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The flavoenzyme proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the oxidation of l-proline to Δ 1 -pyrroline-5-carboxylate. The enzyme is a target for chemical probe discovery because of its role in the metabolism of certain cancer cells. N -propargylglycine is the first and best characterized mechanism-based covalent inactivator of PRODH. This compound consists of a recognition module (glycine) that directs the inactivator to the active site and an alkyne warhead that reacts with the FAD after oxidative activation, leading to covalent modification of the FAD N5 atom. Here we report structural and kinetic data on analogs of N -propargylglycine with the goals of understanding the initial docking step of the inactivation mechanism and to test the allyl group as a warhead. The crystal structures of PRODH complexed with unreactive analogs in which N is replaced by S show how the recognition module mimics the substrate proline by forming ion pairs with conserved arginine and lysine residues. Further, the C atom adjacent to the alkyne warhead is optimally positioned for hydride transfer to the FAD, providing the structural basis for the first bond-breaking step of the inactivation mechanism. The structures also suggest new strategies for designing improved N -propargylglycine analogs. N -allylglycine, which consists of a glycine recognition module and allyl warhead, is shown to be a covalent inactivator; however, it is less efficient than N -propargylglycine in both enzyme inactivation and cellular assays. Crystal structures of the N -allylglycine-inactivated enzyme are consistent with covalent modification of the N5 by propanal.

Objective: Sutter Health launched system-wide general population standardized suicide screening with the Columbia-Suicide Severity Rating Scale (C-SSRS) screen (triage) version in 23 hospitals in 2019, replacing a one-question "danger to self" (DTS) assessment. This study analyzed the impact of C-SSRS implementation on screening rates, positive screenings, and documented psychiatric care within 90 days for all patients and a subgroup diagnosed with Major Depressive Disorder (MDD)., Methods: Adults seen at hospitals in the pre-period (July 1, 2017-June 30, 2019) and post-period (July 1, 2019-December 31, 2020) were identified using electronic health records. Outcomes were compared using chi-square statistics and interrupted time series (ITS) models., Results: Pre-period, 92.8% (740,984/798,653) of patients were screened by DTS versus 84.6% (504,015/595,915) by C-SSRS in the post-period. Positive screening rates were 1.5% pre-period and 2.2% post-period, and 9.2% pre-period versus 10.8% post-period for those with MDD. Among individuals with positive screenings, 64.0% (pre-period) had documented follow-up psychiatric care versus 52.5% post-period and 66.4% of those with moderate or high-risk. Among all patients seen there was an overall increase in documentation of psychiatric care within 90 days (0.87% pre- to 0.96% post-period). ITS models revealed a 9.6% decline in screening, 1.3% increase in positive screenings, and 12.9% decline in documented psychiatric care following C-SSRS implementation (all p  < 0.01)., Conclusions: Following implementation, there was meaningful increase in suicide risk identification, and an increase in the proportion of patients with documented psychiatric care. Observed relative declines in screening warrant future research examining opportunities and barriers to general population C-SSRS use., (© 2024 The Authors. Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.)

The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo . Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Background: Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon carcinogenesis remains ill understood., Methods: A comprehensive analysis was performed using publicly available cancer databases and CRC patient cohorts. Proteomics and biochemical evaluations were performed along with genetic manipulations and in vivo tumor growth assays to gain a mechanistic understanding., Results: PYCR2 expression was significantly upregulated in CRC and associated with poor patient survival, specifically among PYCR isoforms (PYCR1, 2, and 3). The genetic inhibition of PYCR2 inhibited the tumorigenic abilities of CRC cells and in vivo tumor growth. Coinciding with these observations was a significant decrease in cellular proline content. PYCR2 overexpression promoted the tumorigenic abilities of CRC cells. Proteomics (LC-MS/MS) analysis further demonstrated that PYCR2 loss of expression in CRC cells inhibits survival and cell cycle pathways. A subsequent biochemical analysis supported the causal role of PYCR2 in regulating CRC cell survival and the cell cycle, potentially by regulating the expression of MASTL, a cell-cycle-regulating protein upregulated in CRC. Further studies revealed that PYCR2 regulates Wnt/β-catenin-signaling in manners dependent on the expression of MASTL and the cancer stem cell niche., Conclusions: PYCR2 promotes MASTL/Wnt/β-catenin signaling that, in turn, promotes cancer stem cell populations and, thus, colon carcinogenesis. Taken together, our data highlight the significance of PYCR2 as a novel therapeutic target for effectively treating aggressive colon cancer.

Background: During the COVID-19 pandemic, many Americans experienced new or worsened mental health conditions. Concurrently, much care switched from in-person to virtual care, highlighting the value of virtual care but also some of the underlying challenges., Methods: This paper explores one such challenge, the separation of mental health care from physical health care, and a potential solution, collaborative care. It is a team-based approach linking psychiatrists to primary care providers that can help break down the silos of care created through reimbursement models., Results: In this context of collaborative care, high quality virtual care further bridges the divide between physical and mental health care. Asynchronous virtual care for mental and behavioral health is an innovation that can create efficiencies while still supporting collaborative care., Discussion: The barriers and weaknesses of using virtual care exclusively for mental and behavioral health are discussed, as well as examples of policy changes which can improve mental health care through collaborative virtual care., Competing Interests: P.Y. reports employment and ownership in AsyncHealth Inc. All others have no conflict of interest., (© John Scott et al., 2023; Published by Mary Ann Liebert, Inc.)

Significance: Cells depend on well-functioning mitochondria for essential processes such as energy production, redox signaling, coordination of metabolic pathways, and cofactor biosynthesis. Mitochondrial dysfunction, metabolic decline, and protein stress have been implicated in the etiology of multiple late-onset diseases, including various ataxias, diabetes, sarcopenia, neuromuscular disorders, and neurodegenerative diseases such as parkinsonism, amyotrophic lateral sclerosis, and glaucoma. Recent Advances: New evidence supports that increased energy metabolism protects neuron function during aging. Key energy metabolic enzymes, however, are susceptible to oxidative damage making it imperative that the mitochondrial proteome is protected. More than 40 different enzymes have been identified as important factors for guarding mitochondrial health and maintaining a dynamic pool of mitochondria. Critical Issues: Understanding shared mechanisms of age-related disorders of neurodegenerative diseases such as glaucoma, Alzheimer's disease, and Parkinson's disease is important for developing new therapies. Functional mitochondrial shape and dynamics rely on complex interactions between mitochondrial proteases and membrane proteins. Identifying the sequence of molecular events that lead to mitochondrial dysfunction and metabolic stress is a major challenge. Future Directions: A critical need exists for new strategies that reduce mitochondrial protein stress and promote mitochondrial dynamics in age-related neurological disorders. Discovering how mitochondria-associated degradation is related to proteostatic mechanisms in mitochondrial compartments may reveal new opportunities for therapeutic interventions. Also, little is known about how protein and membrane contacts in the inner and outer mitochondrial membrane are regulated, even though they are pivotal for mitochondrial architecture. Future work will need to delineate the molecular details of these processes.

Implementation of suicide risk screening may improve prevention and facilitate mental health treatment. This study analyzed implementation of universal general population screening using the Columbia-Suicide Severity Rating Scale (C-SSRS) within hospitals. The study included adults seen at 23 hospitals from 7/1/2019-12/31/2020. We describe rates of screening, suicide risk, and documented subsequent psychiatric care (i.e., transfer/discharge to psychiatric acute care, or referral/consultation with system-affiliated behavioral health providers). Patients with suicide risk (including those with Major Depressive Disorder [MDD]) were compared to those without using Wilcoxon rank-sum -tests for continuous variables and χ2 tests for categorical variables. Results reported are statistically significant at p < 0.05 level. Among 595,915 patients, 84.5% were screened by C-SSRS with 2.2% of them screening positive (37.6% low risk [i.e., ideation only], and 62.4% moderate or high risk [i.e., with a plan, intent, or suicidal behaviors]). Of individuals with suicide risk, 52.5% had documentation of psychiatric care within 90 days. Individuals with suicide risk (vs. without) were male (48.1% vs 43.0%), Non-Hispanic White (55.0% vs 47.8%), younger (mean age 41.0 [SD: 17.7] vs. 49.8 [SD: 20.4]), housing insecure (12.5% vs 2.6%), with mental health diagnoses (80.3% vs 25.1%), including MDD (41.3% vs 6.7%). Universal screening identified 2.2% of screened adults with suicide risk; 62.4% expressed a plan, intent or suicidal behaviors, and 80.3% had mental health diagnoses. Documented subsequent psychiatric care likely underestimates true rates due to care fragmentation. These findings reinforce the need for screening, and research on whether screening leads to improved care and fewer suicides., (© Society of Behavioral Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pyrroline-5-carboxylate reductase (PYCR) is a proline biosynthetic enzyme that catalyzes the NAD(P)H-dependent reduction of Δ 1 -pyrroline-5-carboxylate (P5C) to proline. Humans have three PYCR isoforms, with PYCR1 often upregulated in different types of cancers. Here, we studied the biochemical and structural properties of the Thr171Met variant of PYCR1, which is found in patients with malignant melanoma and lung adenocarcinoma. Although PYCR1 is strongly associated with cancer progression, characterization of a PYCR1 variant in cancer patients has not yet been reported. Thr171 is conserved in all three PYCR isozymes and is located near the P5C substrate binding site. We found that the amino acid replacement does not affect thermostability but has a profound effect on PYCR1 catalytic activity. The k cat of the PYCR1 variant T171M is 100- to 200-fold lower than wild-type PYCR1 when P5C is the variable substrate, and 10- to 25-fold lower when NAD(P)H is varied. A 1.84 Å resolution X-ray crystal structure of T171M reveals that the Met side chain invades the P5C substrate binding site, suggesting that the catalytic defect is due to steric clash preventing P5C from achieving the optimal pose for hydride transfer from NAD(P)H. These results suggest that any impact on PYCR1 function associated with T171M in cancer does not derive from increased catalytic activity., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Abstract: Adolescent pregnancy and the babies of teen mothers have been a focus of attention and concern for many years. The literature on the health of pregnant and parenting teens, however, is largely silent about the impact of stigma on them and their children. Stigma is a pervasive cultural attitude, which leads us to overlook potentially good outcomes for this vulnerable population and contributes to poor outcomes for these mothers and babies. Stigma is a cause of stress leading to well-known adverse effects on health and development for both mothers and babies. This article reviews manifestations of social stigma in our communities, in the offices of professionals, and in policies that embed bias in our social systems. The impact of inequity has been vividly revealed over the course of the global pandemic. We review findings related to interventions associated with better outcomes and offer suggestions for more humane care and policies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)