Covalent Targeting As a Common Mechanism for Inhibiting NLRP3 Inflammasome Assembly.

The NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines, including IL-1ß and IL-18. Aberrant overactivation of NLRP3 is implicated in numerous inflammatory disorders. However, the activation and regulation of NLRP3 inflammasome signaling remain poorly understood, limiting our ability to develop pharmacologic approaches to target this important inflammatory complex. Here, we developed and implemented a high-throughput screen to identify compounds that inhibit the inflammasome assembly and activity. From this screen, we identify and profile inflammasome inhibition of 20 new covalent compounds across nine different chemical scaffolds, as well as many known inflammasome covalent inhibitors. Intriguingly, our results indicate that NLRP3 possesses numerous reactive cysteines on multiple domains whose covalent targeting blocks the activation of this inflammatory complex. Specifically, focusing on compound VLX1570, which possesses multiple electrophilic moieties, we demonstrate that this compound allows covalent, intermolecular cross-linking of NLRP3 cysteines to inhibit inflammasome assembly. Our results, along with the recent identification of numerous covalent molecules that inhibit NLRP3 inflammasome activation, further support the continued development of electrophilic compounds that target reactive cysteine residues on NLRP3 to regulate its activation and activity.

Reliability and Validity of the Geriatric Depression Scale in a Sample of Portuguese Older Adults with Mild-to-Moderate Cognitive Impairment.

Although the Geriatric Depression Scale (GDS) is a well-established instrument for the assessment of depressive symptoms in older adults, this has not been validated specifically for Portuguese older adults with cognitive impairment. The objective of this study was to analyze the psychometric properties of two Portuguese versions of the GDS (GDS-27 and GDS-15) in a sample of Portuguese older adults with mild-to-moderate cognitive impairment. Clinicians assessed for major depressive disorder and cognitive functioning in 117 participants with mild-to-moderate cognitive decline (76.9% female, Mage = 83.66 years). The internal consistency of GDS-27 and GDS-15 were 0.874 and 0.812, respectively. There was a significant correlation between GDS-27 and GDS-15 with the Beck Depression Inventory-II (GDS-27: rho = 0.738, p < 0.001; GDS-15: rho = 0.760, p < 0.001), suggesting good validity. A cutoff point of 15/16 in GDS-27 and 8/9 in GDS-15 resulted in the identification of persons with depression (GDS-27: sensitivity 100%, specificity 63%; GDS-15: sensitivity 90%, specificity 62%). Overall, the GDS-27 and GDS-15 are reliable and valid instruments for the assessment of depression in Portuguese-speaking older adults with cognitive impairment.

Covalent targeting as a common mechanism for inhibiting NLRP3 inflammasome assembly.

The NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines including IL-1ß and IL-18. Aberrant overactivation of NLRP3 is implicated in numerous inflammatory disorders. However, the activation and regulation of NLRP3 inflammasome signaling remains poorly understood, limiting our ability to develop pharmacologic approaches to target this important inflammatory complex. Here, we developed and implemented a high-throughput screen to identify compounds that inhibit inflammasome assembly and activity. From this screen we identify and profile inflammasome inhibition of 20 new covalent compounds across 9 different chemical scaffolds, as well as many known inflammasome covalent inhibitors. Intriguingly, our results indicate that NLRP3 possesses numerous reactive cysteines on multiple domains whose covalent targeting blocks activation of this inflammatory complex. Specifically, focusing on compound VLX1570, which possesses multiple electrophilic moieties, we demonstrate that this compound allows covalent, intermolecular crosslinking of NLRP3 cysteines to inhibit inflammasome assembly. Our results, along with the recent identification of numerous covalent molecules that inhibit NLRP3 inflammasome activation, suggests that NLRP3 serves as a cellular electrophile sensor important for coordinating inflammatory signaling in response to redox stress. Further, our results support the potential for covalent cysteine modification of NLRP3 for regulating inflammasome activation and activity.

Effectiveness of a year-long individual cognitive stimulation program in Portuguese older adults with cognitive impairment.

Cognitive stimulation is a recommended therapy with positive effects on the cognitive performance of older adults with neurocognitive disorders. However, there are few one-on-one, long-term interventions applied by professionals. The aim of the present study was to determine the effectiveness of 47-week individual cognitive stimulation (iCS) interventions on cognition, mood, instrumental activities of daily living, and quality of life in older adults, with neurocognitive disorders using a single-blind, randomized, parallel two-arm RCT. A sample of 59 older adults with neurocognitive disorders (predominantly Alzheimer's disease), who were non-institutionalized but socially vulnerable, was selected. The intervention group (n = 30) received 47 iCS weekly sessions. The control group (n = 29) maintained their baseline treatments. Outcomes were global cognitive function, cognitive impairment, mood, instrumental activities of daily living, and self-reported quality of life. All participants were assessed at baseline, 25 weeks, and 50 weeks. The results showed a significant effect of the intervention on MMSE, MoCA, GDS-15. Individual cognitive stimulation may have beneficial effects on the cognitive function and mood of older adults with cognitive impairment.

Home-Based Individualized Cognitive Stimulation (iCS) Therapy in Portuguese Psychiatric Patients: A Randomized Controlled Trial.

Cognitive difficulties are common in people with mental health issues, including psychotic disorders, although this population may have difficulty accessing treatments due to various challenges, including transportation, remembering appointments, or discomfort in crowded or unfamiliar places. Home-based services can be crucial and effective for reaching populations with accessibility issues; one home-based intervention technique is individual cognitive stimulation (iCS), which has been shown to be an effective strategy to target and improve cognitive functioning in various samples. Using a previously established Portuguese iCS protocol, based on an initial brief cognitive assessment and the subsequent administration of cognitive stimulation materials and reflection exercises, the current randomized controlled trial explored the effectiveness of the iCS intervention on participants in Portugal with psychotic disorders. Outcome tools included measures of cognition, depression, quality of life, and functional abilities at baseline, the completion of the intervention, and post-intervention follow-up. With two well-matched groups at baseline, the results revealed significant improvements in the intervention group on cognitive functioning, depression, quality of life, and, more modestly, functional activities. These results offer an important contribution to the field of iCS protocols, in an effort to enhance the lives and well-being of various clinical populations, including those with psychotic disorders.

Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation.

Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between energy intake and consumption, therefore balancing energy homeostasis is an attractive target for metabolic diseases. One therapeutic approach consists of increasing the number of brown-like adipocytes in the white adipose tissue (WAT). Whereas WAT stores excess energy, brown adipose tissue (BAT) can dissipate this energy overload in the form of heat, increasing energy expenditure and thus inhibiting metabolic diseases. To facilitate BAT production a high-throughput screening approach was developed on previously known drugs using human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes. The screening allowed us to discover that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased adipocytes into functional brown adipocytes. However, zafirlukast is toxic to human cells at higher dosages. Drug-Initiated Activity Metabolomics (DIAM) was used to investigate zafirlukast as a BAT inducer, and the endogenous metabolite myristoylglycine was then discovered to mimic the browning properties of zafirlukast without impacting cell viability. Myristoylglycine was found to be bio-synthesized upon zafirlukast treatment and was unique in inducing brown adipocyte differentiation, raising the possibility of using endogenous metabolites and bypassing the exogenous drugs to potentially alleviate disease, in this case, obesity and other related metabolic diseases.

Impact of confinement measures due to the COVID-19 pandemic on people living with dementia and their caregivers in Spain.

The COVID-19 pandemic has particularly affected people living with dementia (PLWD) and their caregivers, who have seen their access to social support services and opportunities for socialisation limited. The objective of the study was to explore the impact of COVID-19 on PLWD and their caregivers in Spain. An online survey was conducted between November 27, 2020, and January 19, 2021, that explored compliance with prevention guidelines, changes at the family level and in access to social support services. Instruments were included to estimate levels of anxiety and depression. The survey was answered by 229 people (161 current caregivers, 54 former caregivers, 13 formal caregivers and 1 person with dementia). Analysis of the current and former caregivers showed that they felt well informed, although they find it difficult for PLWD to comply with prevention guidelines. The use of social support services was reduced and the difficulty of access to social and health services increased, there was a negative impact on the economic situation and family relationships, with an increase in perceived overload. In addition, caregivers of PLWD scored above the cut-off points in the tests used to assess depression and anxiety, although the results of the multiple regression analysis do not allow us to conclude that the loss of resources influences the anxiety and depression scores. The negative impact of the pandemic on caregivers of PLWD is verified. It is necessary to adapt social support services and design strategies to maintain the provision of support to these vulnerable groups.

Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension.

Hypertension and kidney disease have been repeatedly associated with genomic variants and alterations of lysine metabolism. Here, we combined stable isotope labeling with untargeted metabolomics to investigate lysine's metabolic fate in vivo. Dietary 13C6 labeled lysine was tracked to lysine metabolites across various organs. Globally, lysine reacts rapidly with molecules of the central carbon metabolism, but incorporates slowly into proteins and acylcarnitines. Lysine metabolism is accelerated in a rat model of hypertension and kidney damage, chiefly through N-alpha-mediated degradation. Lysine administration diminished development of hypertension and kidney injury. Protective mechanisms include diuresis, further acceleration of lysine conjugate formation, and inhibition of tubular albumin uptake. Lysine also conjugates with malonyl-CoA to form a novel metabolite Nε-malonyl-lysine to deplete malonyl-CoA from fatty acid synthesis. Through conjugate formation and excretion as fructoselysine, saccharopine, and Nε-acetyllysine, lysine lead to depletion of central carbon metabolites from the organism and kidney. Consistently, lysine administration to patients at risk for hypertension and kidney disease inhibited tubular albumin uptake, increased lysine conjugate formation, and reduced tricarboxylic acid (TCA) cycle metabolites, compared to kidney-healthy volunteers. In conclusion, lysine isotope tracing mapped an accelerated metabolism in hypertension, and lysine administration could protect kidneys in hypertensive kidney disease.

Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.

In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.

Multicenter randomized controlled trial of the effects of individual reminiscence therapy on cognition, depression and quality of life: Analysis of a sample of older adults with Alzheimer's disease and vascular dementia.

Objective: To determine the effectiveness of a 13-week individual reminiscence therapy (RT) intervention on cognition, memory, executive function, mood, and quality of life of people with Alzheimer's disease and vascular dementia. Method: Non-protocolized analysis using data from a larger multicenter, single-blind, randomized, parallel two-arm RCT of RT for people with neurocognitive disorders. A sample of 148 people with probable Alzheimer's disease or vascular dementia attending 23 Portuguese institutions providing care and support services for older adults were selected. Intervention group (n = 74) received 26 individual RT sessions, twice a week for 13 weeks. Control group (n = 74) maintained their treatment as usual. Outcomes were global cognitive function (MMSE), memory (MAT), executive function (FAB), mood (GDS-15), and self-reported quality of life (QoL-AD). All participants were assessed at baseline (T0) and 15 weeks later (T1). Results: The results showed a significant effect of the intervention on global cognition (Group X Time interaction F(1, 128) = 10.542, p = .001, ηp2 = .076), memory (F(1,128) = 9.881, p = .002, ηp2 = .072), and quality of life (F(1,128) = 0.181, p = .671, ηp2 = .001), with medium effect sizes. A small effect on executive function (F(1,127) = 11.118, p = .001, ηp2 = .080) was also found. No effects were found on depressive symptoms (F(1,128) = 0.181, p = .671, ηp2 = .001). Conclusion: Individual RT may have beneficial effects on cognition and quality of life of people with Alzheimer's disease or vascular dementia.

Effectiveness of a Randomized Controlled Trial of Individual Reminiscence Therapy on Cognition, Mood and Quality of Life in Azorean Older Adults with Neurocognitive Disorders.

Reminiscence therapy (RT) is a form of cognitive stimulation therapy that incorporates discussion of past activities, events, and experiences to stimulate individual memories; it has had some success in treating persons with neurocognitive disorders. This research aims to evaluate the ability of individual RT, using a simple reminiscence format, to improve the overall cognitive function, memory, executive functions, emotional status, and quality of life in older adults with neurocognitive disorders who received social care and support services. A multicenter randomized controlled trial was completed in the Azores archipelago (an independent region of Portugal) using repeated measures (pre-intervention, post-intervention, and follow-up). The intervention group underwent individual RT sessions, twice weekly for 13 weeks, while the control group completed regular activities administered as part of their program. Results did not reveal any significant differences between the intervention and control groups. While results did not reveal significant effects, a number of historical and contextual factors are considered as possible explanations for the lack of effects-namely, data collection occurring during the COVID-19 global pandemic, participant cohort effects, and therapist heterogeneity.

Metabolomics activity screening of T cell-induced colitis reveals anti-inflammatory metabolites.

Untargeted metabolomics of disease-associated intestinal microbiota can detect quantitative changes in metabolite profiles and complement other methodologies to reveal the full effect of intestinal dysbiosis. Here, we used the T cell transfer mouse model of colitis to identify small-molecule metabolites with altered abundance due to intestinal inflammation. We applied untargeted metabolomics to detect metabolite signatures in cecal, colonic, and fecal samples from healthy and colitic mice and to uncover differences that would aid in the identification of colitis-associated metabolic processes. We provided an unbiased spatial survey of the GI tract for small molecules, and we identified the likely source of metabolites and biotransformations. Several prioritized metabolites that we detected as being altered in colitis were evaluated for their ability to induce inflammatory signaling in cultured macrophages, such as NF-κB signaling and the expression of cytokines and chemokines upon LPS stimulation. Multiple previously uncharacterized anti-inflammatory and inflammation-augmenting metabolites were thus identified, with phytosphingosine showing the most effective anti-inflammatory activity in vitro. We further demonstrated that oral administration of phytosphingosine decreased inflammation in a mouse model of colitis induced by the compound TNBS. The collection of distinct metabolites we identified and characterized, many of which have not been previously associated with colitis, may offer new biological insight into IBD-associated inflammation and disease pathogenesis.

Isolation and Differentiation of Primary White and Brown Preadipocytes from Newborn Mice.

The understanding of the mechanisms underlying adipocyte differentiation and function has greatly benefited from the use of immortalized white preadipocyte cell lines. These cultured cell lines, however, have limitations. They do not fully capture the diverse functional spectrum of the heterogenous adipocyte populations that are now known to exist within white adipose depots. To provide a more physiologically relevant model to study the complexity of white adipose tissue, a protocol has been developed and optimized to enable simultaneous isolation of primary white and brown adipocyte progenitors from newborn mice, their rapid expansion in culture, and their differentiation in vitro into mature, fully functional adipocytes. The primary advantage of isolating primary cells from newborn, rather than adult mice, is that the adipose depots are actively developing and are, therefore, a rich source of proliferating preadipocytes. Primary preadipocytes isolated using this protocol differentiate rapidly upon reaching confluence and become fully mature in 4-5 days, a temporal window that accurately reflects the appearance of developed fat pads in newborn mice. Primary cultures prepared using this strategy can be expanded and studied with high reproducibility, making them suitable for genetic and phenotypic screens and enabling the study of the cell-autonomous adipocyte phenotypes of genetic mouse models. This protocol offers a simple, rapid, and inexpensive approach to study the complexity of adipose tissue in vitro.

Machine learning and natural language processing (NLP) approach to predict early progression to first-line treatment in real-world hormone receptor-positive (HR+)/HER2-negative advanced breast cancer patients.

BACKGROUND: CDK4/6 inhibitors plus endocrine therapies are the current standard of care in the first-line treatment of HR+/HER2-negative metastatic breast cancer, but there are no well-established clinical or molecular predictive factors for patient response. In the era of personalised oncology, new approaches for developing predictive models of response are needed. MATERIALS AND METHODS: Data derived from the electronic health records (EHRs) of real-world patients with HR+/HER2-negative advanced breast cancer were used to develop predictive models for early and late progression to first-line treatment. Two machine learning approaches were used: a classic approach using a data set of manually extracted features from reviewed (EHR) patients, and a second approach using natural language processing (NLP) of free-text clinical notes recorded during medical visits. RESULTS: Of the 610 patients included, there were 473 (77.5%) progressions to first-line treatment, of which 126 (20.6%) occurred within the first 6 months. There were 152 patients (24.9%) who showed no disease progression before 28 months from the onset of first-line treatment. The best predictive model for early progression using the manually extracted dataset achieved an area under the curve (AUC) of 0.734 (95% CI 0.687-0.782). Using the NLP free-text processing approach, the best model obtained an AUC of 0.758 (95% CI 0.714-0.800). The best model to predict long responders using manually extracted data obtained an AUC of 0.669 (95% CI 0.608-0.730). With NLP free-text processing, the best model attained an AUC of 0.752 (95% CI 0.705-0.799). CONCLUSIONS: Using machine learning methods, we developed predictive models for early and late progression to first-line treatment of HR+/HER2-negative metastatic breast cancer, also finding that NLP-based machine learning models are slightly better than predictive models based on manually obtained data.

Multicentre randomised controlled trial about the effect of individual reminiscence therapy in older adults with neurocognitive disorders.

OBJECTIVES: To evaluate the effectiveness of a 13-week individual reminiscence therapy (RT) intervention to improve the overall cognitive function, memory, executive function, mood and quality of life (QoL) of people with neurocognitive disorders. METHODS: A single-blind, multicentre, randomised parallel two-arm controlled trial recruited 251 people with neurocognitive disorders attending 24 institutions providing care and support services for older adults in Portugal. The primary outcome measure was cognitive function (Mini-Mental State Examination [MMSE]). Secondary outcomes were memory (Memory Alteration Test [MAT]), executive function (Frontal Assessment Battery [FAB]), mood (Geriatric Depression Scale-15 [GDS-15]) and self-reported QoL-Alzheimer's disease AD). Participants in the intervention group (n = 131) received 26 individual RT sessions, twice a week, over the course of 13 weeks. Participants in the control group (n = 120) maintained their treatment as usual. RESULTS: Intention-to-treat analysis showed that, at endpoint assessment, the intervention group had significantly improved in relation to the control group in MMSE (mean difference 1.84, 95% CI [0.80, 2.89], p = .001, d = .44), MAT (mean difference 2.82, 95% CI [0.72, 4.91], p = .009, d = .34) and QoL-AD (mean difference 1.78, 95% CI [0.17, 3.39], p = .031, d = .28). Non-significant improvements were found on FAB (mean difference 0.74, 95% CI [-0.04, 1.52], p = .062, d = .24) and GDS-15 (mean difference -0.63, 95% CI [-1.45, 0.19], p = .130, d = .19). CONCLUSIONS: For people with neurocognitive disorders attending social care and support services, the individual RT designed for this trial should be considered an intervention with the potential to improve cognition, memory and QoL.

NIH Workshop Report: sensory nutrition and disease.

In November 2019, the NIH held the "Sensory Nutrition and Disease" workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.

Chemical short-range order in derivative Cr-Ta-Ti-V-W high entropy alloys from the first-principles thermodynamic study.

The development of high-entropy alloys (HEAs) focuses on exploring compositional regions in multi-component systems with all alloy elements in equal or near-equal atomic concentrations. Initially it was based on the main idea that high mixing configurational entropy contributions to the alloy free energy could promote the formation of a single solid solution phase. By using the ab-initio based Cluster Expansion (CE) Hamiltonian model constructed for the quinary bcc Cr-Ta-Ti-V-W system in combination with Monte Carlo (MC) simulations, we show that the phase stability and chemical short-range order (SRO) of the equiatomic quinary and five sub-quaternary systems, as well as their derivative alloys, can dramatically change the order-disorder transition temperatures (ODTT) as a function of alloy compositions. In particular, it has been found, that the equiatomic quaternary Ta-Ti-V-W and Cr-Ta-Ti-W alloys had the lowest order-disorder transition temperature (500 K) among all the analysed equiatomic compositions. In all investigated alloy systems, the strongest chemical ordering has been observed between Cr and V, which led to the conclusion that decreasing the concentration of either Cr or V might be beneficial in terms of decreasing the ODTT. It also predicts that increasing concentration of Ti significantly decreases the ODTT. Our analysis of chemical SRO as a function of alloy composition allows to understand the microstructure evolution of HEAs as a function of temperature in excellent agreement with available experimental observations. Importantly, our free energy of mixing and SRO calculations predict that the origin of precipitates formed by Cr- and V-rich in the sub-quaternary Cr-Ta-V-W system is driven by the thermodynamics. The modelling results are in an excellent agreement with experimental observation of Cr and V segregation in the W0.38Ta0.36Cr0.15V0.11 alloy which in turns shows an exceptional radiation resistance.

Protocolo de intervenção individual baseado na terapia de reminiscência em idosos com perturbação neurocognitiva / Individual intervention protocol based on reminiscence therapy for older people with neurocognitive disorders / Protocolo de intervención individual basado en la terapia de reminiscencia en personas mayores con trastornos neurocognitivos

Enquadramento: A literatura sugere que a terapia de reminiscência (TR) é uma das terapias não-farmacológicas com melhores evidências na população idosa com perturbação neurocognitiva (PNC), permitindo estimular a neuroplasticidade e a reserva cognitiva, podendo ter um efeito protetor na pessoa com PNC. Objetivo: Apresentar de forma pormenorizada a estrutura e o conteúdo de um protocolo de intervenção em idosos com PNC, baseado na TR individual. Metodologia: Identificação das fases preliminares ao desenho do protocolo de intervenção. Resultados: Protocolo de intervenção individual baseado na TR, em formato misto, composto por 26 sessões, com frequência bissemanal e com duração aproximada de 50 minutos por sessão, administrado por terapeutas treinados. Conclusão: O programa de TR individual pormenorizado permite uma implementação e replicabilidade adequada, podendo contribuir para atenuar a progressão da PNC.

Background: The literature suggests that reminiscence therapy (RT) is one of the non-pharmacological treatments with better evidence for older people with neurocognitive disorders (NCD). RT stimulates neuroplasticity and cognitive reserve, and it may have a protective effect on the person with NCD. Objective: To describe in detail the structure and contents of an individual RT intervention protocol applied to older people with NCD. Methodology: Identification of the phases prior to the design of the intervention protocol. Results: Individual RT intervention protocol, in a mixed format, consisting of 26 sessions, twice a week, of approximately 50 minutes each, conducted by trained therapists. Conclusion: The detailed individual RT program can be adequately implemented and replicated, and it may delay the progression of NCD.

Marco contextual: La literatura sugiere que la terapia de reminiscencia (TR) es una de las terapias no farmacológicas con mejores resultados en la población anciana con trastorno neurocognitivo (PNC, en portugués), pues permite la estimulación de la neuroplasticidad y la reserva cognitiva, y puede tener un efecto protector en la persona con PNC. Objetivo: Presentar de forma pormenorizada la estructura y el contenido de un protocolo de intervención para personas mayores con PNC, basado en la TR individual. Metodología: Identificación de las fases preliminares al diseño del protocolo de intervención. Resultados: Protocolo de intervención individual basado en la TR, en formato mixto, compuesto por 26 sesiones, con una frecuencia quincenal y una duración aproximada de 50 minutos por sesión, administrado por terapeutas capacitados. Conclusión: El programa de TR individual pormenorizado permite una implementación y una replicabilidad adecuadas, y puede contribuir a suavizar el progreso de la PNC.

Discovery of small-molecule enzyme activators by activity-based protein profiling.

Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse-small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1-a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1's catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.

AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS-based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9th carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease.