Discovery of a non-canonical prototype long-chain monoacylglycerol lipase through a structure-based endogenous reaction intermediate complex.

The identification and characterization of enzyme function is largely lacking behind the rapidly increasing availability of large numbers of sequences and associated high-resolution structures. This is often hampered by lack of knowledge on in vivo relevant substrates. Here, we present a case study of a high-resolution structure of an unusual orphan lipase in complex with an endogenous C18 monoacylglycerol ester reaction intermediate from the expression host, which is insoluble under aqueous conditions and thus not accessible for studies in solution. The data allowed its functional characterization as a prototypic long-chain monoacylglycerol lipase, which uses a minimal lid domain to position the substrate through a hydrophobic tunnel directly to the enzyme's active site. Knowledge about the molecular details of the substrate binding site allowed us to modulate the enzymatic activity by adjusting protein/substrate interactions, demonstrating the potential of our findings for future biotechnology applications.

Balance telerehabilitation and wearable technology for people with Parkinson's disease (TelePD trial).

BACKGROUND: Balance impairments, that lead to falls, are one of the main symptoms of Parkinson's disease (PD). Telerehabilitation is becoming more common for people with PD; however, balance is particularly challenging to assess and treat virtually. The feasibility and efficacy of virtual assessment and virtual treatment of balance in people with PD are unknown. The present study protocol has three aims: I) to determine if a virtual balance and gait assessment (instrumented L-shape mobility test) with wearable sensors can predict a gold-standard, in-person clinical assessment of balance, the Mini Balance Evaluation Systems Test (Mini-BESTest); II) to explore the effects of 12 sessions of balance telerehabilitation and unsupervised home exercises on balance, gait, executive function, and clinical scales; and III) to explore if improvements after balance telerehabilitation transfer to daily-life mobility, as measured by instrumented socks with inertial sensors worn for 7 days. METHODS: The TelePD Trial is a prospective, single-center, parallel-group, single-blind, pilot, randomized, controlled trial. This trial will enroll 80 eligible people with PD. Participants will be randomized at a 1:1 ratio into receiving home-based balance exercises in either: 1) balance telerehabilitation (experimental group, n = 40) or 2) unsupervised exercises (control group, n = 40). Both groups will perform 12 sessions of exercise at home that are 60 min long. The primary outcome will be Mini-BESTest. The secondary outcomes will be upper and lower body gait metrics from a prescribed task (instrumented L-shape mobility test); daily-life mobility measures over 7 days with wearable sensors in socks, instrumented executive function tests, and clinical scales. Baseline testing and 7 days of daily-life mobility measurement will occur before and after the intervention period. CONCLUSION: The TelePD Trial will be the first to explore the usefulness of using wearable sensor-based measures of balance and gait remotely to assess balance, the feasibility and efficacy of balance telerehabilitation in people with PD, and the translation of balance improvements after telerehabilitation to daily-life mobility. These results will help to develop a more effective home-based balance telerehabilitation and virtual assessment that can be used remotely in people with balance impairments. TRIAL REGISTRATION: This trial was prospectively registered on ClinicalTrials.gov (NCT05680597).

Bioinformatic Mining and Structure-Activity Profiling of Baeyer-Villiger Monooxygenases from Mycobacterium tuberculosis.

Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), one of the deadliest infectious diseases. The alarming health context coupled with the emergence of resistant M. tuberculosis strains highlights the urgent need to expand the range of anti-TB antibiotics. A subset of anti-TB drugs in use are prodrugs that require bioactivation by a class of M. tuberculosis enzymes called Baeyer-Villiger monooxygenases (BVMOs), which remain understudied. To examine the prevalence and the molecular function of BVMOs in mycobacteria, we applied a comprehensive bioinformatic analysis that identified six BVMOs in M. tuberculosis, including Rv3083 (MymA), Rv3854c (EthA), Rv0565c, and Rv0892, which were selected for further characterization. Homology modeling and substrate docking analysis, performed on this subset, suggested that Rv0892 is closer to the cyclohexanone BVMO, while Rv0565c and EthA are structurally and functionally similar to MymA, which is by far the most prominent type I BVMO enzyme. Thanks to an unprecedented purification and assay optimization, biochemical studies confirmed that all four BVMOs display BV-oxygenation activity. We also showed that MymA displays a distinctive substrate preference that we further investigated by kinetic parameter determination and that correlates with in silico modeling. We provide insights into distribution of BVMOs and the structural basis of their substrate profiling, and we discuss their possible redundancy in M. tuberculosis, raising questions about their versatility in prodrug activation and their role in physiology and infection. IMPORTANCE Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of death worldwide. The rise in drug resistance highlights the urgent need for innovation in anti-TB drug development. Many anti-TB drugs require bioactivation by Baeyer-Villiger monooxygenases (BVMOs). Despite their emerging importance, BVMO structural and functional features remain enigmatic. We applied a comprehensive bioinformatic analysis and confirmed the presence of six BVMOs in M. tuberculosis, including MymA, EthA, and Rv0565c-activators of the second-line prodrug ethionamide-and the novel BVMO Rv0892. Combining in silico characterization with in vitro validation, we outlined their structural framework and substrate preference. Markedly, MymA displayed an enhanced capacity and a distinct selectivity profile toward ligands, in agreement with its catalytic site topology. These features ground the molecular basis for structure-function comprehension of the specificity in these enzymes and expand the repertoire of BVMOs with selective and/or overlapping activity for application in the context of improving anti-TB therapy.

The protein kinase PknB negatively regulates biosynthesis and trafficking of mycolic acids in mycobacteria.

Mycobacterium tuberculosis is the causative agent of tuberculosis and remains one of the most widespread and deadliest bacterial pathogens in the world. A distinguishing feature of mycobacteria that sets them apart from other bacteria is the unique architecture of their cell wall, characterized by various species-specific lipids, most notably mycolic acids (MAs). Therefore, targeted inhibition of enzymes involved in MA biosynthesis, transport, and assembly has been extensively explored in drug discovery. Additionally, more recent evidence suggests that many enzymes in the MA biosynthesis pathway are regulated by kinase-mediated phosphorylation, thus opening additional drug-development opportunities. However, how phosphorylation regulates MA production remains unclear. Here, we used genetic strategies combined with lipidomics and phosphoproteomics approaches to investigate the role of protein phosphorylation in Mycobacterium The results of this analysis revealed that the Ser/Thr protein kinase PknB regulates the export of MAs and promotes the remodeling of the mycobacterial cell envelope. In particular, we identified the essential MmpL3 as a substrate negatively regulated by PknB. Taken together, our findings add to the understanding of how PknB activity affects the mycobacterial MA biosynthesis pathway and reveal the essential role of protein phosphorylation/dephosphorylation in governing lipid metabolism, paving the way for novel antimycobacterial strategies.

Perfil antropométrico y condición física de jugadores veteranos de básquetbol / Anthropometric and fitness profile of senior basketball players

Los cambios demográficos y sociales están produciendo un incremento progresivo de las personas de más de 60 años a nivel mundial, situación que no es distinta en Chile, por lo que estudiar variables relacionadas con este grupo de la población se vuelve importante. En este sentido, la presente investigación tiene por objetivo conocer el perfil antropométrico y condición física de jugadores veteranos de basquetbol (JVB). El tipo de investigación contempla un diseño descriptivo, transversal, con un enfoque cuantitativo. La muestra seleccionada incluyó a 30 JVB (edad 66,7±6,8 años) pertenecientes a la liga de la Asociación de Básquetbol Sénior de la Región de la Araucanía, Chile. Las variables dependientes estudiadas corresponden a la composición corporal, somatotipo y condición física (fuerza, resistencia aeróbica, flexibilidad, agilidad y equilibrio dinámico). Los resultados indican que los JVB mostraron un componente endomórfico, mesomórfico y ectomórfico de 4,1, 6,1 y 1,0, respectivamente, clasificándolos como meso-endomorfos, con una masa muscular de 45% y masa grasa de 24,5%. La condición física de los JVB presentó un rendimiento igual (40% de los JVB) o superior (40% de los JVB) al esperado según edad y sexo. En conclusión, los JVB poseen un perfil antropométrico y condición física favorable de acuerdo a su edad y sexo, sugiriendo que la práctica sistemática de básquetbol permitiría impactar positivamente sobre la composición corporal y el rendimiento físico-funcional en adultos mayores, sin embargo se requiere de mayor investigación para poder afirmarlo.

The demographic and social changes are causing a gradual increase in people over 60 years worldwide, situation thar is similar in Chile, so the study of variables related to this group of the population becomes important. In this regard, the aim of this study is to determine the anthropometric and physical fitness profile of senior basketball players (SBP). This is a descriptive, cross-sectional, quantitative research. The sample included 30 SBP (age 66.7±6.8 years) belonging to the league of the Senior Basketball Association of the Araucanía Region, Chile. The dependent variables studied correspond to body composition, somatotype and fitness (strength, endurance, flexibility, agility and dynamic balance). Results indicate that the SBP showed endomorphic, mesomorphic and ectomorphic values of 4.1, 6.1 and 1.0, respectively, as meso-endomorphs with a muscle mass of 45% and body fat of 24.5%. Compared to age and sex counterparts, SBP exhibit equal (40% of SBP) or even higher (40% of SBP) values for physical fitness perfomance variables. In conclusion, SBP have a favorable anthropometric and physical fitness profile for their age and sex, suggesting that the systematic practice of basketball would have a positive impact on body composition and physical fitness-function in older adults, however more experimental research is needed to corroborate this.

Somatotipo, composición corporal, estado nutricional y condición física en personas con discapacidad visual que practican goalball / Somatotype, body composition, nutritional state and physical condition in people with visual impairment who practice goalball

Las publicaciones referidas a personas con discapacidad visual que practican Goalball son escasas, dado a estudiar otros grupos de la población o bien por razones que se desconocen. El objetivo de esta investigación fue medir el somatotipo, composición corporal, estado nutricional y condición física por aspectos estructurales y funcionales en personas con discapacidad visual que practican Goalball en la región de la Araucanía. El tipo de investigación contempla un diseño no experimental, descriptivo, transversal, con un enfoque cuantitativo. La población estuvo constituida por 14 deportistas de Goalball de la región de la Araucanía, Chile. La muestra fue seleccionada bajo un criterio probabilístico, que incluyo a 11 personas, todos hombres (edad 42,36±14,46 años), en relación al peso y estatura la media fue de 74,76±10,36 kg y 1,695±0,07 m, respectivamente. Para medir el somatotipo y la composición corporal se utilizó el protocolo descrito por la Sociedad Internacional para el avance de la Kineantropometría (ISAK) y para evaluar el estado nutricional y la condición física, se utilizaron las pruebas empleadas en el Sistema de medición de la calidad de la educación (SIMCE) para el subsector de Educación Física, propuestos por el Ministerio de Educación de Chile (MINEDUC). Los resultados indican que los deportistas evaluados se clasifican como mesoendomorfos, alcanzando un 28,78% de masa grasa y 42,71% de masa muscular, mientras que su IMC fue 26,05 kg/m2. En cuanto a la condición física los valores encontrados señalan que se encuentran en un nivel satisfactorio para las pruebas de abdominales, flexibilidad y resistencia cardiorrespiratoria, mientras que ostentan malos resultados para las pruebas de salto largo a pies juntos y flexoextensión de codos, situación que se puede entender por la edad, discapacidad y características de la disciplina deportiva practicada.

Few publications refer to people with a visual impairment who practice Goalball, given that other groups of the population were studied or for unknown reasons. The aim was to measure the somatotype, the body composition, the nutritional state, and the physical condition (more specifically structural and functional features) of people with visual impairment in the Araucanía Region in Chile. The type of investigation considers a cuantitative, non-experimental, descriptive and transversal design. The sample consists of 14 Goalball athletes of the Araucanía Region. The sample was selected randomly and included 11 male subjects (age 42.36±14.46), with respect to weight and height the average was 74.76±10.36 and 1.695±0.07 respectively. To measure the somatotype and the body composition, the protocol described by the International Society for the Advancement of Kinanthropometry (ISAK) was used, whereas to evaluate the nutritional state and physical condition, the tests employed in the SIMCE (System of Measuring the Quality of Education) for the subsector of Physical Education in Chile (MINEDUC ­ Ministry of Education) were administered. The results indicate that the evaluated athletes classify as meso-endomorph. They reached 28.78% of fat mass and 42.71% of muscle mass, whereas their BMI is 26.05kg/m2. Regarding their physical condition the findings show a satisfactory level for the tests of abdominals, flexibility, and cardiorespiratory resistence. The tests of long jump with joined feet and elbow-flexo-extention were not as good, however. These outcomes can possibly be explained by the age, visual impairment, and by characteristics of the sport discipline practiced.

Trastorno por déficit de atención con hiperactividad y el consumo de sustancias / Disorder attention deficit hyperactivity disorder and substance use

Se realizó una investigación bibliográfica para conocer, si existe una relación entre trastorno por déficit de atención con hiperactividad TDAH y los desórdenes por consumo de sustancias (SUD en inglés). Se analizaron publicaciones que hicieran referencia a la relación de comorbilidad entre TDAH y el consumo de sustancias. Se Investigó si existe una relación de comorbilidad directa, específica y estadísticamente significativa entre TDAH y el consumo de cocaína. En los trabajos consultados existen abundantes referencias bibliográficas, desde los años noventa, que relacionan el trastorno por déficit de atención con hiperactividad (TDAH) y la aparición de trastornos por consumo de sustancias psicoactivas en adolescentes y adultos con TDAH. Muchos de estos trabajos postulan una relación de comorbilidad directamente proporcional entre el TDAH y los trastornos de consumo de sustancias. Metanálisis actualizados ponen en duda esta relación por entender, que muchas de las muestras tomadas, no pertenecen al universo de la población general y que hay un sesgo y una mixtura de: TDAH, SUD, trastornos de la personalidad y trastornos de la conducta (CD) en las muestras. Estos últimos trastornos que serían los contaminantes de la mayoría de las muestras, tendrían una relación más directa con SUD que el TDAH propiamente dicho.

ABSTRACT: We conducted a bibliographic research to know if there is a relationship between attention deficit disorder with hyperactivity ADHD and substance use disorders (SUD). We analyzed publications which referred to the relation of comorbidity between ADHD and the consumption of substances. We investigated whether there is a direct comorbidity, specific and statistically significant between ADHD and cocaine consumption. In the works consulted bibliographic references there are abundant, since the nineties, relating the attention deficit disorder with hyperactivity (ADHD) and the onset of disorders psychoactive substance use in adolescents and adults with ADHD. Many of these works postulate a directly proportional relationship of comorbidity between ADHD and substance use disorders. Updated meta-analysis put in doubt this relationship to understand that many of the samples taken, not belong to universe of the general population and that there is a bias and a mixture of: ADHD, SUD, personality disorders and conduct disorder (CD ) in the samples. These latter conditions that contaminants in the would most samples would have a direct relationship with ADHD LDS itself.

Trastorno por déficit de atención con hiperactividad y el consumo de sustancias / Disorder attention deficit hyperactivity disorder and substance use

Se realizó una investigación bibliográfica para conocer, si existe una relación entre trastorno por déficit de atención con hiperactividad TDAH y los desórdenes por consumo de sustancias (SUD en inglés). Se analizaron publicaciones que hicieran referencia a la relación de comorbilidad entre TDAH y el consumo de sustancias. Se Investigó si existe una relación de comorbilidad directa, específica y estadísticamente significativa entre TDAH y el consumo de cocaína. En los trabajos consultados existen abundantes referencias bibliográficas, desde los años noventa, que relacionan el trastorno por déficit de atención con hiperactividad (TDAH) y la aparición de trastornos por consumo de sustancias psicoactivas en adolescentes y adultos con TDAH. Muchos de estos trabajos postulan una relación de comorbilidad directamente proporcional entre el TDAH y los trastornos de consumo de sustancias. Metanálisis actualizados ponen en duda esta relación por entender, que muchas de las muestras tomadas, no pertenecen al universo de la población general y que hay un sesgo y una mixtura de: TDAH, SUD, trastornos de la personalidad y trastornos de la conducta (CD) en las muestras. Estos últimos trastornos que serían los contaminantes de la mayoría de las muestras, tendrían una relación más directa con SUD que el TDAH propiamente dicho.(AU)

ABSTRACT: We conducted a bibliographic research to know if there is a relationship between attention deficit disorder with hyperactivity ADHD and substance use disorders (SUD). We analyzed publications which referred to the relation of comorbidity between ADHD and the consumption of substances. We investigated whether there is a direct comorbidity, specific and statistically significant between ADHD and cocaine consumption. In the works consulted bibliographic references there are abundant, since the nineties, relating the attention deficit disorder with hyperactivity (ADHD) and the onset of disorders psychoactive substance use in adolescents and adults with ADHD. Many of these works postulate a directly proportional relationship of comorbidity between ADHD and substance use disorders. Updated meta-analysis put in doubt this relationship to understand that many of the samples taken, not belong to universe of the general population and that there is a bias and a mixture of: ADHD, SUD, personality disorders and conduct disorder (CD ) in the samples. These latter conditions that contaminants in the would most samples would have a direct relationship with ADHD LDS itself.(AU)