In silico evidence of bitopertin's broad interactions within the SLC6 transporter family.

The Glycine Transporter Type 1 (GlyT1) significantly impacts central nervous system functions, influencing glycinergic and glutamatergic neurotransmission. Bitopertin, the first GlyT1 inhibitor in clinical trials, was developed for schizophrenia treatment but showed limited efficacy. Despite this, bitopertin's repositioning could advance treating various pathologies. This study aims to understand bitopertin's mechanism of action using computational methods, exploring off-target effects, and providing a comprehensive pharmacological profile. Similarity Ensemble Approach (SEA) and SwissTargetPrediction initially predicted targets, followed by molecular modeling on SWISS-MODEL and GalaxyWeb servers. Binding sites were identified using PrankWeb, and molecular docking was performed with DockThor and GOLD software. Molecular dynamics analyses were conducted on the Visual Dynamics platform. Reverse screening on SEA and SwissTargetPrediction identified GlyT1 (SLC6A9), GlyT2 (SLC6A5), PROT (SLC6A7), and DAT (SLC6A3) as potential bitopertin targets. Homology modeling on SwissModel generated high-resolution models, optimized further on GalaxyWeb. PrankWeb identified similar binding sites in GlyT1, GlyT2, PROT, and DAT, indicating potential interaction. Docking studies suggested bitopertin's interaction with GlyT1 and proximity to GlyT2 and PROT. Molecular dynamics confirmed docking results, highlighting bitopertin's target stability beyond GlyT1. The study concludes that bitopertin potentially interacts with multiple SLC6 family targets, indicating a broader pharmacological property.

Improving physicochemical and nutritional attributes of rice starch through green modification techniques.

Rice, has long been an inseparable part of the human diet all over the world. As one of the most rapidly growing crops, rice has played a key role in securing the food chain of low-income food-deficit countries. Starch is the main component in rice granules which other than its nutritional essence, plays a key role in defining the physicochemical attributes of rice-based products. However, rice starch suffers from weak techno-functional characteristics (e.g., retrogradability of pastes, opacity of gels, and low shear/temperature resistibility. Green modification techniques (i.e. Non-thermal methods, Novel thermal (e.g., microwave, and ohmic heating) and enzymatic approaches) were shown to be potent tools in modifying rice starch characteristics without the exertion of unfavorable chemical reagents. This study corroborated the potential of green techniques for rice starch modification and provided deep insight for their further application instead of unsafe chemical methods.

Walking training with auditory cueing improves walking speed more than walking training alone in ambulatory people with Parkinson's disease: a systematic review.

QUESTIONS: In people with Parkinson's disease, what is the effect of adding external cueing (ie, visual, auditory or somatosensorial cueing) to walking training compared with walking training alone in terms of walking, mobility, balance, fear of falling and freezing? Are any benefits carried over to participation or maintained beyond the intervention period? DESIGN: Systematic review of randomised trials with meta-analysis. PARTICIPANTS: Ambulatory adults with Parkinson's disease. INTERVENTION: Walking training with external cueing compared with walking training without external cueing. OUTCOME MEASURES: Walking (ie, speed, stride length and cadence), mobility, balance, fear of falling, freezing and participation. RESULTS: Ten trials involving a total of 309 participants were included. The mean PEDro score of the included trials was 5 (range 4 to 8). Walking training with auditory cueing improved walking speed by 0.09 m/s (95% CI 0.02 to 0.15) more than walking training alone. Although the best estimate was that auditory cueing may also improve stride length by 5 cm, this estimate was imprecise (95% CI -2 to 11). The addition of visual cueing to walking training did not improve walking speed or stride length. Results regarding cadence, mobility, balance, fear of falling, and freezing and maintenance of benefits beyond the intervention period remain uncertain. CONCLUSION: This systematic review provided low-quality evidence that walking training with auditory cueing is more effective than walking training alone for improving walking speed in Parkinson's disease. Cueing is an inexpensive and easy to implement intervention, so the mean estimate might be considered clinically worthwhile, although the confidence interval spans clinically trivial and worthwhile effects. REGISTRATION: PROSPERO CRD42021255065.

Ultrasound-assisted extraction and concentration of phenolic compounds from jabuticaba sabará (Plinia peruviana (Poir.) Govaerts) peel by nanofiltration membrane.

Jabuticaba peel, rich in antioxidants, offering health benefits. In this study, the extraction of phenolic compounds from jabuticaba peel using ultrasound-assisted (UA) and their subsequent concentration by nanofiltration (NF) employing a polyamide 200 Da membrane was evaluated. The UA extractions were conducted using the Central Composite Rotatable Design (CCRD) 22 methodology, with independent variables extraction time (11.55 to 138 min) and temperature (16.87 to 53.3 °C), and fixed variables mass to ethanol solution concentration at pH 1.0 (1:25 g/mL), granulometry (1 mm), and ultrasonic power (52.8 W). The maximum concentrations obtained were 700.94 mg CE/100 g for anthocyanins, 945.21 mg QE/100 g for flavonoids, 133.19 mg GAE/g for phenols, and an antioxidant activity IC50 of 24.36 µg/mL. Key phenolic compounds identified included cyanidin-3-glucoside, delphinidin-3-glucoside, and various acids like syringic and gallic. NF successfully concentrated these compounds, enhancing their yield by up to 45%. UA and NF integrate for sustainable extraction.

Inspiratory Training for Improving Respiratory Strength, Pulmonary Function, and Walking in Cerebral Palsy: A Meta-Analysis.

PURPOSE: To investigate the effects of inspiratory strength training on respiratory muscle strength, pulmonary function, and walking capacity in children with cerebral palsy, with Gross Motor Function Classification System I to III. METHODS: Searches were conducted in CINAHL, LILACS, MEDLINE, and Physiotherapy Evidence Database (PEDro) databases. The outcomes of interest were respiratory muscle strength, pulmonary function, and walking capacity. The quality was assessed by PEDro Scale. The Grading of Recommendations Assessment, Development, and Evaluation system was used to summarize the quality of evidence. RESULTS: Inspiratory strength training increased the strength of inspiratory muscles and may increase the strength of the expiratory muscles. No changes were observed in pulmonary function or walking capacity. CONCLUSIONS: This systematic review provides moderate-quality evidence that inspiratory strength training is effective for increasing inspiratory muscle strength in children with cerebral palsy. Benefits may be carried over to improving expiratory muscle strength but were not observed on pulmonary function or walking capacity.

Procedures and measurement properties of the 6-min step test: A systematic review with clinical recommendations.

OBJECTIVE: To provide information regarding the procedures, safety, tolerability, and measurement properties of the 6-min step test. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and SPORTDiscus (from inception until January 2024). REVIEW METHODS: Studies that examined adults with acute or chronic diseases, and outcomes related to procedures, safety, tolerability, or measurement properties of the 6-min step test were included. Outcome data were summarized and combined in meta-analyses. The quality of included studies was assessed by the Consensus-based Standards for the selection of health Measurement Instruments checklist, and the quality of evidence was determined according to the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: Fourteen studies, involving 847 participants, were included. All studies performed the 6-min step test in 6 min; however, some studies varied the step height and the use of upper limb support. The test appears to be safe and well tolerated by individuals. Moderate- to high-quality evidence demonstrated appropriate results for test-retest reliability (4 studies; Intraclass correlation coefficient 0.96; 95% CI 0.91-0.98; n = 125), criterion validity (4 studies; r = 0.53; 95% CI 0.30-0.71; n = 307), and construct validity (4 studies; r = 0.63; 95% CI 0.52-0.73; n = 233). CONCLUSION: This review provides recommendations for applying the 6-min step test in clinical and research settings. No adverse events were reported, and the test appears to be well tolerated. Adequate results were found for test-retest reliability, criterion validity, and construct validity. REVIEW REGISTRATION: PROSPERO (CRD42022347744).

Identification of eQTLs using different sets of single nucleotide polymorphisms associated with carcass and body composition traits in pigs.

BACKGROUND: Mapping expression quantitative trait loci (eQTLs) in skeletal muscle tissue in pigs is crucial for understanding the relationship between genetic variation and phenotypic expression of carcass traits in meat animals. Therefore, the primary objective of this study was to evaluate the impact of different sets of single nucleotide polymorphisms (SNP), including scenarios removing SNPs pruned for linkage disequilibrium (LD) and SNPs derived from SNP chip arrays and RNA-seq data from liver, brain, and skeletal muscle tissues, on the identification of eQTLs in the Longissimus lumborum tissue, associated with carcass and body composition traits in Large White pigs. The SNPs identified from muscle mRNA were combined with SNPs identified in the brain and liver tissue transcriptomes, as well as SNPs from the GGP Porcine 50 K SNP chip array. Cis- and trans-eQTLs were identified based on the skeletal muscle gene expression level, followed by functional genomic analyses and statistical associations with carcass and body composition traits in Large White pigs. RESULTS: The number of cis- and trans-eQTLs identified across different sets of SNPs (scenarios) ranged from 261 to 2,539 and from 29 to 13,721, respectively. Furthermore, 6,180 genes were modulated by eQTLs in at least one of the scenarios evaluated. The eQTLs identified were not significantly associated with carcass and body composition traits but were significantly enriched for many traits in the "Meat and Carcass" type QTL. The scenarios with the highest number of cis- (n = 304) and trans- (n = 5,993) modulated genes were the unpruned and LD-pruned SNP set scenarios identified from the muscle transcriptome. These genes include 84 transcription factor coding genes. CONCLUSIONS: After LD pruning, the set of SNPs identified based on the transcriptome of the skeletal muscle tissue of pigs resulted in the highest number of genes modulated by eQTLs. Most eQTLs are of the trans type and are associated with genes influencing complex traits in pigs, such as transcription factors and enhancers. Furthermore, the incorporation of SNPs from other genomic regions to the set of SNPs identified in the porcine skeletal muscle transcriptome contributed to the identification of eQTLs that had not been identified based on the porcine skeletal muscle transcriptome alone.

Visible light-driven CO2 photoreduction by a Re(I) complex immobilized onto CuO/Nb2O5 heterojunctions.

The immobilization of Re(I) complexes onto metal oxide surfaces presents an elegant strategy to enhance their stability and reusability toward photocatalytic CO2 reduction. In this study, the photocatalytic performance of fac-[ClRe(CO)3(dcbH2)], where dcbH2 = 4,4'-dicarboxylic acid-2,2'-bipyridine, anchored onto the surface of 1%m/m CuO/Nb2O5 was investigated. Following adsorption, the turnover number for CO production (TONCO) in DMF/TEOA increased significantly, from ten in solution to 370 under visible light irradiation, surpassing the TONCO observed for the complex onto pristine Nb2O5 or CuO surfaces. The CuO/Nb2O5 heterostructure allows for efficient electron injection by the Re(I) center, promoting efficient charge separation. At same time CuO clusters introduce a new absorption band above 550 nm that contributes for the photoreduction of the reaction intermediates, leading to a more efficient CO evolution and minimization of side reactions.

Antioxidant activity of rosemary extract, acerola extract and a mixture of tocopherols in sausage during storage at 8 °C.

Sausage is an emulsified meat product that, due to its composition, undergoes physicochemical changes during its shelf life, which makes the use of additives for its conservation necessary. The goal of the present study was to evaluate the antioxidant capacity of rosemary extract, acerola extract, and a mixture of tocopherols applied to industrialized sausages during storage at 8 °C. The antioxidant activity (IC50) in vitro showed values of 0.043, 0.489, 0.494, and 0.509 mg/mL for sodium erythorbate, rosemary extract, acerola extract, and a mixture of tocopherols, respectively. Formulations of sausage obtained in industrial installations were evaluated in terms of physicochemical, microbiological, and sensorial analyses. The pH and acidity values were stable during 23 days of storage. Treatments 1 and 3 with acerola extract and a mixture of tocopherols associated with sodium erythorbate showed the best results against lipid oxidation (TBARs), respectively. The hydroperoxides were only found after the 12th day of storage, consequently reducing the formation of malondialdehyde. The treatments with natural antioxidants showed an antimicrobial effect for the group of mesophilic bacteria; their results did not exceed 4 log10 CFU/g, while the control reached 5 log10 CFU/g on the 23rd day of storage. In regard to other microorganisms evaluated, no significant differences were found between treatments with natural antioxidants. Thus, the natural extracts evaluated in association with sodium erythorbate contributed to the antioxidant action for the application on an industrial scale, as they improved the sausage characteristics after 23 days of storage at 8 °C. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05815-y.

R3-Walk and R6-Walk, Simple Clinical Equations to Accurately Predict Independent Walking at 3 and 6 Months After Stroke: A Prospective, Cohort Study.

OBJECTIVE: To investigate if independent walking at 3 and 6 months poststroke can be accurately predicted within the first 72 hours, based on simple clinical bedside tests. DESIGN: Prospective observational cohort study with 3-time measurements: immediately after stroke, and 3 and 6 months poststroke. SETTING: Public hospital. PARTICIPANTS: Adults with first-ever stroke evaluated at 3 (N=263) and 6 (N=212) months poststroke. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The outcome of interest was independent walking at 3 and 6 months after stroke. Predictors were age, walking ability, lower limb strength, motor recovery, spatial neglect, continence, and independence in activities of daily living. RESULTS: The equation for predicting walking 3 months poststroke was 3.040 + (0.283 × FAC baseline) + (0.021 × Modified Barthel Index), and for predicting walking 6 months poststroke was 3.644 + (-0.014 × age) + (0.014 × Modified Barthel Index). For walking ability 3 months after stroke, sensitivity was classified as high (91%; 95% CI: 81-96), specificity was moderate (57%; 95% CI: 45-69), positive predictive value was high (76%; 95% CI: 64-86), and negative predictive value was high (80%; 95% CI: 60-93). For walking ability 6 months after stroke, sensitivity was classified as moderate (54%; 95% CI: 47-61), specificity was high (81%; 95% CI: 61-92), positive predictive value was high (87%; 95% CI: 70-96), and negative predictive value was low (42%; 95% CI: 50-73). CONCLUSIONS: This study provided 2 simple equations that predict walking ability 3 and 6 months after stroke. This represents an important step to accurately identify individuals, who are at high risk of walking dependence early after stroke.

Massage, laser and shockwave therapy improve pain and scar pruritus after burns: a systematic review.

QUESTIONS: In adults with a burn injury, do non-invasive therapies improve pain and burn scar pruritus, elasticity and vascularisation? Are any effects maintained beyond the intervention period? DESIGN: Systematic review of randomised trials with meta-analyses. PARTICIPANTS: Adults with burn scars. INTERVENTION: The experimental intervention was a non-invasive (ie, non-surgical or non-pharmacological) therapy applied to the burn scar. OUTCOME MEASURES: Pain intensity, pruritus intensity, elasticity and vascularisation. RESULTS: Fifteen trials involving 780 participants were included. The results indicated a beneficial effect on pain intensity on a 0-to-10 scale after massage (MD -1.5, 95% CI -1.8 to -1.1), shockwave therapy (MD -0.8, 95% CI -1.2 to -0.4) and laser (MD -4.0, 95% CI -6.0 to -2.0). The results indicated a beneficial effect on pruritus intensity on a 0-to-10 scale after massage (MD -0.4, 95% CI -0.7 to -0.2), shockwave therapy (MD -1.3, 95% CI -2.3 to -0.3) and laser (MD -4.8, 95% CI -6.1 to -3.5). Massage, shockwave therapy and silicone produced negligible or unclear benefits on scar elasticity and vascularisation. The quality of evidence varied from low to moderate. CONCLUSION: Among all commonly used non-invasive therapies for the treatment of burn scars, low-to-moderate quality evidence indicated that massage, laser and shockwave therapy reduce pain and the intensity of scar pruritus. Low-to-moderate quality evidence suggested that massage, shockwave therapy and silicone have negligible or unclear effects for improving scar elasticity and vascularisation. REVIEW REGISTRATION: PROSPERO (CRD42021258336).

Estudos de síntese de dendrons dirigidos de NFOH com potencial antichagásico e modelagem molecular do receptor de manose de macrófagos / Studying the synthesis of NFOH targeted dendrons, potentially active in Chagas disease, and the molecular modeling of manose receptor from macrophages

A doença de Chagas, considerada doença extremamente negligenciada, acomete mais de 6 milhões de pessoas ao redor do mundo e mais de 75 milhões de pessoas vivem sob risco da doença. Considerada endêmica em 21 países da América Latina. No Brasil, grassa, sobretudo, na região Norte, especialmente, na região amazônica. Apesar de se constituir em risco global, a doença de Chagas conta com apenas com dois fármacos, o benznidazol e o nifurtimox, que, além de tóxicos, não apresentam eficácia significativa na fase crônica da parasitose. Assim sendo, torna-se imperativa a busca por quimioterápicos mais eficazes, mormente na fase crônica da doença. A introdução de novos fármacos da terapêutica várias fases, consumindo tempo e recursos. No entanto, há processos que permitem a otimização de fármacos já existentes e de compostos bioativos, com vistas à busca de candidatos a fármacos, que, uma vez bem-sucedidos nos ensaios clínicos, são aprovados para uso terapêutico. Entre esses processos, destaca-se a latenciação, forma de aprimoramento de propriedades farmacêuticas, farmacocinéticas e, indiretamente, farmacodinâmicas, que utiliza, em geral, transportadores para a resolução de problemas dessas naturezas. Os transportadores variam de acordo com o problema a ser resolvido e, entre eles, os dendrons e dendrímeros podem ser ressaltados pela sua natureza química, que permite a ligação de várias moléculas de fármacos/compostos bioativos e, também, de grupos diretores para certos compartimentos ou células. Dessa forma, podem-se obter fármacos dirigidos, que se constituem em formas latentes de alta seletividade. Face ao exposto e, estimulados pela busca de novas alternativas terapêuticas para a doença de Chagas, o objetivo deste trabalho foi a obtenção de dendrons dirigidos, por meio de manose, derivados de hidroximetilnitrofural (NFOH). Esse composto foi mostrou-se altamente ativo contra T. cruzi, também na fase crônica NFOH e menos tóxico que o protótipo e o benznidazol. Efetuaram-se estudos para a síntese desses compostos derivados de dendron triazólico, sintetizado através de click chemistry, tendo a manose como grupo diretor para os macrófagos, onde, também, são encontrados os amastigotas de Trypanosoma cruzi. Obtiveram-se alguns intermediários, que foram caracterizados por RMN 1H e 13C. A rota sintética proposta não pôde ser finalizada. Por outro lado, efetuaram-se estudos de modelagem molecular, utilizando-se dinâmica molecular, com o intuito de conhecer como se dá a interação da manose e de polimanosídeos com seu respectivo receptor e como se realiza a liberação do composto bioativo da ligação com o dendron. Anteriormente, procedeu-se à caracterização da biologia estrutural do receptor de manose e de suas estruturas primárias, secundárias e terciárias, com ênfase para o domínio CRD4 o papel do cálcio principal na interação com o monossacarídeo. A movimentação do domínio foi muito pouco diferente nos meios simulados (neutro, ácido, contendo ligantes e contendo o cálcio auxiliar), evidenciado pelo RMSF e estudo de PCA desses sistemas. Foi possível concluir que este domínio não apresenta nenhuma alteração conformacional responsável pela liberação de ligantes em meio lisossômico, e que o cálcio auxiliar e os ligantes não causam impactos na estabilidade conformacional do CRD4. Há necessidade de mais estudos para o conhecimento dos requisitos estruturais envolvidos na da formação do complexo receptor-composto bioativo

Chagas disease, considered an extremely neglected one, affects more than 6 million people all over de world, with more than 75 million people living under its risk, while endemics in 21 countries in Latin America. In Brazil, it propagates, mainly in North region, especially in Amazon region. Although being a global risk, only two drugs, benznidazole and nifurtimox, are currently available for Chagas disease. These drugs are toxic and not significantly efficient against the chronic phase of the disease. Therefore, the search for more active chemotherapeutic agents, mainly against the chronic phase of the parasitosis, is imperative. The introduction of new drugs in the therapeutics involves many phases, consuming time, and money. Notwithstanding, there are processes that allow either drugs or bioactive compounds to be optimized, towards drug candidates. These derivatives, once well-succeeded in the clinical trials, can be approved for therapeutic uses. Among those processes, prodrug design stands out. It is a way to improve the pharmaceutics, pharmacokinetics and, indirectly, pharmacodynamics, properties of drugs/bioactive compounds, which requires adequate carriers, in general, for these problems´ solution. The carriers vary according to the problem to be solved, and, among them, dendrons and dendrimers can be emphasized due to their chemical nature, which allows the link of many molecules/bioactive compounds and of directing groups to specific compartments or cells. Thus, targeted drugs, which are latent forms of drugs/bioactive compounds with high selectivity. In this connection and stimulated by the search for new therapeutic alternatives for Chagas disease, the objective of this work was obtaining hydroxymethylnitrofurazone (NFOH) targeted dendrons, by means of mannose, as directing groups. NFOH is highly active against T. cruzi, even in chronic phase of the disease, and less toxic than the prototype and benznidazole. Studies have been developed to synthesize these compounds with a triazole dendron, planned to be obtained by click chemistry. Mannose was designed to be the directing groups to macrophages, where the T. cruzi amastigotes can also be found. Some intermediaries have been obtained and structurally characterized by 1H and 13C NMR, but the proposed synthetic route could not be finished. On the other hand, molecular modeling studies have been developed, using molecular dynamics, with the aim to know how the interaction of mannose, and also of polymannoside, occur with the specific receptor, and how NFOH is released from its linkage to the dendron. The structural biology characterization, as well as of primary, secondary and tertiary structures of the mannose receptor was previously performed, with emphasis onCRD4 and main calcium role in the interaction of the mannoside. All systems simulated (neutral medium, acid medium, complexes with ligands and auxiliary calcium) showed little movement differences when analyzed by RMSF and PCA calculations. It was possible to conclude that this domain shows no conformational changes involved in ligand releasing in lysosomal environment and its conformation is not altered when in presence of ligands or the auxiliary calcium. Much more studies are needed to the knowledge of the structural requirements to the complex receptor-drug-compound bioactive to the receptor

Kinetic and stoichiometric parameters in the fed-batch bioreactor production of poly(3-hydroxybutyrate) by Bacillus megaterium using different carbon sources.

This study investigates the effects of different strategies on poly(3-hydroxybutyrate)-P(3HB) production in a fed-batch bioreactor by Bacillus megaterium using candy industry effluent (CIE), sucrose, and rice parboiled water (RPW) as carbon sources. In biosynthesis, kinetic and stoichiometric parameters of substrate conversion into products and/or cells, productivity, instantaneous, and specific conversion rates were evaluated. The maximum concentration of P(3HB) was 4.00 g.L-1 (77% of the total dry mass) in 42 h of cultivation in minimal medium/RPW added with a carbon source based on CIE, demonstrating that the fed-batch provided an increase of approximately 22% in the polymer concentration and 32% in the overall productivity in relation to medium based on commercial sucrose. Fed-batch cultivation also had the advantage of avoiding the extra time required for inoculum preparation and sterilization of the bioreactor during the batch, which thereby increased the overall industrial importance of the process. Effluents from the candy, confectionery, and/or rice parboiling industries can be used as alternative substrates for P(3HB) production at a low cost.

Is transcranial direct current stimulation (tDCS) effective to improve cognition and functionality after severe traumatic brain injury? A perspective article and hypothesis.

Severe traumatic brain injury (sTBI) is an important cause of disability and mortality and affects people of all ages. Current scientific evidence indicates that motor dysfunction and cognitive impairment are the main limiting factors in patients with sTBI. Transcranial direct current stimulation (tDCS) seems to be a good therapeutic option, but when it comes to patients with sTBI, the results are inconclusive, and some protocols have not yet been tested. In addition, there is still a lack of information on tDCS-related physiological mechanisms, especially during the acute phase. In the present study, based on current evidence on tDCS mechanisms of action, we hypothesized that performing tDCS sessions in individuals with sTBI, especially in the acute and subacute phases, together with conventional therapy sessions, could improve cognition and motor function in this population. This hypothesis presents a new possibility for treating sTBI, seeking to elucidate the extent to which early tDCS may affect long-term clinical outcomes.

Addition of backward walking training to forward walking training improves walking speed in children with cerebral palsy: a systematic review with meta-analysis.

The objective was to examine the effects of backward walking training for improving walking speed and balance in children with cerebral palsy. A systematic review of randomized trials was conducted. Trials had to include children with cerebral palsy, with a Gross Motor Function Classification System, between I and III, that delivered backward walking training as a solo intervention or in combination with forward walking training. The outcomes of interest were walking speed and balance. The methodological quality of included trials was assessed by the PEDro scale, and the quality of evidence was assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight papers, involving 156 participants, were included. Using random-effects meta-analysis, we estimated that backward walking training improved walking speed by 0.10 m/s [95% confidence interval (CI) 0.05-0.16] and by 2 points on the Pediatric Balance Scale (0-56) (95% CI 1.5-2.2) more than forward walking training. We also estimated that the addition of backward walking training increased walking speed by 0.20 m/s (95% CI 0.07-0.34) and reduced the angular excursion of the center of gravity by 0.5 degrees (95% CI -0.7 to -0.3). The quality of the evidence was classified as low to moderate. In conclusion, overall, backward walking training appears to be as effective or slightly superior to forward walking training for improving walking speed in children with CP. The addition of backward walking training statistically significantly and clinically important enhanced benefits on walking speed.

Predictors of Mortality and Functional recovery after severe traumatic brain injury: protocol for a prospective cohort study

Introduction: traumatic brain injury is a global public health problem due to its severity and high rates of morbimortality worldwide. Identifying predictors associated with increased mortality and unfavorable functional outcomes after the traumatic brain injury event is crucial for minimizing morbidity and mortality rates. Therefore, this study aims to establish a protocol to investigate the predictors of mortality and functional recovery after severe traumatic brain injury in Brazil.Methods: The study will include all patients admitted for severe traumatic brain injury (Glasgow Coma Scale ≤ 8) at the State Hospital of Urgency and Emergency, which is the referral trauma hospital of Espirito Santo. The outcomes of interest are hospital mortality and functional recovery 24 months after hospital discharge. Subjects will be followed up at seventy-two hours, three months, six months, twelve months, and twenty-four months after the trauma. Morbidity will be determined by assessing: 1) the level of motor and cognitive disability, 2) functional impairment and quality of life, and 3) aspects of rehabilitation treatment. Additionally, the traumatic brain injury load, estimated by the years of life lost, will be calculated. Discussion: the results of this study will help identify variables that can predict morbidity and mortality, as well as diagnostic and therapeutic targets for patients with severe traumatic brain injury. Furthermore, the findings will have practical implications for: 1) the development of public policies, 2) investments in hospital infrastructure 3) understanding the socioeconomic impact of functional loss in the individuals.Study registration: the study received approval from the Ethics Committee of the Federal University of Espirito Santo under protocol number 4.222.002 on August 18, 2020.

Introdução: traumatismo cranioencefálico é um problema global de saúde pública devido à sua gravidade e altas taxas de morbimortalidade em todo o mundo. Identificar preditores associados ao aumento da mortalidade e desfechos funcionais desfavoráveis após o evento do traumatismo craniencefálico é primordial para minimizar as taxas de morbidade e mortalidade. Portanto, este estudo tem como objetivo estabelecer um protocolo para investigar os preditores de mortalidade e recuperação funcional após traumatismo cranioencefálico grave no Brasil. Métodos: este estudo tem como objetivo investigar os preditores de mortalidade e recuperação funcional em pacientes com traumatismo cranioencefálico, além de fornecer uma visão geral do traumatismo cranioencefálico no estado do Espírito Santo. O estudo abrangerá todos os pacientes internados por traumatismo cranioencefálico grave (Escala de Coma de Glasgow ≤ 8) no Hospital Estadual de Urgência e Emergência, o hospital de referência para traumas no Espírito Santo. Os desfechos de interesse incluem mortalidade hospitalar e recuperação funcional após 24 meses da alta hospitalar. Os participantes serão acompanhados em setenta e duas horas, três meses, seis meses, doze meses e vinte e quatro meses após o trauma. A morbidade será determinada pela avaliação de: 1) nível de incapacidade motora e cognitiva, 2) comprometimento funcional e qualidade de vida, e 3) aspectos do tratamento e reabilitação. Além disso, a carga de traumatismo cranioencefálico, estimada em anos de vida perdidos, será calculada. Discussão: os resultados deste estudo ajudarão a identificar variáveis que podem predizer a morbidade e a mortalidade após traumatismo cranioencefálico grave. Além disso, as descobertas terão implicações práticas para: 1) o desenvolvimento de políticas públicas, 2) investimentos em infraestrutura hospitalar e 3) compreensão do impacto socioeconômico da perda funcional nesses indivíduos. Registro do estudo: o estudo recebeu aprovação do Comitê de Ética da Universidade Federal do Espírito Santo sob o número de protocolo 4.222.002 em 18 de agosto de 2020

Exploring the conformational dynamics of the CRD4: a model for receptor lysosomal activity shifts in search of 'sweet' and 'sour' states.

The macrophage mannose receptor (RMM) is a crucial component of the immune system involved in immune responses, inflammation resolution, and tissue remodeling. When RMM is activated by a specific ligand, it undergoes internalization, forming an endosome that matures into a lysosome. Within the lysosome, structural changes in RMM facilitate the dissociation of ligands for further processing. However, the precise details of these structural changes are not well understood. In this study, we used molecular dynamics simulations to investigate the conformational dynamics of a specific region called CRD4 in RMM. Our simulations explored different conditions, including pH variations and the presence of Ca2+ ions. By analyzing the simulation data, we found that conformational changes primarily occur in loop regions, while the secondary structure remains stable. The binding site of CRD4, essential for ligand interaction, is located on the protein surface between two specific loop regions. Ligand binding is stabilized by three important amino acids. Interestingly, the interaction patterns differ between monosaccharide and disaccharide ligands. These findings improve our understanding of CRD4's dynamics and how it recognizes ligands. They provide insights into the structure of CRD4 and its role in ligand dissociation within lysosomes. The study also highlights the significance of loop regions in functional dynamics and interactions. Further research is needed to fully uncover the complete structure of CRD4, understand ligand binding modes, and explore the influence of environmental factors. This study lays the foundation for future investigations targeting carbohydrate-protein interactions and the development of therapeutics based on RMM's unique properties.Communicated by Ramaswamy H. Sarma.

Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options.

Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the majority of these diseases, there are few or no drugs available for patient treatment, and the few drugs that do exist often lack adequate safety and efficacy. As a result, there is a pressing need to discover and design new drugs to address these neglected diseases. This requires the identification of different targets and interactions to be studied. In recent years, there has been a growing focus on studying enzyme covalent inhibitors as a potential treatment for neglected diseases. In this review, we will explore examples of how these inhibitors have been used to target Human African Trypanosomiasis, Chagas disease, and Malaria, highlighting some of the most promising results so far. Ultimately, this review aims to inspire medicinal chemists to pursue the development of new drug candidates for these neglected diseases, and to encourage greater investment in research in this area.

Manual Therapy Applied to the Cervial Joint Reduces Pain and Improves Jaw Function in Individuals with Temporomandibular Disorders: A Systematic Review on Manual Therapy for Orofacial Disorders.

AIMS: To examine the effect of manual therapy applied to the cervical joint for reducing pain and improving mouth opening and jaw function in people with TMDs. METHODS: A systematic review of randomized controlled trials was performed. Participants were adults diagnosed with TMDs. The experimental intervention was manual therapy applied to the cervical joint compared to no intervention/placebo. Outcome data relating to orofacial pain intensity, pressure pain threshold (PPT), maximum mouth opening, and jaw function were extracted and combined in meta-analyses. RESULTS: The review included five trials involving 213 participants, of which 90% were women. Manual therapy applied to the cervical joint decreased orofacial pain (mean difference: -1.8 cm; 95% CI: -2.8 to -0.9) and improved PPT (mean difference: 0.64 kg/cm2; 95% CI: 0.02 to 1.26) and jaw function (standardized mean difference: 0.65; 95% CI: 0.3 to 1.0). CONCLUSION: Manual therapy applied to the cervical joint had short-term benefits for reducing pain intensity and improving jaw function in women with TMDs. Further studies are needed to improve the quality of the evidence and to investigate the maintenance of benefits beyond the intervention period.

Validation of the NAT Chagas IVD Kit for the Detection and Quantification of Trypanosoma cruzi in Blood Samples of Patients with Chagas Disease.

In the absence of validated biomarkers to control the cure of Chagas disease, PCR-based diagnosis is being used as the main tool for an early indication of therapeutic failure. However, since it is considered a technique of complex reproducibility, mainly due to difficulties in establishing accurate controls to guarantee the quality of the reaction, the use of PCR for Chagas disease diagnosis is restricted to specialized centers. In an effort to disseminate the molecular diagnosis of Chagas disease and its applications, new diagnostic kits based on qPCR have been made available in the market in recent years. Here, we show the results of the validation of the NAT Chagas kit (Nucleic Acid Test for Chagas Disease) for the detection and quantification of T. cruzi in blood samples of patients suspected of Chagas disease infection. The kit, composed of a TaqMan duplex reaction targeting the T. cruzi satellite nuclear DNA and an exogenous internal amplification control, presented a reportable range from 104 to 0.5 parasite equivalents/mL and a limit of detection (LOD) of 0.16 parasite equivalents/mL of blood. In addition, the NAT Chagas kit detected T. cruzi belonging to all six discrete typing units (DTUs-TcI to TcVI), similarly to the in-house real-time PCR performed with commercial reagents, which has been selected as the best performance assay in the international consensus for the validation of qPCR for Chagas disease. In the clinical validation presented here, the kit showed 100% sensitivity and 100% specificity when compared to the consensus in-house real-time PCR assay. Thus, the NAT Chagas kit, which is produced entirely in Brazil under the international standards of good manufacturing practices (GMP), appears as an excellent alternative to enable the molecular diagnosis of Chagas disease in public and private diagnostic centers, as well as to facilitate the monitoring of patients under etiological treatment participating in clinical trials.