Interventions to Change Movement Behaviors After Stroke: A Systematic Review and Meta-analysis.

OBJECTIVE: This systematic review aimed to determine which interventions increase physical activity (PA) and decrease sedentary behavior (SB) based on objective measures of movement behavior in individuals with stroke. DATA SOURCES: The PubMed (Medline), EMBASE, Scopus, CINAHL (EBSCO), and Web of Science databases were searched for articles published up to January 3, 2023. STUDY SELECTION: The StArt 3.0.3 BETA software was used to screen titles, abstracts, and full texts for studies with randomized controlled trial designs; individuals with stroke (≥18 years of age); interventions aimed at increasing PA or decreasing SB; and objective measurement instruments. DATA EXTRACTION: Data extraction was standardized, considering participants and assessments of interest. The risk of bias and quality of evidence of the included studies were assessed. DATA SYNTHESIS: Twenty-eight studies involving 1855 patients were included. Meta-analyses revealed that in the post-stroke acute/subacute phase, exercise interventions combined with behavior change techniques (BCTs) increased both daily steps (standardized mean difference [SMD]=0.65, P=.0002) and time spent on moderate-to-vigorous intensity physical activities (MVPAs) duration of PA (SMD=0.68, P=.0004) with moderate-quality evidence. In addition, interventions based only on BCTs increased PA levels with very low-quality evidence (SMD (low-intensity physical activity)=0.36, P=.02; SMD (MVPA)=0.56, P=.0004) and decreased SB with low-quality evidence (SMD=0.48, P=.03). In the post-stroke chronic phase, there is statistical significance in favor of exercise-only interventions in PA frequency (steps/day) with moderate-quality evidence (SMD=0.68, P=.002). In general, the risk of bias in the included studies was low. CONCLUSIONS: In the acute/subacute phase after stroke, the use of BCTs combined with exercise can increase the number of daily steps and time spent on MVPA. In contrast, in the post-stroke chronic phase, exercise-only interventions resulted in a significant increase in daily steps.

A Systematic Review of Automated Segmentation Methods and Public Datasets for the Lung and its Lobes and Findings on Computed Tomography Images.

OBJECTIVES: Automated computational segmentation of the lung and its lobes and findings in X-Ray based computed tomography (CT) images is a challenging problem with important applications, including medical research, surgical planning, and diagnostic decision support. With the increase in large imaging cohorts and the need for fast and robust evaluation of normal and abnormal lungs and their lobes, several authors have proposed automated methods for lung assessment on CT images. In this paper we intend to provide a comprehensive summarization of these methods. METHODS: We used a systematic approach to perform an extensive review of automated lung segmentation methods. We chose Scopus, PubMed, and Scopus to conduct our review and included methods that perform segmentation of the lung parenchyma, lobes or internal disease related findings. The review was not limited by date, but rather by only including methods providing quantitative evaluation. RESULTS: We organized and classified all 234 included articles into various categories according to methodological similarities among them. We provide summarizations of quantitative evaluations, public datasets, evaluation metrics, and overall statistics indicating recent research directions of the field. CONCLUSIONS: We noted the rise of data-driven models in the last decade, especially due to the deep learning trend, increasing the demand for high-quality data annotation. This has instigated an increase of semi-supervised and uncertainty guided works that try to be less dependent on human annotation. In addition, the question of how to evaluate the robustness of data-driven methods remains open, given that evaluations derived from specific datasets are not general.

Hemispheric lateralization, endothelial function, and arterial compliance in chronic post-stroke individuals: A cross-sectional exploratory study.

Purpose/Aim: Cardiovascular function is controlled and regulated by a functional brain-heart axis. Although the exact mechanism is not fully understood, several studies suggest a hemispheric asymmetry in the neural control of cardiovascular function. Thus, the purpose of this study was to examine whether endothelial function and arterial compliance differ between individuals with left- and right-sided strokes.Materials and Methods: This was a cross-sectional exploratory study. Thirty individuals more than 6 months after stroke participated in the study. The endothelial function was assessed by ultrasound-measured flow-mediated dilation of the nonparetic arm brachial artery (baFMD). The arterial stiffness was assessed by measuring carotid-femoral pulse wave velocity (cfPWV) and central aortic pulse wave analysis [augmentation index (AIx), augmentation index normalized to a heart rate of 75 bpm (AIx@75) and reflection magnitude (RM)] using applanation tonometry. Results: Participants with right-sided stroke had worse endothelial function than those with left-sided stroke. This difference (baFMD = 2.51%) was significant (p = 0.037), and it represented a medium effect size (r = 0.38). Likewise, they had higher arterial stiffness than those with left-sided stroke. This difference (AIx = 10%; RM = 7%) was significant (p = 0.011; p = 0.012), and it represented a medium effect size (r = 0.48; r = 0.47).Conclusions: Our findings suggest that individuals with right-sided stroke have reduced endothelial function and arterial compliance compared to those with left-sided stroke. These data may indicate that those with right-sided strokes are more susceptible to cardiovascular events.

Concurrent validity and reliability of an activity monitoring for rehabilitation (AMoR) platform for step counting and sitting/lying time in post-stroke individuals.

BACKGROUND: Objective and reliable measurements to investigate daily behavior patterns in people with stroke could help therapeutic interventions after a stroke. OBJECTIVE: To evaluate whether the Activity Monitoring for Rehabilitation (AMoR) platform has adequate concurrent validity and reliability for step counting and time spent sitting/lying in people post-stroke and to investigate its percentage accuracy for step counting at different walking speeds. METHODS: Cross-sectional observational study. Fifty chronic post-stroke subjects used the AMoR platform and SAM simultaneously while a Video camera recorded the same activities during clinical trials. Spearman's correlation coefficient, the mean absolute percentage error, the intraclass correlation coefficient and Bland-Altman plot analyses were used to estimate the validity and reliability of the AMoR platform and StepWatchTM Activity Monitor (SAM). The accuracy percentage was calculated for each device and plotted as a function of the walking speed during the 10-meter walk test (10MWT). RESULTS: There was a very high correlation for step counting in all tests and a high correlation for time spent sitting/lying. The mean absolute percentage error values remained below 4% for step counting and time sitting/lying. The AMoR platform also showed excellent reliability for step counting and sitting/lying time, with values within the limit of agreement in the Bland-Altman plots. A high percentage of accuracy for step counting in the AMoR platform was observed during the 10MWT. CONCLUSION: The AMoR platform is valid and reliable for step counting and time spent sitting/lying, with a high percentage of accuracy at different walking speeds in the post-stroke population.

Serum activity of matrix metalloproteinase-2 and -9 is increased in chronic post-stroke individuals: a cross-sectional exploratory study.

BACKGROUND: High concentrations of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) are associated with inflammation early after stroke. In chronic stages, the elevation of some cytokines is related to the presence of co-morbid conditions in these individuals. In addition to this, some characteristics such as sensorimotor impairment, atrophy, and sedentary lifestyle predispose the system to an inflammatory response. OBJECTIVE: To quantify MMP-2 and -9 serum activity in chronic post-stroke individuals and correlate it with variables of physical activity level, body composition, functional and walking capacity, and with inflammatory biomarkers. Additionally, gelatinase activity was characterized according to motor impairment. METHODS: Fourteen patients with stroke onset >6 months and seven healthy individuals were enrolled in this study. The clinical assessment included: body composition, measure by bioelectrical impedance analyzer; Fugl-Meyer Motor Assessment Scale; six-minute and ten-meter walk tests, and physical activity level assessed by the StepWatch® Activity Monitor. Blood samples were collected from antecubital vein and serum MMP-2 and -9 activity was analyzed using gelatin Zymography, and the TNFα, IL-6, IL-1ß, IL-10 biomarkers using ELISA kits. RESULTS: Chronic post-stroke individuals presented an increased activity of MMP-2 and -9 compared to healthy individuals. Positive correlations with time and steps in low cadence and negative ones with medium cadence and peak activity index were observed. According to the motor impairment, the MMP-2 activity was increased in the mild-moderate group compared to the control group. CONCLUSION: Increased gelatinases in chronic post-stroke individuals could describe an inflammation process related to the limited capacity of walking in high intensities.

A structure-based approach for the discovery of inhibitors against methylcitrate synthase of Paracoccidioides lutzii.

Paracoccidioidomycosis (PCM) is a systemic mycosis, endemic in Latin America, caused by fungi of the genus Paracoccidioides. The treatment of PCM is complex, requiring a long treatment period, which often results in serious side effects. The aim of this study was to screen for inhibitors of a specific target of the fungus that is absent in humans. Methylcitrate synthase (MCS) is a unique enzyme of microorganisms and is responsible for the synthesis of methylcitrate at the beginning of the propionate degradation pathway. This pathway is essential for several microorganisms, since the accumulation of propionyl-CoA can impair virulence and prevent the development of the pathogen. We performed the modeling and molecular dynamics of the structure of Paracoccidioides lutzii MCS (PlMCS) and performed a virtual screening on 89,415 compounds against the active site of the enzyme. The compounds were selected according to the affinity and efficiency criteria of in vitro tests. Six compounds were able to inhibit the enzymatic activity of recombinant PlMCS but only the compound ZINC08964784 showed fungistatic and fungicidal activity against Paracoccidioides spp. cells. The analysis of the interaction profile of this compound with PlMCS showed its effectiveness in terms of specificity and stability when compared to the substrate (propionyl-CoA) of the enzyme. In addition, this compound did not show cytotoxicity in mammalian cells, with an excellent selectivity index. Our results suggest that the compound ZINC08964784 may become a promising alternative antifungal against Paracoccidioides spp. Communicated by Ramaswamy H. Sarma.

Ipameri x Goiânia: rivalidade na bola ao cesto goiana (1939 a 1942) / Ipameri x Goiânia: rivalry in goiano basketball (1939 to 1942) / Ipameri x Goiânia: rivalidad en el baloncesto de Goiás (1939 a 1942)

RESUMO Este estudo tem por objetivo investigar o processo de transferência da representação institucional e do protagonismo da bola ao cesto goiana da cidade de Ipameri para a nova capital do estado de Goiás, Goiânia, entre os anos de 1939 e 1942. O recorte temporal considera os registros presentes nos periódicos Correio Official - Estado de Goyaz e O Popular, que destacam a criação e o desaparecimento da Federação Goiana de Bola ao Cesto em Ipameri e as pioneiras movimentações esportivas em torno da modalidade em Goiânia. Desde sua criação em 1939, a presença da entidade em uma cidade do interior foi questionada, e, em 1942, a Federação Goiana de Bola ao Cesto de Ipameri foi extinta, deixando sequelas no movimento esportivo em torno da modalidade.

ABSTRACT This study aims to investigate the process of transferring institutional representation and the role of the basketball in Goiás from the city of Ipameri to the new capital of the state of Goiás, Goiânia, between 1939 and 1942. The temporal cut considers the records present in the journals Correio Official - Estado de Goyaz and O Popular, which highlight the creation and the disappearance of the Goiana Federation of the Basketball in Ipameri and the pioneering sports movements around the modality in Goiânia. Since its creation in 1939, the presence of the entity in a city in the interior has been questioned and in 1942, the Goiana Federation of the Basketball in Ipameri was extinguished, leaving sequels in the sports movement around the modality.

RESUMEN Este estudio tiene como objetivo investigar el proceso de transferencia de la representación institucional y el papel de lo baloncesto de Goiás de la ciudad de Ipameri para la nueva capital del estado de Goiás, Goiânia, entre los años de 1939 y 1942. El marco temporal considera los registros presentes en los periódicos Correio Official - Estado de Goyaz y O Popular, que destacan la creación y desaparición de la Federación de baloncesto de Goiás en Ipameri y los movimientos deportivos pioneros en torno a la modalidad en Goiânia. Desde su creación en 1939, la presencia de la entidad en una ciudad del interior fue cuestionada y en 1942, la Federación de baloncesto de Goiás de Ipameri fue extinguida, dejando secuelas en el movimiento deportivo en torno a la modalidad.

Prognostic molecular markers for motor recovery in acute hemorrhagic stroke: A systematic review.

BACKGROUND AND AIMS: Molecular biomarkers are associated with poor prognosis in ischemic stroke individuals. However, it might not be generalizable to post-acute hemorrhagic stroke since the underlying mechanisms of this brain damage differ from those found in ischemic stroke. The main purpose of this review was to synthesize the potential predictive molecular biomarkers for motor recovery following acute hemorrhagic stroke. MATERIALS AND METHODS: An electronic search was conducted by 2 independent reviewers in the following databases: PubMed (Medline), EMBASE, Web of Science, and CINAHL. We included studies that addressed the following: collected blood, urine, or cerebrospinal fluid samples within 72 h after hemorrhagic stroke and that reported the prognostic association with functional motor recovery for each molecular biomarker. Screening of titles, abstracts, and full texts and data extraction were undertaken independently by pairs of reviewers. RESULTS: Twelve thousand, five hundred and sixty-four studies were identified and 218 were considered eligible. Finally, we included 70 studies, with 96 biomarkers analyzed, of which 61 were considered as independent prognostic biomarkers, and 10 presented controversial results. CONCLUSION: This systematic review shows that motor functional recovery can be predicted by 61 independent prognostic molecular biomarkers assessed in the acute phase after a hemorrhagic stroke.

Adiponectin Concentration and Chronic Stroke Individuals, Associations with Body Composition, Physical Activity Levels and Lipid Profile: A Cross-Sectional Explorative Study.

OBJECTIVE: Higher adiponectin concentration has been associated with the presence of sarcopenia in individuals with cardiovascular diseases. Post-stroke individuals presented higher adiponectin concentrations than non-stroke ones. However, no previous study has investigated the association between the adiponectin concentration and skeletal muscle mass in post-stroke individuals. On the other hand, higher adiponectin concentration has been associated with a more favorable lipid profile and the physical activity level might regulate adiponectin concentration. These associations have not been studied in this population. Thus, the main objective of this study was to determine whether the adiponectin concentration is associated with: (1) body composition; (2) lipid profile; and (3) physical activity level in chronic post-stroke individuals. MATERIALS AND METHODS: This study was a correlational, cross-sectional exploratory study. Data on body composition and lipid profile were collected using a bioelectrical impedance analyzer (InBody® 720) and an automated method analyzer (CELL-DYN Ruby), respectively. The physical activity level was measured by the StepWatch® Activity Monitor and the serum adiponectin concentration was analyzed using an enzyme-linked immunosorbent assay kit. Correlation analyses were made using Spearman's rank correlation coefficient (rs). RESULTS: Twenty-one post-stroke participants took part in the study. The adiponectin concentration was associated with the following: skeletal muscle mass (rs = -0.78), skeletal muscle mass index (rs = -0.75) and high-density lipoprotein (rs = 0.43). CONCLUSIONS: A greater adiponectin concentration is associated with a lower skeletal muscle mass and a higher high-density lipoprotein level in chronic post-stroke individuals, but not with physical activity levels.

Noninvasive Intracranial Pressure Monitoring in Chronic Stroke Patients with Sedentary Behavior: A Pilot Study.

OBJECTIVE: This study aimed to correlate the P2/P1 ratio of intracranial pressure waveforms with sedentary behavior during the chronic stage of stroke. MATERIALS AND METHODS: Eight patients from São Carlos, Brazil, who had hemiparesis and stroke onset within the previous 6 months, participated in this study. To monitor their intracranial pressure, we used noninvasive Brain4Care® intracranial pressure monitoring during a postural change maneuver involving 15 min in a supine position and 15 min in an orthostatic position. The patients' sedentary behavior was continually monitored at home using a StepWatch Activity Monitor™ for 1 week. Moreover, the patients completed the International Physical Activity Questionnaire before and after using the StepWatch Activity Monitor™. RESULTS: In the supine and orthostatic positions, the P2/P1 ratios were 0.84 ± 0.14 and 0.98 ± 0.17, respectively. The percentage of time spent in inactivity was 71 ± 11%, and the number of steps walked per day was 4220 ± 2239. We found a high positive correlation (r = 0.881, p = 0.004) between the P2/P1 ratio and the percentage of time spent in inactivity. CONCLUSION: This preliminary study showed a correlation between sedentary behavior and cerebral compliance. Thus, monitoring of intracranial pressure during the late stage of a stroke could guide the clinician's treatment to reduce sedentary behavior and the risks of recurrent stroke and cardiovascular diseases.

Underlying mechanisms of oxygen uptake kinetics in chronic post-stroke individuals: A correlational, cross-sectional pilot study.

Post-stroke individuals presented deleterious changes in skeletal muscle and in the cardiovascular system, which are related to reduced oxygen uptake ([Formula: see text]) and take longer to produce energy from oxygen-dependent sources at the onset of exercise (mean response time, MTRON) and during post-exercise recovery (MRTOFF). However, to the best of our knowledge, no previous study has investigated the potential mechanisms related to [Formula: see text] kinetics response (MRTON and MRTOFF) in post-stroke populations. The main objective of this study was to determine whether the MTRON and MRTOFF are related to: 1) body composition; 2) arterial compliance; 3) endothelial function; and 4) hematological and inflammatory profiles in chronic post-stroke individuals. Data on oxygen uptake ([Formula: see text]) were collected using a portable metabolic system (Oxycon Mobile®) during the six-minute walk test (6MWT). The time to achieve 63% of [Formula: see text] during a steady state (MTRON) and recovery (MRTOFF) were analyzed by the monoexponential model and corrected by a work rate (wMRTON and wMRTOFF) during 6MWT. Correlation analyses were made using Spearman's rank correlation coefficient (rs) and the bias-corrected and accelerated bootstrap method was used to estimate the 95% confidence intervals. Twenty-four post-stroke participants who were physically inactive took part in the study. The wMRTOFF was correlated with the following: skeletal muscle mass (rs = -0.46), skeletal muscle mass index (rs = -0.45), augmentation index (rs = 0.44), augmentation index normalized to a heart rate of 75 bpm (rs = 0.64), reflection magnitude (rs = 0.43), erythrocyte (rs = -0.61), hemoglobin (rs = -0.54), hematocrit (rs = -0.52) and high-sensitivity C-reactive protein (rs = 0.58), all p < 0.05. A greater amount of oxygen uptake during post-walking recovery is partially related to lower skeletal muscle mass, greater arterial stiffness, reduced number of erythrocytes and higher systemic inflammation in post-stroke individuals.

Molecular design aided by random forests and synthesis of potent trypanocidal agents as cruzain inhibitors for Chagas disease treatment.

Cruzain is an established target for the identification of novel trypanocidal agents, but how good are in vitro/in vivo correlations? This work describes the development of a random forests model for the prediction of the bioavailability of cruzain inhibitors that are Trypanosoma cruzi killers. Some common properties that characterize drug-likeness are poorly represented in many established cruzain inhibitors. This correlates with the evidence that many high-affinity cruzain inhibitors are not trypanocidal agents against T. cruzi. On the other hand, T. cruzi killers that present typical drug-like characteristics are likely to show better trypanocidal action than those without such features. The random forests model was not outperformed by other machine learning methods (such as artificial neural networks and support vector machines), and it was validated with the synthesis of two new trypanocidal agents. Specifically, we report a new lead compound, Neq0565, which was tested on T. cruzi Tulahuen (ß-galactosidase) with a pEC50 of 4.9. It is inactive in the host cell line showing a selectivity index (SI = EC50cyto /EC50T. cruzi ) higher than 50.

Crystal structure of Leishmania mexicana cysteine protease B in complex with a high-affinity azadipeptide nitrile inhibitor.

Leishmania mexicana is an obligate intracellular protozoan parasite that causes the cutaneous form of leishmaniasis affecting South America and Mexico. The cysteine protease LmCPB is essential for the virulence of the parasite and therefore, it is an appealing target for antiparasitic therapy. A library of nitrile-based cysteine protease inhibitors was screened against LmCPB to develop a treatment of cutaneous leishmaniasis. Several compounds are sufficiently high-affinity LmCPB inhibitors to serve both as starting points for drug discovery projects and as probes for target validation. A 1.4 Å X ray crystal structure, the first to be reported for LmCPB, was determined for the complex of this enzyme covalently bound to an azadipeptide nitrile ligand. Mapping the structure-activity relationships for LmCPB inhibition revealed superadditive effects for two pairs of structural transformations. Therefore, this work advances our understanding of azadipeptidyl and dipeptidyl nitrile structure-activity relationships for LmCPB structure-based inhibitor design. We also tested the same series of inhibitors on related cysteine proteases cathepsin L and Trypanosoma cruzi cruzain. The modulation of these mammalian and protozoan proteases represents a new framework for targeting papain-like cysteine proteases.

Linha de pesquisa "história e memória do lazer" do programa de pós-graduação interdisciplinar em estudos do lazer da UFMG produção e análise / Line of research "history and memory of the leisure" of interdisciplinary post-graduation program in leisure studies of UFMG: production and analysis

Este estudo propõe uma análise da produção vinculada à linha de pesquisa "Memória e História do Lazer" do Programa de Pós-Graduação Interdisciplinar em Estudos do Lazer (PPGIEL) da Universidade Federal de Minas Gerais (UFMG). A partir da análise de conteúdo proposta por Bardin (2009) foram investigadas as teses e dissertações defendidas entre 2009 e 2017. O estudo apontou que nos 32 trabalhos examinados, o primeiro quartel do século XXI e a cidade de Belo Horizonte são, nessa ordem, o período e a localidade mais pesquisados. A dimensão física do Lazer é preponderante e os professores Victor Melo e Helder Isayama se destacam respectivamente pelo número de trabalhos orientados e participação em bancas de defesa. O ano de 2017 surge como o ápice da produção do programa. O "estado da arte" apontado poderá auxiliar pesquisas históricas desenvolvidas no campo do Lazer, potencializando questionamentos e reflexões.

This study proposes an analysis of the production linked to the research line "Memory and Leisure History" of the Interdisciplinary Post-Graduation Program in Leisure Studies (PPGIEL) of the Federal University of Minas Gerais (UFMG). From the analysis of content proposed by Bardin (2009) the theses and dissertations defended between 2009 and 2017 were investigated. The study pointed out that in the 32 papers examined, the first quarter of the 21st century and the city of Belo Horizonte are, in that order, the most searched period and location. The physical dimension of Leisure is preponderant and Professors Victor Melo and Helder Isayama stand out respectively for the number of jobs oriented and participation in defense stalls. The year 2017 emerges as the apex of the program's production. The pointed state of the art may help historical research developed in the field of Leisure, enhancing questions and reflections.

Optimization strategy of single-digit nanomolar cross-class inhibitors of mammalian and protozoa cysteine proteases.

Cysteine proteases (CPs) are involved in a myriad of actions that include not only protein degradation, but also play an essential biological role in infectious and systemic diseases such as cancer. CPs also act as biomarkers and can be reached by active-based probes for diagnostic and mechanistic purposes that are critical in health and disease. In this paper, we present the modulation of a CP panel of parasites and mammals (Trypanosoma cruzi cruzain, LmCPB, CatK, CatL and CatS), whose inhibition by nitrile peptidomimetics allowed the identification of specificity and selectivity for a given CP. The activity cliffs identified at the CP inhibition level are useful for retrieving trends through multiple structure-activity relationships. For two of the cruzain inhibitors (10g and 4e), both enthalpy and entropy are favourable to Gibbs binding energy, thus overcoming enthalpy-entropy compensation (EEC). Group contribution of individual molecular modification through changes in enthalpy and entropy results in a separate partition on the relative differences of Gibbs binding energy (ΔΔG). Overall, this study highlights the role of CPs in polypharmacology and multi-target screening, which represents an imperative trend in the actual drug discovery effort.

Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents.

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1´ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 µM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.

Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement.

The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.

Energy Cost During the 6-Minute Walk Test and Its Relationship to Real-World Walking After Stroke: A Correlational, Cross-Sectional Pilot Study.

BACKGROUND: After experiencing stroke, individuals expend more energy walking than people who are healthy. However, among individuals who have experienced stroke, the correlation between the energy cost of walking, as measured by validated tests (such as the 6-minute walk test), and participation in walking, as measured by more sensitive tools (such as an ambulatory activity monitor), remains unknown. OBJECTIVE: The main objective of this study was to determine whether the energy cost of walking is correlated with participation in walking. DESIGN: This study was a correlational, cross-sectional pilot study. METHODS: Data from 23 participants who had experienced chronic stroke were analyzed. On the first day, data on oxygen uptake were collected using a portable metabolic system while participants walked during the 6-minute walk test. Then, the ambulatory activity monitor was placed on the participants' nonparetic ankle and removed 9 days later. The energy cost of walking was calculated by dividing the mean oxygen uptake recorded during the steady state by the walking speed. RESULTS: The energy cost of walking was correlated with the following: the number of steps (Spearman rank correlation coefficient [rs] = -0.59); the percentage of time spent in inactivity (rs = 0.48), low cadence (rs = 0.67), medium cadence (rs = -0.56), high cadence (rs = -0.65), and the percentages of steps taken at low cadence (rs = 0.65) and high cadence (rs = -0.64). LIMITATIONS: Individuals who were physically inactive, convenience sampling, and a small sample size were used in this study. CONCLUSIONS: Higher energy costs of walking were associated with fewer steps per day and lower cadence in real-world walking in individuals who had experienced stroke.

Similarity search combined with docking and molecular dynamics for novel hAChE inhibitor scaffolds.

The main purpose of this study was to address the performance of virtual screening methods based on ligands and the protein structure of acetylcholinesterase (AChE) in order to retrieve novel human AChE (hAChE) inhibitors. In addition, a protocol was developed to identify novel hit compounds and propose new promising AChE inhibitors from the ZINC database with 10 million commercially available compounds. In this sense, 3D similarity searches using rapid overlay of chemical structures and similarity analysis through comparison of electrostatic overlay of docked hits were used to retrieve AChE inhibitors from collected databases. Molecular dynamics simulation of 100 ns was carried out to study the best docked compounds from similarity searches. Some key residues were identified as crucial for the dual binding mode of inhibitor with the interaction site. All results indicated the relevant use of EON and docking strategy for identifying novel hit compounds as promising potential anticholinesterase candidates, and seven new structures were selected as potential hAChE inhibitors. Graphical abstract Compound N01 in the 4M0E hAChE crystallography structure from docking results. Yellow dashed lines Hydrogen bonds, blue dashed lines π-stacking interactions, green dashed lines cation-π interactions.

A comparative study of warheads for design of cysteine protease inhibitors.

The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude.