Partisan animosity through the lens of blame: Partisan animosity can be reduced by a historicist thinking intervention.

Partisan animosity has been on the rise in America. Partisan animosity involves blame, wherein political partisans blame outparty members for their beliefs and actions. Here, we examine whether a historicist thinking intervention-drawn from research on blame mitigation-can reduce partisan animosity. The intervention consisted of three components: (1) a narrative about the idiosyncratic development of one political opponent paired with (2) a message about how unique life experiences shape everyone's political beliefs and (3) a suggestion that outparty members can be changed by future formative experiences. Experiments 1 and 2 showed that the intervention reduced cold feelings-measured via Feeling Thermometer-towards the outparty for both Democrats and Republicans. Experiments 3 and 4 focused on more specific emotional changes. Experiment 3 showed that, for Democrats, the intervention increased compassion. Experiment 4 showed that, for Republicans, the intervention reduced disgust, disapproval, anger, and contempt, but had no impact on compassion. For Democrats, but not for Republicans, reductions in animosity were mediated by reduced perceptions of control of self-formation, the mediator identified in prior work on historicist thinking and blame mitigation.

What do other people think he deserves? Social influence on utilization of mitigating information regarding a violent offender's unfortunate life history.

The blameworthiness of an offender is often discussed in groups. Yet, the research literature overwhelmingly examines individuals assessing blameworthiness in isolation. To address this gap in the literature, the present study examines group deliberations about blameworthiness, with a particular focus on how group deliberations impact utilization of mitigating information about an offender's unfortunate life history. Participants from introductory psychology courses at a U.S. university were placed in groups of two or three and each group also included a confederate who followed a script. Groups were randomly assigned to one of four conditions. In one condition (deed only), groups learned only about the offender's heinous crimes. In the three remaining conditions, participants also received a historicist narrative regarding how the offender's unfortunate history deformed his moral character. These conditions differed in terms of the confederate's arguments: Neutral arguments, arguments to ignore the narrative, or arguments to give great weight to the narrative. Results showed that the historicist narrative was particularly effective at reducing outrage and increasing compassion when the confederate argued for its utilization. The reduction in outrage mediated a reduction in spiteful punitiveness toward the offender. Interestingly, the confederate who urged fellow deliberators to ignore the historicist narrative had no impact on outrage or compassion. We also examined mediation of the impact of historicist narratives on outrage and compassion. We found that when the confederate remained neutral the impact of historicist narratives on outrage and compassion was mediated via diminished perceptions of the offender's control of self-formation. This mirrors what is typically found in prior work focused on individual judgments. In contrast, when the confederate argued that great weight should be given to the narrative, reductions in outrage were mediated via diminished perceptions of offender freedom of action. This pattern of mediation is not typically found but has been found in one previous study where participants received social encouragement to mitigate blame. Results are discussed in terms of how social influence might alter the inferences draw from historicist narratives. Suggestions for future research on social influence in the context of blame are presented.

Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration.

BACKGROUND: A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events. METHODS: We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates. FINDINGS: The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15-45) and 52 in non-initiators (39 months; 18-47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (-0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9-29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15-37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference -0·068% (-0·60 to 0·52). INTERPRETATION: We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV. FUNDING: National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.

Ultrarare Missense Variants Implicated in Utah Pedigrees Multiply Affected With Schizophrenia.

Background: Recent work from the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium showed significant enrichment of ultrarare variants in schizophrenia cases. Family-based studies offer a unique opportunity to evaluate rare variants because risk in multiplex pedigrees is more likely to be influenced by the same collection of variants than an unrelated cohort. Methods: Here, we examine whole genome sequencing data from 35 individuals across 6 pedigrees multiply affected by schizophrenia. We applied a rigorous filtering pipeline to search for classes of protein-coding variants that cosegregated with disease status, and we examined these for evidence of enrichment in the SCHEMA dataset. Additionally, we applied a family-based consensus approach to call copy number variants and screen against a list of schizophrenia-associated risk variants. Results: We identified deleterious missense variants in 3 genes (ATP2B2, SLC25A28, and GSK3A) that cosegregated with disease in 3 of the pedigrees. In the SCHEMA, the gene ATP2B2 shows highly suggestive evidence for deleterious missense variants in schizophrenia cases (p = .000072). ATP2B2 is involved in intracellular calcium homeostasis, expressed in multiple brain tissue types, and predicted to be intolerant to loss-of-function and missense variants. Conclusions: We have identified genes that are likely to increase schizophrenia risk in 3 of the 6 pedigrees examined, the strongest evidence being for a gene involved in calcium homeostasis. Further work is required to examine other classes of variants that may be contributing to disease burden.

Tailoring evidence into action: using a codesign approach for biodiversity information in the Tropical Andes / Toma de decisiones basadas en la evidencia: un enfoque de codiseño para la información sobre biodiversidad en los Andes tropicales / Tomada de decisão baseada em evidências: uma abordagem de co-design para informações sobre biodiversidade nos Andes tropicais

Biodiversity conservation is a complex and transdisciplinary problem that requires engagement and cooperation among scientific, societal, economic, and political institutions. However, historical approaches have often failed to bring together and address the needs of all relevant stakeholders in decision­making processes. The Tropical Andes, a biodiversity hotspot where conservation efforts often conflict with socioeconomic issues and policies that prioritize economic development, provides an ideal model to develop and implement more effective approaches. In this study, we present a co­design approach that mainstreams and improves the flow of biodiversity information in the Tropical Andes, while creating tailored outputs that meet the needs of economic and societal stakeholders. We employed a consultative process that brought together biodiversity information users and producers at the local, national, and regional levels through a combination of surveys and workshops. This approach identified priority needs and limitations of the flow of biodiversity information in the region, which led to the co­design of user­relevant biodiversity indicators. By leveraging the existing capacities of biodiversity information users and producers, we were able to co­design multiple biodiversity indicators and prioritize two for full implementation ensuring that the data was findable, accessible, interoperable, and reusable based on the FAIR principles. This approach helped address limitations that were identified in the stakeholder engagement process, including gaps in data availability and the need for more accessible biodiversity information. Additionally, capacity­building workshops were incorporated for all producers of biodiversity information involved, which aimed to not only improve the current flow of biodiversity information in the region but also facilitate its future sustainability. Our approach can serve as a valuable blueprint for mainstreaming biodiversity information and making it more inclusive in the future, especially considering the diverse worldviews, values, and knowledge systems between science, policy, and practice.

La conservación de la biodiversidad es un problema complejo y transdisciplinario que requiere el compromiso y la cooperación entre instituciones científicas, sociales, económicas y políticas. Sin embargo, los enfoques tradicionales/convencionales  a menudo no logran  reunir y abordar las necesidades de todos los actores relevantes en los procesos de toma de decisiones. Los Andes tropicales, un área clave  de biodiversidad donde los esfuerzos de conservación a menudo entran en conflicto con cuestiones socioeconómicas y políticas que priorizan el desarrollo económico, proporcionan un modelo ideal para desarrollar e implementar enfoques más efectivos. En este estudio, presentamos un enfoque co-diseño que integra y mejora el flujo de información sobre biodiversidad en los Andes tropicales, creando resultados personalizados que satisfacen las necesidades, tanto económicas como sociales, de las partes interesadas. Empleamos un proceso de consulta que reunió a usuarios y productores de información sobre biodiversidad a nivel local, nacional y regional, a través de encuestas y talleres. Este enfoque ha permitido identificar necesidades prioritarias y limitaciones del flujo de información sobre biodiversidad en la región; lo cual llevó al codiseño de indicadores de biodiversidad relevantes para los usuarios. Aprovechando las capacidades existentes de los usuarios y productores de información sobre biodiversidad, pudimos co-diseñar múltiples indicadores de biodiversidad y priorizar dos de estos para su implementación completa, asegurando que los datos sean localizables, accesibles, interoperables y reutilizables, según los principios FAIR. Este enfoque ayudó a abordar las limitaciones que se identificaron en el proceso de participación de las partes interesadas; incluidas las brechas en la disponibilidad de datos y la necesidad de información sobre biodiversidad más accesible. Además, se incorporaron talleres de desarrollo de capacidades para todos los productores de información sobre biodiversidad involucrados, los cuales apuntaron no sólo a mejorar el flujo actual de información sobre biodiversidad en la región, sino también facilitar su sostenibilidad futura. Nuestro enfoque puede servir como un modelo valioso para incorporar la información sobre biodiversidad y hacerla más inclusiva en el futuro; especialmente si consideramos las diversas perspectivas globales, valores y sistemas de conocimiento implicados en las interacciones entre  la ciencia, la política y su aplicación práctica.

A conservação da biodiversidade é um problema complexo e transdisciplinar que requer compromisso e cooperação entre instituições científicas, sociais, económicas e políticas. No entanto, as abordagens tradicionais/convencionais muitas vezes não conseguem reunir e responder às necessidades de todos os intervenientes relevantes nos processos de tomada de decisão. Os Andes tropicais, uma área chave para a biodiversidade onde os esforços de conservação entram frequentemente em conflito com questões socioeconómicas e políticas que dão prioridade ao desenvolvimento económico, fornecem um modelo ideal para desenvolver e implementar abordagens mais eficazes. Neste estudo, apresentamos uma abordagem de co-design que integra e melhora o fluxo de informações sobre biodiversidade nos Andes tropicais, criando resultados personalizados que atendem às necessidades, tanto econômicas quanto sociais, das partes interessadas. Empregamos um processo de consulta que reuniu usuários e produtores de informações sobre biodiversidade nos níveis local, nacional e regional, por meio de pesquisas e workshops. Esta abordagem permitiu identificar necessidades prioritárias e limitações do fluxo de informação sobre a biodiversidade na região; o que levou à concepção conjunta de indicadores de biodiversidade relevantes para os utilizadores. Aproveitando as capacidades existentes dos utilizadores e produtores de informação sobre biodiversidade, fomos capazes de conceber em conjunto vários indicadores de biodiversidade e priorizar dois deles para implementação total, garantindo que os dados sejam localizáveis, acessíveis, interoperáveis ​​e reutilizáveis, de acordo com os princípios FAIR. Esta abordagem ajudou a resolver as limitações identificadas no processo de envolvimento das partes interessadas; incluindo lacunas na disponibilidade de dados e a necessidade de informações mais acessíveis sobre biodiversidade. Além disso, foram incorporados workshops de capacitação para todos os produtores de informação sobre biodiversidade envolvidos, que visaram não só melhorar o fluxo actual de informação sobre biodiversidade na região, mas também facilitar a sua sustentabilidade futura. A nossa abordagem pode servir como um modelo valioso para incorporar informações sobre biodiversidade e torná-las mais inclusivas no futuro; especialmente se considerarmos as diversas perspectivas globais, valores e sistemas de conhecimento envolvidos nas interações entre ciência, política e sua aplicação prática.

Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.

Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.

Genetic diversity goals and targets have improved, but remain insufficient for clear implementation of the post-2020 global biodiversity framework.

Genetic diversity among and within populations of all species is necessary for people and nature to survive and thrive in a changing world. Over the past three years, commitments for conserving genetic diversity have become more ambitious and specific under the Convention on Biological Diversity's (CBD) draft post-2020 global biodiversity framework (GBF). This Perspective article comments on how goals and targets of the GBF have evolved, the improvements that are still needed, lessons learned from this process, and connections between goals and targets and the actions and reporting that will be needed to maintain, protect, manage and monitor genetic diversity. It is possible and necessary that the GBF strives to maintain genetic diversity within and among populations of all species, to restore genetic connectivity, and to develop national genetic conservation strategies, and to report on these using proposed, feasible indicators.

A hospital to community exercise referral pathway: results of a pilot project.

BACKGROUND: People living with chronic disease should ideally engage with community-based exercise services following hospital-based rehabilitation. However, transition from hospital to community exercise settings is extremely challenging and strategies to support this transition are underdeveloped. AIMS: The aims of this study were to develop and explore the feasibility of a pilot exercise referral pathway between an acute hospital and community gyms for patients with chronic health conditions and to evaluate patient satisfaction with the exercise referral pathway. METHODS: A stakeholder-informed exercise referral pathway was developed and offered to patients following completion of a hospital-based exercise programme for a chronic health condition. The pathway was evaluated using a mixed-methods approach. Quantitative data examining participant engagement was used to examine feasibility. Quantitative survey data and qualitative data from semi-structured interviews examined satisfaction with the pathway. RESULTS: Forty-nine people living with chronic conditions (mean age 72 ± 7.8 years) participated (recruitment rate 59%). The average number of community gym visits over 4 months was 17.4 (range 0-51). Twenty-nine (78%) participants reported that they planned to continue their gym membership when the programme ended. Themed responses from participant interviews (n = 12) highlighted the benefits of a supported transition from hospital to gym membership and the need for more structured exercise support in community gyms. CONCLUSION: A structured exercise referral pathway to support exercise transition between hospital and community settings in populations with chronic health conditions appears feasible. Participants reported high levels of satisfaction with the referral pathway.

Synchronous robotic repair of anterior diaphragmatic (Morgagni) hernia & low anterior resection for rectal cancer.

BACKGROUND: We present the case report of synchronous trans-fascial repair of a large congenital Morgagni hernia (MH) and low anterior resection using a fully robotic approach. METHODS: A 61-year old female presented with fresh red blood in her stool. She had a previous history of abdominal hysterectomy and a performance status of 0. Imaging revealed a low rectal cancer and incidental large MH. RESULTS: Using the Da Vinci X platform the procedure was successfully performed; total operating time of 450 min, <200 ml blood loss and 5 days hospital stay. Post-operative scan at 6 months, 1 and 2 years showed no evidence of hernia or cancer recurrence. CONCLUSION: We have demonstrated that complex multi-visceral procedures can be safely performed on fully robotic platforms, even in previously disturbed surgical fields. The robotic approach may provide the opportunity for seamless multi-speciality operating simultaneously in multiple body cavities.

Identity-by-descent analysis of a large Tourette's syndrome pedigree from Costa Rica implicates genes involved in neuronal development and signal transduction.

Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data.

The theoretical and practical arguments against the unilateral withdrawal of life-sustaining treatment during crisis standards of care: Does the Knobe effect apply to unilateral withdrawal?

Some argue that it is ethically justifiable to unilaterally withdraw life-sustaining treatment during crisis standards of care without the patient's consent in order to reallocate it to another patient with a better chance of survival. This justification has been supported by two lines of argument: the equivalence thesis and the rule of the double effect. We argue that there are theoretical issues with the first and practical ones with the second, as supported by an experiment aimed at exploring whether the Knobe effect, which affects the folk concept of intention, applies to situations of unilateral withdrawal. Fifty-two critical care physicians from one university were asked to ascribe intention in two hypothetical scenarios A and B in which outcomes differ-the patient from whom life-sustaining treatment is withdrawn dies in scenario A but survives in scenario B-but the intention, to save the other patient regardless of the outcome of the other, is the same. The survey was administered via a web-based survey and all answers were anonymous. A paired proportion test was used to compare responses to both questions. All 52 surveyed individuals responded in scenario A and 30 (57.7%) ascribed intention when outcomes were unfavorable, whereas 50 responded in scenario B and 8 (16%) ascribed intention when outcomes were favorable, a difference that was statistically significant (p < 0.001). There are theoretical and practical issues with the arguments proposed to justify the unilateral withdrawal of life-sustaining treatment based on the equivalence thesis and the rule of double effect.

Indocyanine green colonic perfusion demonstration following robotic da Vinci X inferior mesenteric artery ligation for the treatment of type II endoleak.

BACKGROUND: We describe the technical operative details of the robotic repair of a type II endoleak (T2E) following endovascular abdominal aortic aneurysm repair (EVAR). We demonstrate that indocyanine green (ICG) can be used intra-operatively to demonstrate perfusion of the colon following ligation of the inferior mesenteric artery (IMA) vessel feeding the aneurysm sac. METHODS: A 74-year old male underwent EVAR for a 5.8 cm infra-renal abdominal aortic aneurysm using an E-Tegra, Jotec Device (JOTEC Gmb, Lotzenäcker 23,D-72379 Hechingen). Surveillance contrast CT (CTA) over the ensuing 30 months confirmed progressive sac expansion. RESULTS: ICG confirmed colonic perfusion via the marginals after IMA ligation. Total operative time 56 min < 50 mls blood loss and 1-day hospital stay. 3-month follow-up: CTA and ultrasound demonstrated complete resolution of T2E and adequately perfused colon. CONCLUSION: A total robotic approach can be performed safely with intra-operative ICG used to demonstrate colonic perfusion as an added safety measure.

A novel group of genes that cause endocrine resistance in breast cancer identified by dynamic gene expression analysis.

Breast cancer (BC) is the most common type of cancer diagnosed in women. Among female cancer deaths, BC is the second leading cause of death worldwide. For estrogen receptor-positive (ER-positive) breast cancers, endocrine therapy is an effective therapeutic approach. However, in many cases, an ER-positive tumor becomes unresponsive to endocrine therapy, and tumor regrowth occurs after treatment. While some genetic mutations contribute to resistance in some patients, the underlying causes of resistance to endocrine therapy are mostly undetermined. In this study, we utilized a recently developed statistical approach to investigate the dynamic behavior of gene expression during the development of endocrine resistance and identified a novel group of genes whose time course expression significantly change during cell modelling of endocrine resistant BC development. Expression of a subset of these genes was also differentially expressed in microarray analysis of endocrine-resistant and endocrine-sensitive tumor samples. Surprisingly, a subset of those genes was also differentially genes expressed in triple-negative breast cancer (TNBC) as compared with ER-positive BC. The findings suggest shared genetic mechanisms may underlie the development of endocrine resistant BC and TNBC. Our findings identify 34 novel genes for further study as potential therapeutic targets for treatment of endocrine-resistant BC and TNBC.

Which Measures From a Sustained Attention Task Best Predict ADHD Group Membership?

Difficulty with sustaining attention to a task is a hallmark of ADHD. It would be useful to know which measures of sustained attention best predict a diagnosis of ADHD. Participants were 129 children with a diagnosis of ADHD and 129 matched controls who completed the fixed Sustained Attention to Response Task (SART). The number of commission and omission errors, standard deviation of response time (SDRT), tau, fast and slow frequency variability, d-prime, and mu were able to successfully classify children with and without ADHD. The mean response time, criterion, and sigma were not able to classify participants. The best classifiers were d-prime (0.75 Area Under the Receiver Operated Characteristic), tau (.74), SDRT (0.74), omission errors (0.72), commission errors (0.71), and SFAUS (0.70). This list of the best classifier measures derived from the SART may prove useful for the planning of future studies.

Predicting the Plateau Modulus from Molecular Parameters of Conjugated Polymers.

The relationship between Kuhn length l k , Kuhn monomer volume v 0, and plateau modulus G N 0, initially proposed by Graessley and Edwards for flexible polymers, and extended by Everaers, has a large gap in experimental data between the flexible and stiff regimes. This gap prevents the prediction of mechanical properties from the chain structure for any polymer in this region. Given the chain architecture, including a semiflexible backbone and side chains, conjugated polymers are an ideal class of material to study this crossover region. Using small angle neutron scattering, oscillatory shear rheology, and the freely rotating chain model, we have shown that 12 polymers with aromatic backbones populate a large part of this gap. We also have shown that a few of these polymers exhibit nematic ordering, which lowers G N 0. When fully isotropic, these polymers follow a relationship between l k , v 0, and G N 0, with a simple crossover proposed in terms of the number of Kuhn segments in an entanglement strand N e.

The Determination of Sucrose Content in Maple Sap Using Time-Domain Magnetic Resonance.

The natural variation of sucrose concentration in maple tree sap is investigated using time-domain magnetic resonance (MR). The current study, which includes a concise introduction to the relevant MR properties, is a demonstration of principle showing how the relaxation time constant T 2 and the self-diffusion coefficient relate to the amount of sucrose and ionic content present in the collected sap samples. T 2 and self-diffusion coefficient for maple saps from six different trees, each sampled weekly in the spring of 2019, were measured using MR. The results were plotted against the sucrose concentration of each sample with the aim of determining if either quantity could serve as the basis for a non-invasive sucrose measurement for maple trees. The T 2 relaxation time constant was found not to be a reliable proxy for sucrose content in maple sap as it showed sensitivity to the slight changes in sap chemistry throughout the season and natural variation from tree to tree. The diffusion coefficient, determined through a standard pulsed-gradient spin-echo experiment, was insensitive to the changes in sap chemistry and showed a strong relationship to sucrose content. A diffusion measurement is thus proposed as the most suitable candidate for a non-invasive sucrose measurement for maple tree sap.

Normalization of impaired emotion inhibition in bipolar disorder mediated by cholinergic neurotransmission in the cingulate cortex.

The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and affective mechanisms of emotional processing, functionally altered in BD. Emotion processing can be assessed by the ability to inhibit a response when the content of the image is emotional. Impaired regulatory capacity of cholinergic neurotransmission conferred by reduced M2-autoreceptor availability is hypothesized to play a role in elevated salience of negative emotional distractors in euthymic BD relative to individuals with no history of mood instability. Thirty-three euthymic BD type-I (DSM-V-TR) and 50 psychiatrically-healthy controls underwent functional magnetic resonance imaging (fMRI) and an emotion-inhibition paradigm before and after intravenous cholinergic challenge using the acetylcholinesterase inhibitor, physostigmine (1 mg), or placebo. Mood, accuracy, and reaction time on either recognizing or inhibiting a response associated with an image involving emotion and regional functional activation were examined for effects of cholinergic challenge physostigmine relative to placebo, prioritizing any interaction with the diagnostic group. Analyses revealed that (1) at baseline, impaired behavioral performance was associated with lower activation in the anterior cingulate cortex in BD relative to controls during emotion processing; (2) physostigmine (vs. placebo) affected behavioral performance during the inhibition of negative emotions, without altering mood, and increased activation in the posterior cingulate cortex in BD (vs. controls); (3) In BD, lower accuracy observed during emotion inhibition of negative emotions was remediated by physostigmine and was associated with cingulate cortex overactivation. Our findings implicate abnormal regulation of cholinergic neurotransmission in the cingulate cortices in BD, which may mediate exaggerated emotional salience processing, a core feature of BD.

Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278.

In a Phase 2 clinical trial, BMS-986020, a lysophosphatidic acid receptor-1 (LPA1) antagonist, produced hepatobiliary toxicity (increased ALT, AST, and ALP; cholecystitis) and increases in plasma bile acids (BA). Nonclinical investigations conducted to identify a potential mechanism(s) for this toxicity examined BMS-986020 and two LPA1 antagonists structurally distinct from BMS-986020 (BMS-986234 and BMS-986278). BMS-986020 inhibited hepatic BA efflux transporters BSEP (IC50 1.8 µM), MRP3 (IC50 22 µM), and MRP4 (IC50 6.2 µM) and inhibited BA canalicular efflux in human hepatocytes (68% at 10 µM). BMS-986020 inhibited mitochondrial function (basal and maximal respiration, ATP production, and spare capacity) in human hepatocytes and cholangiocytes at ≥10 µM and inhibited phospholipid efflux in human hepatocytes (MDR3 IC50 7.5 µM). A quantitative systems toxicology analysis (DILIsym®), considering pharmacokinetics, BA homeostasis, mitochondrial function, oxidative phosphorylation, and reactive intermediates performed for BMS-986020 recapitulated clinical findings ascribing the effects to BA transporter and mitochondrial electron transport chain inhibition. BMS-986234 and BMS-986278 minimally inhibited hepatic BA transporters (IC50 ≥20 µM) and did not inhibit MDR3 activity (IC50 >100 µM), nor did BMS-986234 inhibit BA efflux (≤50 µM) or mitochondrial function (≤30 µM) (BMS-986278 not evaluated). Multiple mechanisms may be involved in the clinical toxicity observed with BMS-986020. The data indicate that this toxicity was unrelated to LPA1 antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA1 antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278.