Extending MeCP2 interactome: canonical nucleosomal histones interact with MeCP2.

MeCP2 is a general regulator of transcription involved in the repression/activation of genes depending on the local epigenetic context. It acts as a chromatin regulator and binds with exquisite specificity to gene promoters. The set of epigenetic marks recognized by MeCP2 has been already established (mainly, cytosine modifications in CpG and CpA), as well as many of the constituents of its interactome. We unveil a new set of interactions for MeCP2 with the four canonical nucleosomal histones. MeCP2 interacts with high affinity with H2A, H2B, H3 and H4. In addition, Rett syndrome associated mutations in MeCP2 and histone epigenetic marks modulate these interactions. Given the abundance and the structural/functional relevance of histones and their involvement in epigenetic regulation, this new set of interactions and its modulating elements provide a new addition to the 'alphabet' for this epigenetic reader.

Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation.

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 µM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.

Compartmentalized primary cultures of dorsal root ganglion neurons to model peripheral pathophysiological conditions.

Neurosensory disorders such as pain and pruritus remain a major health problem greatly impacting the quality of life, and often increasing the risk of mortality. Current pre-clinical models to investigate dysfunction of sensory neurons have shown a limited clinical translation, in part, by failing to mimic the compartmentalized nociceptor anatomy that exhibits a central compartment containing the soma and a peripheral one harboring the axon endings with distinct molecular and cellular environmental composition. Thus, there is a need to validate compartmentalized preclinical neurosensory models for investigating the pathophysiology of peripheral sensory disorders and to test drug candidates. Here, we have addressed this issue and developed a microfluidic-based preclinical nociceptor model and validated it for investigating inflammatory and neuropathic peripheral disorders. We show that this model reproduces the peripheral sensitization and resolution produced by an inflammatory soup and by the chemotherapeutic drug paclitaxel. Furthermore, compartmentalized nociceptor primary cultures were amenable to co-culture with keratinocytes in the axonal compartment. Interaction of axonal endings with keratinocytes modulated neuronal responses, consistent with a crosstalk between both cell types. These findings pave the way towards translational pre-clinical sensory models for skin pathophysiological research and drug development.

Temporal trends and outcomes of heart transplantation in Spain (2002-2021): propensity score matching analysis to compare patients with and without type 2 diabetes.

BACKGROUND: The impact of Type 2 Diabetes (T2D) on the outcomes of heart transplantation (HT) has not yet been clearly established. The objectives of this study were to examine the trends in the prevalence of T2D among individuals who underwent a HT in Spain from 2002 to 2021, and to compare the clinical characteristics and hospitalization outcomes between HT recipients with and without T2D. METHODS: We used the national hospital discharge database to select HT recipients aged 35 and older. The International Classification of Diseases, Ninth and Tenth Revisions (ICD-9 and ICD-10) were used to identify patients with and without T2D. We also recorded comorbidities, complications of HT, and procedures. Propensity score matching (PSM) and Cox regression were used to analyze the effect of T2D on in-hospital mortality (IHM). RESULTS: Between 2002 and 2021, a total of 4429 HTs (T2D, 19.14%) were performed in Spain. The number of HTs in patients with T2D decreased from 2002 to 2005 (n = 171) to 2014-2017 (n = 154), then rose during 2018-2021 (n = 186). Complications of HT increased in patients with and without T2D over the study period (26.9% and 31.31% in 2002-2005 vs. 42.47% and 45.01% in 2018-2021, respectively). The results of the PSM showed that pneumonia and Gram-negative bacterial infections were less frequent in patients with T2D and that these patients less frequently required hemodialysis, extracorporeal membrane oxygenation (ECMO), and tracheostomy. They also had a shorter hospital stay and lower IHM than patients without diabetes. The variables associated with IHM in patients with T2D were hemodialysis and ECMO. IHM decreased over time in people with and without T2D. The Cox regression analysis showed that T2D was associated with lower IHM (HR 0.77; 95% CI 0.63-0.98). CONCLUSIONS: The number of HTs increased in the period 2018-2021 compared with 2002-2005 in patients with and without T2D. Over time, complications of HT increased in both groups studied, whereas IHM decreased. The presence of T2D is associated with lower IHM.

Sex-related disparities in the incidence and outcomes of infective endocarditis according to type 2 diabetes mellitus status in Spain, 2016-2020.

BACKGROUND: We performed a study to assess sex-differences in incidence (2016-2020), clinical characteristics, use of therapeutic procedures, and in-hospital outcomes in patients with infective endocarditis (IE) according to T2DM status. METHODS: Ours was a retrospective cohort study using data from the Spanish National Hospital Discharge Database. We estimated the incidence of hospitalizations for IE in men and women aged ≥ 40 years with and without T2DM. Propensity score matching (PSM) and multivariable logistic regression were used to compare subgroups according to sex and the presence of T2DM. RESULTS: From 2016 to 2020, IE was coded in 9,958 patients (66.79% men). T2DM was diagnosed in 2,668 (26.79%). The incidence of IE increased significantly from 15.29 cases per 100,000 persons with T2DM in 2016 to 17.69 in 2020 (p < 0.001). However, this increment was significant only among men with T2DM (19.47 cases per 100,000 in 2016 vs. 22.84 in 2020; p = 0.003). The age-adjusted incidence of IE was significantly higher in people with T2DM (both sexes) than in those without T2DM (IRR, 2.86; 95% CI, 2.74-2.99). The incidence of IE was higher in men with T2DM than in women with T2DM (adjusted IRR, 1.85; 95% CI, 1.54-3.31). After PSM, in-hospital mortality (IHM) was higher among T2DM women than matched T2DM men (22.65% vs. 18.0%; p = 0.018). The presence of T2DM was not associated with IHM in men or women. CONCLUSIONS: T2DM is associated with a higher incidence of hospitalization for IE. Findings for T2DM patients who had experienced IE differed by sex, with higher incidence rates and lower IHM in men than in women. T2DM was not associated to IHM in IE in men or in women.

Time trends (2001-2019) and sex differences in incidence and in-hospital mortality after lower extremity amputations among patients with type 1 diabetes in Spain.

BACKGROUND: We examined trends in incidence (2001-2019), clinical characteristics, and in-hospital outcomes following major and minor lower extremity amputations (LEAs) among type 1 diabetes mellitus (T1DM) patients in Spain and attempted to identify sex differences. METHODS: Retrospective cohort study using data from the Spanish National Hospital Discharge Database. We estimated the incidence of the LEA procedure stratified by type of LEA. Joinpoint regression was used to estimate incidence trends, and logistic regression was used to estimate factors associated with in-hospital mortality (IHM). RESULTS: LEA was coded in 6011 patients with T1DM (66.4% minor and 33.6% major). The incidence of minor LEA decreased by 9.55% per year from 2001 to 2009 and then increased by 1.50% per year, although not significantly, through 2019. The incidence of major LEA decreased by 13.39% per year from 2001 to 2010 and then remained stable through 2019. However, incidence increased in men (26.53% per year), although not significantly, from 2017 to 2019. The adjusted incidence of minor and major LEA was higher in men than in women (IRR 3.01 [95% CI 2.64-3.36] and IRR 1.85 [95% CI 1.31-2.38], respectively). Over the entire period, for those who underwent a minor LEA, the IHM was 1.58% (2.28% for females and 1.36% for males; p = 0.045) and for a major LEA the IHM was 8.57% (10.52% for females and 7.59% for males; p = 0.025). IHM after minor and major LEA increased with age and the presence of comorbid conditions such as peripheral arterial disease, ischemic heart disease or chronic kidney disease. Female sex was associated with a higher IHM after major LEA (OR 1.37 [95% CI 1.01-1.84]). CONCLUSIONS: Our data show a decrease in incidence rates for minor and major LEA in men and women with T1DM and a slight, albeit insignificant, increase in major LEA in men with T1DM in the last two years of the study. The incidence of minor and major LEA was higher in men than in women. Female sex is a predictor of IHM in patients with T1DM following major LEA.

Sex-differences in incidence of hospitalizations and in hospital mortality of community-acquired pneumonia among children in Spain: a population-based study.

The aim of this study is to examine trends from 2016 to 2019 in the incidence of hospitalizations and in-hospital mortality (IHM) of subjects < 18 years with community-acquired pneumonia (CAP), assessing possible sex differences. We used Spanish national hospital discharge data to select all patients < 18 years with CAP. We identified 43,511 children (53% boys) hospitalized with CAP. The incidence of CAP was significantly higher in boys than in girls, with an age-adjusted incidence rate ratio of 1.05 (95%CI 1.03-1.07) for boys compared to girls, and rose from 126 per 100,000 children in 2016 to 131 in 2019 (p < 0.0001). There were no sex differences in isolated pathogens, comorbidities, length of hospital stay, or IHM. Variables independently associated with IHM were age 10 to 17 years, congenital heart disease, neurological diseases, and use of invasive mechanical ventilation. Asthma was a protective factor for IHM among girls. CONCLUSION: The incidence of hospital admissions for CAP was higher among boys than among girls and rose significantly from 2016 to 2019. There were no sex differences in hospital outcomes. Age 10 to 17 years, congenital heart disease, neurological diseases, and use of mechanical ventilation were risk factors for IHM in both sexes, while asthma was a protective factor among girls. No differences were found in IHM over time. WHAT IS KNOWN: • Community-acquired pneumonia is one of the most common reasons for hospitalizations among children. • There are few studies that allow to know the evolution of community-acquired pneumonia in children. WHAT IS NEW: • Incidence of hospital admissions for community-acquired pneumonia was higher in boys than girls and it rose significantly from 2016 to 2019. • Age 10 to 17 years, congenital heart disease, neurological diseases and use of mechanical ventilation were risk factors for in-hospital mortality in both sexes.

Sex-related disparities in the incidence and outcomes of hemorrhagic stroke among type 2 diabetes patients: a propensity score matching analysis using the Spanish National Hospital Discharge Database for the period 2016-18.

BACKGROUND: To analyze incidence, use of therapeutic procedures, use of oral anticoagulants (OACs) and antiplatelet agents prior to hospitalization, and in-hospital outcomes among patients who were hospitalized with hemorrhagic stroke (HS) according to the presence of type 2 diabetes mellitus (T2DM) in Spain (2016-2018) and to assess the role of sex differences among those with T2DM. METHODS: Using the Spanish National Hospital Discharge Database we estimated the incidence of HS hospitalizations in men and women aged ≥ 35 years with and without T2DM. Propensity score matching (PSM) was used to compare population subgroups according to sex and the presence of T2DM. RESULTS: HS was coded in 31,425 men and 24,975 women, of whom 11,915 (21.12%) had T2DM. The adjusted incidence of HS was significantly higher in patients with T2DM (both sexes) than in non-T2DM individuals (IRR 1.15; 95% CI 1.12-1.17). The incidence of HS was higher in men with T2DM than in T2DM women (adjusted IRR 1.60; 95% CI 1.57-1.63). After PSM, men and women with T2DM have significantly less frequently received decompressive craniectomy than those without T2DM. In-hospital mortality (IHM) was higher among T2DM women than matched non-T2DM women (32.89% vs 30.83%; p = 0.037), with no differences among men. Decompressive craniectomy was significantly more common in men than in matched women with T2DM (5.81% vs. 3.33%; p < 0.001). IHM was higher among T2DM women than T2DM men (32.89% vs. 28.28%; p < 0.001). After adjusting for confounders with multivariable logistic regression, women with T2DM had a 18% higher mortality risk than T2DM men (OR 1.18; 95% CI 1.07-1.29). Use of OACs and antiplatelet agents prior to hospitalization were associated to higher IHM in men and women with and without T2DM. CONCLUSIONS: T2DM is associated with a higher incidence of HS and with less frequent use of decompressive craniectomy in both sexes, but with higher IHM only among women. Sex differences were detected in T2DM patients who had experienced HS, with higher incidence rates, more frequent decompressive craniectomy, and lower IHM in men than in women.

Are there sex differences in the effect of type 2 diabetes in the incidence and outcomes of myocardial infarction? A matched-pair analysis using hospital discharge data.

BACKGROUND: To analyze incidence, use of therapeutic procedures, and in-hospital outcomes in patients with ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) according to the presence of type 2 diabetes (T2DM) in Spain (2016-2018) and to investigate sex differences. METHODS: Using the Spanish National Hospital Discharge Database, we estimated the incidence of myocardial infarctions (MI) in men and women with and without T2DM aged ≥ 40 years. We analyzed comorbidity, procedures, and outcomes. We matched each man and woman with T2DM with a non-T2DM man and woman of identical age, MI code, and year of hospitalization. Propensity score matching was used to compare men and women with T2DM. RESULTS: MI was coded in 109,759 men and 44,589 women (30.47% with T2DM). The adjusted incidence of STEMI (IRR 2.32; 95% CI 2.28-2.36) and NSTEMI (IRR 2.91; 95% CI 2.88-2.94) was higher in T2DM than non-T2DM patients, with higher IRRs for NSTEMI in both sexes. The incidence of STEMI and NSTEMI was higher in men with T2DM than in women with T2DM. After matching, percutaneous coronary intervention (PCI) was less frequent among T2DM men than non-T2DM men who had STEMI and NSTEMI. Women with T2DM and STEMI less frequently had a code for PCI that matched that of non-T2DM women. In-hospital mortality (IHM) was higher among T2DM women with STEMI and NSTEMI than in matched non-T2DM women. In men, IHM was higher only for NSTEMI. Propensity score matching showed higher use of PCI and coronary artery bypass graft and lower IHM among men with T2DM than women with T2DM for both STEMI and NSTEMI. CONCLUSIONS: T2DM is associated with a higher incidence of STEMI and NSTEMI in both sexes. Men with T2DM had higher incidence rates of STEMI and NSTEMI than women with T2DM. Having T2DM increased the risk of IHM after STEMI and NSTEMI among women and among men only for NSTEMI. PCI appears to be less frequently used in T2DM patients After STEMI and NSTEMI, women with T2DM less frequently undergo revascularization procedures and have a higher mortality risk than T2DM men.

Reproducibility and accuracy of microscale thermophoresis in the NanoTemper Monolith: a multi laboratory benchmark study.

Microscale thermophoresis (MST), and the closely related Temperature Related Intensity Change (TRIC), are synonyms for a recently developed measurement technique in the field of biophysics to quantify biomolecular interactions, using the (capillary-based) NanoTemper Monolith and (multiwell plate-based) Dianthus instruments. Although this technique has been extensively used within the scientific community due to its low sample consumption, ease of use, and ubiquitous applicability, MST/TRIC has not enjoyed the unambiguous acceptance from biophysicists afforded to other biophysical techniques like isothermal titration calorimetry (ITC) or surface plasmon resonance (SPR). This might be attributed to several facts, e.g., that various (not fully understood) effects are contributing to the signal, that the technique is licensed to only a single instrument developer, NanoTemper Technology, and that its reliability and reproducibility have never been tested independently and systematically. Thus, a working group of ARBRE-MOBIEU has set up a benchmark study on MST/TRIC to assess this technique as a method to characterize biomolecular interactions. Here we present the results of this study involving 32 scientific groups within Europe and two groups from the US, carrying out experiments on 40 Monolith instruments, employing a standard operation procedure and centrally prepared samples. A protein-small molecule interaction, a newly developed protein-protein interaction system and a pure dye were used as test systems. We characterized the instrument properties and evaluated instrument performance, reproducibility, the effect of different analysis tools, the influence of the experimenter during data analysis, and thus the overall reliability of this method.

Discovery of Diverse Natural Products as Inhibitors of SARS-CoV-2 Mpro Protease through Virtual Screening.

SARS-CoV-2 is a type of coronavirus responsible for the international outbreak of respiratory illness termed COVID-19 that forced the World Health Organization to declare a pandemic infectious disease situation of international concern at the beginning of 2020. The need for a swift response against COVID-19 prompted to consider different sources to identify bioactive compounds that can be used as therapeutic agents, including available drugs and natural products. Accordingly, this work reports the results of a virtual screening process aimed at identifying antiviral natural product inhibitors of the SARS-CoV-2 Mpro viral protease. For this purpose, ca. 2000 compounds of the Selleck database of Natural Compounds were the subject of an ensemble docking process targeting the Mpro protease. Molecules that showed binding to most of the protein conformations were retained for a further step that involved the computation of the binding free energy of the ligand-Mpro complex along a molecular dynamics trajectory. The compounds that showed a smooth binding free energy behavior were selected for in vitro testing. From the resulting set of compounds, five compounds exhibited an antiviral profile, and they are disclosed in the present work.

Gender differences in incidence and in-hospital outcomes of community-acquired, ventilator-associated and nonventilator hospital-acquired pneumonia in Spain.

AIMS: We aim to compare the incidence and in-hospital outcomes of community-acquired pneumonia (CAP), ventilator-associated pneumonia (VAP) and nonventilator hospital-acquired pneumonia (NV-HAP) according to gender. METHODS: This was a retrospective observational epidemiological study using the Spanish National Hospital Discharge Database for the years 2016 and 2017. RESULTS: Of 277 785 hospital admissions, CAP was identified in 257 455 (41.04% females), VAP was identified in 3261 (30.42% females) and NV-HAP was identified in 17 069 (36.58% females). The incidence of all types of pneumonia was higher amongst males (CAP: incidence rate ratio [IRR] 1.05, 95% CI 1.03-1.06; VAP: IRR 1.36, 95% CI 1.26-1.46; and NV-HAP: IRR 1.16, 95% CI 1.14-1.18). The crude in-hospital mortality (IHM) rate for CAP was 11.44% in females and 11.80% in males (P = .005); for VAP IHM, the rate was approximately 35% in patients of both genders and for NV-HAP IHM, the rate was 23.97% for females and 26.40% for males (P < .001). After multivariable adjustment, in patients of both genders, older age and comorbidities were factors associated with IHM in the three types of pneumonia analysed. Female gender was a risk factor for IHM after VAP (OR 1.24; 95% CI 1.06-1.44), and no gender differences were found for CAP or NV-HAP. CONCLUSIONS: Our findings show a difference between females and males, with females presenting a lower incidence of all types of pneumonia. However, female gender was a risk factor for IHM after VAP.

Residual Helicity at the Active Site of the Histidine Phosphocarrier, HPr, Modulates Binding Affinity to Its Natural Partners.

The phosphoenolpyruvate-dependent phosphotransferase system (PTS) modulates the preferential use of sugars in bacteria. The first proteins in the cascade are common to all organisms (EI and HPr). The active site of HPr involves a histidine (His15) located immediately before the beginning of the first α-helix. The regulator of sigma D (Rsd) protein also binds to HPr. The region of HPr comprising residues Gly9-Ala30 (HPr9-30), involving the first α-helix (Ala16-Thr27) and the preceding active site loop, binds to both the N-terminal region of EI and intact Rsd. HPr9-30 is mainly disordered. We attempted to improve the affinity of HPr9-30 to both proteins by mutating its sequence to increase its helicity. We designed peptides that led to a marginally larger population in solution of the helical structure of HPr9-30. Molecular simulations also suggested a modest increment in the helical population of mutants, when compared to the wild-type. The mutants, however, were bound with a less favorable affinity than the wild-type to both the N-terminal of EI (EIN) or Rsd, as tested by isothermal titration calorimetry and fluorescence. Furthermore, mutants showed lower antibacterial properties against Staphylococcus aureus than the wild-type peptide. Therefore, we concluded that in HPr, a compromise between binding to its partners and residual structure at the active site must exist to carry out its function.

Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of Mpro and Its Antiviral Activity in Cells against SARS-CoV-2.

The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (Mpro) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (1) and 8-(p-tolylselenyl)quercetin (2d) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 µM and 8 µM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.

l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells.

The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with l-arginine. Tests of the rutin/l-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization.

Is TRPA1 Burning Down TRPV1 as Druggable Target for the Treatment of Chronic Pain?

Over the last decades, a great array of molecular mediators have been identified as potential targets for the treatment of chronic pain. Among these mediators, transient receptor potential (TRP) channel superfamily members have been thoroughly studied. Namely, the nonselective cationic channel, transient receptor potential ankyrin subtype 1 (TRPA1), has been described as a chemical nocisensor involved in noxious cold and mechanical sensation and as rivalling TRPV1, which traditionally has been considered as the most important TRP channel involved in nociceptive transduction. However, few TRPA1-related drugs have succeeded in clinical trials. In the present review, we attempt to discuss the latest data on the topic and future directions for pharmacological intervention.

The ageing of people living with cystic fibrosis: what to expect now?

The prognosis of people with cystic fibrosis (pwCF) has improved dramatically with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm). The ageing of the cystic fibrosis (CF) population is changing the disease landscape with the emergence of different needs and increasing comorbidities related to both age and long-term exposure to multiple treatments including CFTRm. Although the number of pwCF eligible for this treatment is expected to increase, major disparities in care and outcomes still exist in this population. Moreover, the long-term impact of the use of CFTRm is still partly unknown due to the current short follow-up and experience with their use, thus generating some uncertainties. The future spread and initiation of these drugs at an earlier stage of the disease is expected to reduce the systemic burden of systemic inflammation and its consequences on health. However, the prolonged life expectancy is accompanied by an increasing burden of age-related comorbidities, especially in the context of chronic disease. The clinical manifestations of the comorbidities directly or indirectly associated with CFTR dysfunction are changing, along with the disease dynamics and outcomes. Current protocols used to monitor slow disease progression will need continuous updates, including the composition of the multidisciplinary team for CF care, with a greater focus on the needs of the adult population.

Cognitive Reserve and Frontotemporal Disorders: Exploring the Relationship Between Education, Physical Activity, and Cognitive Dysfunction in Older Adults.

In this study we investigated the relationship between cognitive reserve (CR) proxies, such as education, physical activity (PA), and cognitive dysfunction (CD) in the presence or absence of frontotemporal disorders (FTD). Previous research has suggested that education and PA may delay the onset of CD and reduce the risk of developing dementia. However, it remains unclear whether these CR proxies can protect against CD when FTD is present. We aimed to explore this relationship and determine whether sustained CR may be evident regardless of FTD. We recruited 149 older adults (aged 65-99 years) from community centers where they were voluntarily participating in leisure activities. We used bioelectrical impedance to measure their body composition, and we administered the International PA Questionnaire and the Mini-Mental State Examination to measure their PA and cognitive function, respectively. We used the Frontal Assessment Battery to screen for frontotemporal dementia. Our results showed that people with FTD were older, had lower education, and engaged in less PA, relative to other participants. Regression models revealed that age, education, and PA were significant predictors of FTD. More specifically, FTD was negatively associated with cognitive functioning, and there were significant interaction effects between FTD and education and PA. PA and education were significant predictors of cognitive functioning, and, when values for PA and education were high, they offset the effects of FTD on cognitive function. These findings support impressions that PA and years of education provide an insulating or compensatory effect on cognitive functioning in older adults with executive dysfunction or frontotemporal dementia, highlighting the importance of encouraging both pursuits.

Model predictive manipulation of compliant objects with multi-objective optimizer and adversarial network for occlusion compensation.

BACKGROUND: The manipulation of compliant objects by robotic systems remains a challenging task, largely due to their variable shapes and the complex, high-dimensional nature of their interaction dynamics. Traditional robotic manipulation strategies struggle with the accurate modeling and control necessary to handle such materials, especially in the presence of visual occlusions that frequently occur in dynamic environments. Meanwhile, for most unstructured environments, robots are required to have autonomous interactions with their surroundings. METHODS: To solve the shape manipulation of compliant objects in an unstructured environment, we begin by exploring the regression-based algorithm of representing the high-dimensional configuration space of deformable objects in a compressed form that enables efficient and effective manipulation. Simultaneously, we address the issue of visual occlusions by proposing the integration of an adversarial network, enabling guiding the shaping task even with partial observations of the object. Afterwards, we propose a receding-time estimator to coordinate the robot action with the computed shape features while satisfying various performance criteria. Finally, model predictive controller is utilized to compute the robot's shaping motions subject to safety constraints. Detailed experiments are presented to evaluate the proposed manipulation framework. SIGNIFICANT FINDINGS: Our MPC framework utilizes the compressed representation and occlusion-compensated information to predict the object's behavior, while the multi-objective optimizer ensures that the resulting control actions meet multiple performance criteria. Through rigorous experimental validation, our approach demonstrates superior manipulation capabilities in scenarios with visual obstructions, outperforming existing methods in terms of precision and operational reliability. The findings highlight the potential of our integrated approach to significantly enhance the manipulation of compliant objects in real-world robotic applications.