Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

Enzymatic Fluoromethylation as a Tool for ATP-Independent Ligation.

S-adenosylmethionine-dependent methyltransferases are involved in countless biological processes, including signal transduction, epigenetics, natural product biosynthesis, and detoxification. Only a handful of carboxylate methyltransferases have evolved to participate in amide bond formation. In this report we show that enzyme-catalyzed F-methylation of carboxylate substrates produces F-methyl esters that readily react with N- or S-nucleophiles under physiological conditions. We demonstrate the applicability of this approach to the synthesis of small amides, hydroxamates, and thioesters, as well as to site-specific protein modification and native chemical ligation.

Targeting mitochondrial dysfunction with elamipretide.

Although currently employed therapies for heart failure decrease overall mortality and improve patient quality of life temporarily, the disease is known to progress even for patients who receive all guideline-recommended therapies. This indicates that our concise understanding of heart failure and of disease progression is incomplete, and there is a need for new interventions that may augment, or even supplant, currently available options. A literature review reveals that an exciting, novel area of current research is focused on mitochondria, which are uniquely juxtaposed at the sites of both generation of high-energy molecules and initiation of programmed cell death. Elamipretide is being studied both to maintain cellular biogenetics and prevent reactive oxygen species-induced cell damage by targeting and stabilizing the cardiolipin-cytochrome c supercomplex. Thus far, elamipretide has been shown to increase left ventricular ejection fraction in dog models of heart failure with reduced ejection fraction and to prevent left ventricular remodeling in rats. In early-phase clinical trials, elamipretide administration has not resulted in any severe adverse events, and it has shown promising improvements in cardiac hemodynamics at highest doses. Nonetheless, additional studies are necessary to describe the long-term safety and efficacy of elamipretide.

Are witnesses able to avoid highly accessible misinformation? Examining the efficacy of different warnings for high and low accessibility postevent misinformation.

The reliability of eyewitness memory continues to be an area of concern, particularly in situations that involve conflicting sources of information (e.g., the misinformation effect; Loftus et al., 1978, Journal of Experimental Psychology: Human Learning and Memory, 4[1], 19-31). To mitigate the negative effects of misinformation, researchers have examined the efficacy of warnings that highlight the unreliability of postevent information. However, warnings have proven less effective for highly accessible misinformation (Eakin et al., 2003, Journal of Experimental Psychology: Learning, Memory, and Cognition, 29[5], 813-825). In the present study, we examined the effects of different types of warnings for low accessibility misinformation in a standard single test misinformation paradigm, and highly accessible misinformation in a repeated testing misinformation paradigm (Chan et al., 2009, Psychological Science, 20[1], 66-73). We modeled these warnings after Eakin et al. (2003) to include both general warnings and specific question-by-question warnings. We found that warnings were effective in both types of misinformation paradigms. Additionally, memory accuracy in situations where participants were exposed to misleading information was improved when specific and general warnings were combined. We argue that both retrieval blocking of low accessibility items and enhanced contextual discrimination account for these findings.

Angiotensin II: A Review of Current Literature.

Up to one-third of all patients admitted to intensive care units carry a diagnosis of shock. The use of angiotensin II is becoming widespread in all forms of shock, including cardiogenic, after the U.S. Food and Drug Administration's (FDA's) initial approval for vasoplegic shock in 2017. Here, the authors review the literature on angiotensin II's mechanism of action, benefits, and future therapeutic opportunities.

Acute stress enhances general-knowledge semantic memory.

Acute psychological stress consistently impairs episodic memory, which consists of memory for events that are associated with a specific context. However, researchers have not yet established how stress influences semantic memory, which consists of general knowledge that is devoid of context. In the present study, participants either underwent stress induction or a control task prior to taking a trivia test that was designed to measure semantic memory. In contrast to the wealth of prior research on episodic memory, we found that stress enhanced semantic-memory retrieval. Supporting this finding, higher cortisol reactivity to stress was associated with better performance on the trivia test. Together with the results from previous studies of episodic memory, our findings suggest that stress differentially influences memory retrieval, depending on the degree to which the retrieval of a given memory relies on medial-temporal, neocortical, and striatal brain regions.

Andexanet Alfa (Andexxa®) for the Reversal of Direct Oral Anticoagulants.

Andexanet alfa (Andexxa®) for the reversal of direct oral anticoagulants.

Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors.

We have screened small molecule libraries specifically for inhibitors that target WWP2, an E3 ubiquitin ligase associated with tumour outgrowth and spread. Selected hits demonstrated dose-dependent WWP2 inhibition, low micromolar IC50 values, and inhibition of PTEN substrate-specific ubiquitination. Binding to WWP2 was confirmed by ligand-based NMR spectroscopy. Furthermore, we used a combination of STD NMR, the recently developed DEEP-STD NMR approach, and docking calculations, to propose for the first time an NMR-validated 3D molecular model of a WWP2-inhibitor complex. These first generation WWP2 inhibitors provide a molecular framework for informing organic synthetic approaches to improve activity and selectivity.

Ledipasvir/Sofosbuvir (harvoni): improving options for hepatitis C virus infection.

Ledipasvir/sofosbuvir (Harvoni): improving options for hepatitis C virus infection.

Edoxaban: an investigational factor xa inhibitor.

Edoxaban: an investigational factor Xa inhibitor.

Enzymatic Fluoromethylation as a Tool for ATP-Independent Ligation.

S-adenosylmethionine-dependent methyltransferases are involved in countless biological processes, including signal transduction, epigenetics, natural product biosynthesis, and detoxification. Only a handful of carboxylate methyltransferases have evolved to participate in amide bond formation. In this report we show that enzyme-catalyzed F-methylation of carboxylate substrates produces F-methyl esters that readily react with N- or S-nucleophiles under physiological conditions. We demonstrate the applicability of this approach to the synthesis of small amides, hydroxamates, and thioesters, as well as to site-specific protein modification and native chemical ligation.

Addressing the Complex Needs of Customers Who Contact the Veterans Crisis Line.

Since its creation in 2007, the Veterans Crisis Line (VCL) has provided 24/7, confidential crisis support services for Veterans, Service Members, and their families, supporting the VA's highest clinical priority of suicide prevention. As part of this effort, VCL created the Customers with Complex Needs (CWCN) program to manage the individual needs and operational impact of VCL customers who call at a high frequency, are abusive toward hotline staff, exhibit sexually inappropriate behavior, and/or make threats of violence. This paper describes the VCL CWCN program and customer characteristics. Call data from 2012 to 2022, including operational data for 1,096 CWCN customers identified from October 2017 to December 2020, were used for analysis. At the cohort's peak size in 2020, calls from CWCN customers accounted for 0.4% of all distinct phone numbers received by VCL and for 22.1% of total VCL call volume. Implementation of the CWCN program was associated with significant annual reductions in average individual call volume among high frequency callers. However, no change in call volume was observed among nonhigh frequency callers. Formative challenges and future directions for the CWCN program and implications for other crisis lines are discussed.

Algorithmic Spaced Retrieval Enhances Long-Term Memory in Alzheimer Disease: Case-Control Pilot Study.

BACKGROUND: Spaced retrieval is a learning technique that involves engaging in repeated memory testing after increasingly lengthy intervals of time. Spaced retrieval has been shown to improve long-term memory in Alzheimer disease (AD), but it has historically been difficult to implement in the everyday lives of individuals with AD. OBJECTIVE: This research aims to determine, in people with mild cognitive impairment (MCI) due to AD, the efficacy and feasibility of a mobile app that combines spaced retrieval with a machine learning algorithm to enhance memory retention. Specifically, the app prompts users to answer questions during brief daily sessions, and a machine learning algorithm tracks each user's rate of forgetting to determine the optimal spacing schedule to prevent anticipated forgetting. METHODS: In this pilot study, 61 participants (young adults: n=21, 34%; healthy older adults: n=20, 33%; people with MCI due to AD: n=20, 33%) used the app for 4 weeks to learn new facts and relearn forgotten name-face associations. Participation during the 4-week period was characterized by using the app once per day to answer 15 questions about the facts and names. After the 4-week learning phase, participants completed 2 recognition memory tests approximately 1 week apart, which tested memory for information they had studied using the app as well as information they had not studied. RESULTS: After using the mobile app for 1 month, every person with MCI due to AD demonstrated improvements in memory for new facts that they had studied via the app compared to baseline (P<.001). All but one person with MCI due to AD (19/20, 95%) showed improvements of more than 10 percentage points, comparable to the improvements shown by young adults and healthy older adults. Memory for name-face associations was similarly improved for all participant groups after using the app but to a lesser degree. Furthermore, for both new facts and name-face associations, we found no memory decay for any participant group after they took a break of approximately 1 week from using the app at the end of the study. Regarding usability, of the 20 people with MCI due to AD, 16 (80%) self-adhered to the app's automated practice schedule, and half of them (n=10, 50%) expressed an interest in continuing to use it. CONCLUSIONS: These results demonstrate early evidence that spaced retrieval mobile apps are both feasible for people with early-stage AD to use in their everyday lives and effective for supporting memory retention of recently learned facts and name-face associations.

Implementing and evaluating a veterans crisis line quality improvement initiative: The safety planning pilot program.

The Veterans Crisis Line (VCL) is part of the U.S. Department of Veterans Affairs' suicide prevention mission. In 2021, VCL assessed the impact of a pilot implementation project of conducting six-part safety plans (SPs) instead of VCL's usual risk mitigation plan. VCL responders offered to complete six-part SPs with eligible callers. Parametric and nonparametric methods compared call characteristics and Veteran Health Administration (VHA) utilization of eligible callers, by SP completion. We forecasted the operational impact of VCL-wide implementation. 27.37% (N = 448/1,637) of calls to designated responders were eligible for SPs. Of those, 27.23% (N = 122/448) completed SPs. Common barriers were call interruptions and the veteran declining. Among veteran callers who use VHA, SP completers were more likely to accept clinical referrals and had more outpatient mental health appointments before and after their VCL call. Calls involving SPs had a call plus documentation time 175% longer than eligible calls without SPs (87.78 vs. 49.66 min). If SPs were implemented VCL-wide, this would require 3-5(4.12%) more responders per hour to maintain current VCL call answer speed. SPs are adaptable to VCL; however, implementation presents logistical barriers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Ligand-dependent site-selective Suzuki cross-coupling of 3,5-dichloropyridazines.

General methods for the highly site-selective Suzuki monocoupling of 3,5-dichloropyridazines have been discovered. By changing the ligand employed, the preferred coupling site can be switched from the 3-position to the 5-position, typically considered the less reactive C-X bond. These conditions are applicable to the coupling of a wide variety of aryl-, heteroaryl-, and vinylboronic acids with high selectivities, thus enabling the rapid construction of diverse arrays of diarylpyradazines in a modular fashion.

CropLife Europe Crop Development Database: An open-source, pan-European, harmonized crop development database for use in regulatory pesticide exposure modeling and risk assessment.

There is a regulatory need for crop development dates to assess current default values used within chemical exposure assessments as well as to justify refinements within risk assessments. However, a readily available pan-European crop phenology database covering key FOrum for the Co-ordination of pesticide fate models and their USe (FOCUS) crops and scenarios to meet this need is not currently available. Therefore, we describe the development of a harmonized, pan-European, CropLife Europe Crop Development Database (C2D2), that is fully aligned with this regulatory requirement utilizing efficacy trials data generated for regulatory submissions when registering plant protection products under Regulation (EU)1107/2009. Evaluation of C2D2 against an independent data set showed good agreement for equivalent time periods, crop growth stages, and geographical regions. We illustrate how this database can be used to evaluate existing default crop development dates mandated by regulatory agencies for use within exposure assessments. Despite the large data set compiled and the geographical coverage of C2D2, not all FOCUSsw/gw scenarios have sufficient data to facilitate comparison, with less significant scenarios, like FOCUSgw Porto, being underrepresented. For those scenarios with sufficient data, clear differences between C2D2 and crop development dates assumed in the FOCUS modeling framework (using the AppDate tool) are often indicated over many growth stages, suggesting that amendment of the existing representation of crop development within the risk assessment process may be required. C2D2 is freely available under a Creative Commons license to facilitate innovation in exposure science to allow for more accurate and realistic risk assessment leading to enhanced crop and environmental protection. Integr Environ Assess Manag 2023;00:1-15. © 2023 CropLife Europe (Corteva Agriscience) and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Qualitative Evaluation of a Caring Letters Suicide Prevention Intervention for the Veterans Crisis Line.

OBJECTIVE: Suicide is a leading cause of death in the United States. This has prompted the U.S. surgeon general to issue a report describing actionable items to reduce suicide rates, including a recommendation to increase the use of the caring letters intervention. This intervention involves mailing brief, nondemanding messages of care. As part of the Department of Veterans Affairs' (VA's) efforts to reduce suicide rates among veterans, a caring letters project was developed for veterans who contact the Veterans Crisis Line (VCL). This article describes the results of qualitative interviews conducted to better understand the experiences of veterans who received caring letters. METHODS: Beginning in 2020, all identifiable veterans who used Veterans Health Administration services and contacted the VCL received nine letters over 1 year, along with a list of mental health resources. Semistructured interviews (N=23) were conducted, and content analysis was used to identify veterans' perspectives and suggestions for improving the intervention. RESULTS: Sixteen men and seven women participated (mean age=53 years). Feedback varied, with most participants reporting that receiving caring letters had a positive impact and others noting aspects that could be improved to enhance the intervention's caring intent. Some also reported that the letters helped them engage with community resources and made them more likely to seek VA care. CONCLUSIONS: The caring letters intervention, received after contact with the VCL, was well received by participants. They described feeling appreciated, cared for, encouraged, and connected. The results of this study will inform future evaluation examining veteran outcomes.

When Memory and Metamemory Align: How Processes at Encoding Influence Delayed Judgment-of-Learning Accuracy.

Judgments of learning are most accurate when made at a delay from the initial encoding of the assessed material. A wealth of evidence suggests that this is because a delay encourages participants to base their predictions on cues retrieved from long-term memory, which are generally the most diagnostic of later memory performance. We investigated the hypothesis that different types of study techniques affect delayed JOL accuracy by influencing the accessibility of cues stored in long-term memory. In two experiments, we measured the delayed-JOL accuracy of participants who encoded semantically unrelated and weakly related word pairs through one of three study techniques: reading the pairs twice (study practice), generating keywords (elaborative encoding), or taking a cued-recall test with feedback (retrieval practice). We also measured the accessibility, utilization, and diagnostic quality of two long-term memory cues at the time of the delayed JOL: (a) retrieval of the target, and (b) noncriterial cues (retrieval of contextual details pertaining to the encoding of the target). We found that the accessibility of targets was positively associated with delayed-JOL accuracy. Further, we provide evidence that when study techniques enhance the accessibility of targets, they likewise enhance delayed-JOL accuracy.

Development of the Veterans Crisis Line Caring Letters Suicide Prevention Intervention.

OBJECTIVE: To describe the design, implementation, and plans to evaluate the Veterans Crisis Line (VCL) Caring Letters intervention. DATA SOURCES: Veterans with VCL contact and VHA service utilization. STUDY DESIGN: Caring Letters is an evidence-based post-acute care suicide prevention intervention in which brief messages are mailed to individuals at high risk of suicide repeatedly over time to communicate that people care about them and are concerned for their well-being. An effectiveness-implementation hybrid type 1 trial using the RE-AIM evaluation framework is underway to examine the use of Caring Letters with veterans who contact the VCL. A team of suicide prevention subject matter experts, researchers, and operational partners from the VCL will evaluate the effects of Caring Letters on clinical outcomes and Department of Veterans Affairs - Veterans Health Administration (VHA) clinical utilization rates and examine facilitators and barriers to implementing the Caring Letters campaign. DATA COLLECTION METHODS: Veterans who contact the VCL are linked with national administrative VHA data. Semi-structured interviews were conducted as part of a qualitative formative evaluation. PRINCIPAL FINDINGS: In the first 12 months of the intervention, Caring Letters have been sent to over 100,000 veterans with VCL contact (over 500,000 letters mailed). A formative qualitative evaluation early in implementation revealed a variety of positive veteran perspectives on the intervention. CONCLUSIONS: Partnered program design and evaluation with a high level of stakeholder engagement and participant feedback can result in a rigorous and feasible evaluation plan that improves implementation processes and produces actionable results. The initial results of this evaluation will be used to better inform care in the VHA and, specifically, the VCL.

Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of tertiary alcohol-bearing piperidines.

The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.