 log decline in serum HBV DNA levels at a once daily dose of 1 mg/kg.

Detecting schizophrenia, bipolar disorder, psychosis vulnerability and major depressive disorder from 5 minutes of online-collected speech.

Background: Psychosis poses substantial social and healthcare burdens. The analysis of speech is a promising approach for the diagnosis and monitoring of psychosis, capturing symptoms like thought disorder and flattened affect. Recent advancements in Natural Language Processing (NLP) methodologies enable the automated extraction of informative speech features, which has been leveraged for early psychosis detection and assessment of symptomology.

Multivariate Association Between Functional Connectivity Gradients and Cognition in Schizophrenia Spectrum Disorders.

Background: Schizophrenia spectrum disorders (SSDs), which are characterized by social cognitive deficits, have been associated with dysconnectivity in unimodal (e.g., visual, auditory) and multimodal (e.

Rational Design, Synthesis, and Structure-Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836.

Inhibition of Hepatitis B Virus (HBV) replication by small molecules that modulate capsid assembly and the encapsidation of pgRNA and viral polymerase by HBV core protein is a clinically validated approach toward the development of new antivirals. Through definition of a minimal pharmacophore, a series of isoquinolinone-based capsid assembly modulators (CAMs) was identified. Structural biology analysis revealed that lead molecules possess a unique binding mode, exploiting electrostatic interactions with accessible phenylalanine and tyrosine residues.

Exploring online and offline social experiences and interaction patterns of young adults with psychosis with the social media and internet social engagement questionnaire: Analyses and future directions.

Objective: Social interactions and experiences are increasingly occurring online, including for young adults with psychosis. Healthy social interactions and experiences are widely recognized as a critical component of social recovery, yet research thus far has focused predominantly on offline interactions with limited understanding of these interactions online. We developed the Social Media and Internet sociaL Engagement (SMILE) questionnaire to assess the type, frequency, and nature of online social interactions and experiences among young adults with early psychosis to better assess online social activity and ultimately support personalized interventions.

Functional phenotypes in schizophrenia spectrum disorders: defining the constructs and identifying biopsychosocial correlates using data-driven methods.

Functional impairments contribute to poor quality of life in schizophrenia spectrum disorders (SSD). We sought to (Objective I) define the main functional phenotypes in SSD, then (Objective II) identify key biopsychosocial correlates, emphasizing interpretable data-driven methods. Objective I was tested on independent samples: Dataset I (N = 282) and Dataset II (N = 317), with SSD participants who underwent assessment of multiple functioning areas.

Expanding Complex Morpholines Using Systematic Chemical Diversity.

The morpholine heterocycle is a structural unit found in many bioactive compounds and FDA-approved drugs, but the generation of more complex C-functionalized morpholine derivatives remains considerably underexplored. Using systematic chemical diversity (SCD), a concept that guides the expansion of saturated drug-like scaffolds through regiochemical and stereochemical variation, we describe the synthesis of a collection of methyl-substituted morpholine acetic acid esters starting from enantiomerically pure amino acids and amino alcohols. In total, 24 diverse substituted morpholines were produced that vary systematically in regiochemistry and stereochemistry (relative and absolute).

Structure-Activity Relationships and Discovery of ()-6-Isopropyl-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6-pyrido[1,2-][1,7]naphthyridine-9-carboxylic Acid (AB-452), a Novel Orally Available HBV RNA Destabilizer.

Approved therapies for hepatitis B virus (HBV) treatment include nucleos(t)ides and interferon alpha (IFN-α) which effectively suppress viral replication, but they rarely lead to cure. Expression of viral proteins, especially surface antigen of the hepatitis B virus (HBsAg) from covalently closed circular DNA (cccDNA) and the integrated genome, is believed to contribute to the persistence of HBV. This work focuses on therapies that target the expression of HBV proteins, in particular HBsAg, which differs from current treatments.

Racial and ethnic inequities in psychiatric inpatient building and unit assignment.

Racism is a social determinant of mental health which has a disproportionally negative impact on the experiences of psychiatric inpatients of color. Distinct differences in the physical space and clinical settings of two inpatient buildings at a hospital system in the tristate (New York, New Jersey, Connecticut) area of the United States led to the present investigation of racial inequities in the assignment of patients to specific buildings and units. Archival electronic medical record data were analyzed from over 18,000 unique patients over a period of six years.

Race-Based Disparities in the Frequency and Duration of Restraint Use in a Psychiatric Inpatient Setting.

Objective: Patients' race and age have each been identified as risk factors for experiencing restraint events during psychiatric hospitalization. Restraint duration is also an important variable in determining disparities in treatment. To the authors' knowledge, no studies to date have examined the effect of the interaction of race and age on restraint use and duration in inpatient psychiatric settings.

Rational Screening for Cooperativity in Small-Molecule Inducers of Protein-Protein Associations.

The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading to the formation of a ternary complex, despite weaker binding toward one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, which constitute a second class of inducers of protein-protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues.

Design, synthesis, and structure-activity relationship of a bicyclic HBV capsid assembly modulator chemotype leading to the identification of clinical candidate AB-506.

Disruption of the HBV capsid assembly process through small-molecule interaction with HBV core protein is a validated target for the suppression of hepatitis B viral replication and the development of new antivirals. Through combination of key structural features associated with two distinct series of capsid assembly modulators, a novel aminochroman-based chemotype was identified. Optimization of anti-HBV potency through generation of SAR in addition to further core modifications provided a series of related functionalized aminoindanes.

Characterizing and detecting delirium with clinical and computational measures of speech and language disturbance.

Background: Delirium is a critically underdiagnosed syndrome of altered mental status affecting more than 50% of older adults admitted to hospital. Few studies have incorporated speech and language disturbance in delirium detection. We sought to describe speech and language disturbances in delirium, and provide a proof of concept for detecting delirium using computational speech and language features.

Rational screening for cooperativity in small-molecule inducers of protein-protein associations.

The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading to the formation of a ternary complex, despite weaker binding towards one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, a second class of inducers of protein-protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues.

Latent Factors of Language Disturbance and Relationships to Quantitative Speech Features.

Background And Hypothesis: Quantitative acoustic and textual measures derived from speech ("speech features") may provide valuable biomarkers for psychiatric disorders, particularly schizophrenia spectrum disorders (SSD). We sought to identify cross-diagnostic latent factors for speech disturbance with relevance for SSD and computational modeling.

Study Design: Clinical ratings for speech disturbance were generated across 14 items for a cross-diagnostic sample (N = 334), including SSD (n = 90).

Who does what to whom? graph representations of action-predication in speech relate to psychopathological dimensions of psychosis.

Graphical representations of speech generate powerful computational measures related to psychosis. Previous studies have mostly relied on structural relations between words as the basis of graph formation, i.e.

Clinical and computational speech measures are associated with social cognition in schizophrenia spectrum disorders.

In this study, we compared three domains of social cognition (emotion processing, mentalizing, and attribution bias) to clinical and computational language measures in 63 participants with schizophrenia spectrum disorders. Based on the active inference model for discourse, we hypothesized that emotion processing and mentalizing, but not attribution bias, would be related to language disturbances. Clinical ratings for speech disturbance assessed disorganized and underproductive dimensions.

Feasibility of Mobile Health and Social Media-Based Interventions for Young Adults With Early Psychosis and Clinical Risk for Psychosis: Survey Study.

Background: Digital technology, the internet, and social media are increasingly investigated as promising means for monitoring symptoms and delivering mental health treatment. These apps and interventions have demonstrated preliminary acceptability and feasibility, but previous reports suggest that access to technology may still be limited among individuals with psychotic disorders relative to the general population.

Objective: We evaluated and compared access to and use of technology and social media in young adults with psychotic disorders (PD), young adults with clinical risk for psychosis (CR), and psychosis-free youths (PF).

A Concise Synthetic Method for Constructing 3-Substituted Piperazine-2-Acetic Acid Esters from 1,2-Diamines.

We report a short synthetic route for synthesizing 2,3-substituted piperazine acetic acid esters. Optically pure amino acids were efficiently converted into 1,2-diamines that could be utilized to deliver the title 2,3-substituted piperazines in five steps with a high enantiomeric purity. The novel route facilitated, for the first time, the synthesis of 3-phenyl substituted-2-piperazine acetic acid esters that were difficult to achieve using other methods; however, in this case, the products underwent racemization.

Metabolic disturbances, hemoglobin A1c, and social cognition impairment in Schizophrenia spectrum disorders.

Social cognitive impairments are core features of schizophrenia spectrum disorders (SSD) and are associated with greater functional impairment and decreased quality of life. Metabolic disturbances have been related to greater impairment in general neurocognition, but their relationship to social cognition has not been previously reported. In this study, metabolic measures and social cognition were assessed in 245 participants with SSD and 165 healthy comparison subjects (HC), excluding those with hemoglobin A1c (HbA1c) > 6.