Synuclein Proteins in Cancer Development and Progression.

Synucleins are a family of small, soluble proteins mainly expressed in neural tissue and in certain tumors. Since their discovery, tens of thousands of scientific reports have been published about this family of proteins as they are associated with severe human diseases. Although the physiological function of these proteins is still elusive, their relationship with neurodegeneration and cancer has been clearly described over the years. In this review, we summarize data connecting synucleins and cancer, going from the structural description of these molecules to their involvement in tumor-related processes, and discuss the putative use of these proteins as cancer molecular biomarkers.

Microbial carbon use efficiency promotes global soil carbon storage.

Soils store more carbon than other terrestrial ecosystems1,2. How soil organic carbon (SOC) forms and persists remains uncertain1,3, which makes it challenging to understand how it will respond to climatic change3,4. It has been suggested that soil microorganisms play an important role in SOC formation, preservation and loss5-7. Although microorganisms affect the accumulation and loss of soil organic matter through many pathways4,6,8-11, microbial carbon use efficiency (CUE) is an integrative metric that can capture the balance of these processes12,13. Although CUE has the potential to act as a predictor of variation in SOC storage, the role of CUE in SOC persistence remains unresolved7,14,15. Here we examine the relationship between CUE and the preservation of SOC, and interactions with climate, vegetation and edaphic properties, using a combination of global-scale datasets, a microbial-process explicit model, data assimilation, deep learning and meta-analysis. We find that CUE is at least four times as important as other evaluated factors, such as carbon input, decomposition or vertical transport, in determining SOC storage and its spatial variation across the globe. In addition, CUE shows a positive correlation with SOC content. Our findings point to microbial CUE as a major determinant of global SOC storage. Understanding the microbial processes underlying CUE and their environmental dependence may help the prediction of SOC feedback to a changing climate.

Research integrity in randomized clinical trials: A scoping umbrella review.

BACKGROUND: Randomized clinical trials (RCTs) are experiencing a crisis of confidence in their trustworthiness. Although a comprehensive literature search yielded several reviews on RCT integrity, an overarching overview is lacking. OBJECTIVES: The authors undertook a scoping umbrella review of the research integrity literature concerning RCTs. SEARCH STRATEGY AND SELECTION CRITERIA: Following prospective registration (https://osf.io/3ursn), two reviewers independently searched PubMed, Scopus, The Cochrane Library, and Google Scholar, without language or time restrictions, until November 2021. The authors included systematic reviews covering any aspect of research integrity throughout the RCT lifecycle. DATA COLLECTION AND ANALYSIS: The authors assessed methodological quality using a modified AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) tool and collated the main findings. MAIN RESULTS: A total of 55 relevant reviews, summarizing 6001 studies (median per review, 63; range, 8-1106) from 1964 to 2021, had an overall critically low quality of 96% (53 reviews). Topics covered included general aspects (15%), design and approval (22%), conduct and monitoring (11%), reporting (38%), postpublication concerns (2%), and future research (13%). The most common integrity issues covered were ethics (18%) and transparency (18%). CONCLUSIONS: Low-quality reviews identified various integrity issues across the RCT lifecycle, emphasizing the importance of high ethical standards and professionalism while highlighting gaps in the integrity landscape. Multistakeholder consensus is needed to develop specific RCT integrity standards.

Association of gloves change and surgical site complications in elective cesarean sections of low-risk pregnancies.

BACKGROUND: The aim of this study was to assess whether the change of gloves is associated with reduced surgical site complications of elective cesarean sections in low-risk pregnancies. METHODS: A prospective and observational study was conducted, with 169 patients selected for elective cesarean sections, and divided into two groups: group 1 (N.=100) (no change of gloves); and group 2 (N.=94) (gloves changed during surgery). Fisher's Exact Test was used to test hypotheses and existence of associations between variables. The receiver operating characteristic curve (ROC) was used to determine the best value of surgical time to identify complications in the surgical site. RESULTS: There was significant effect on surgical time (group 1: 72.6 vs. group 2: 65.1 min, P=0.006). There was no association between changing gloves and the presence of complications of the surgical site. Approximately 22.5% of patients had at least one complication up to 60 days after cesarean section, with no association between the change of gloves and the presence of comorbidities during prenatal follow-up (P>0.999). Surgical time >70 min was able to correctly identify 59.1% of cases of surgical site complications up to 60 days after cesarean section with a false positive rate of 34% (area under ROC curve: 0.627, P=0.0126, 95% CI: 0.554-0.695). CONCLUSIONS: In low-risk patients submitted to elective cesarean sections, change of gloves did not reduce the incidence of complications of the surgical site. Surgical time was an independent predictor for the presence of complications of the surgical site up to 60 days after cesarean section.

The physiology of alternative splicing.

Alternative splicing is a substantial contributor to the high complexity of transcriptomes of multicellular eukaryotes. In this Review, we discuss the accumulated evidence that most of this complexity is reflected at the protein level and fundamentally shapes the physiology and pathology of organisms. This notion is supported not only by genome-wide analyses but, mainly, by detailed studies showing that global and gene-specific modulations of alternative splicing regulate highly diverse processes such as tissue-specific and species-specific cell differentiation, thermal regulation, neuron self-avoidance, infrared sensing, the Warburg effect, maintenance of telomere length, cancer and autism spectrum disorders (ASD). We also discuss how mastering the control of alternative splicing paved the way to clinically approved therapies for hereditary diseases.

VEMERS 2.0: Upgrading of an Emergency Use Ventilator from a Single Mandatory Volume Control Mode of Ventilation (VEMERS 1.0) to 8 Modes of Ventilation.

The upgrading of an emergency use ventilator from a single mandatory volume control mode of ventilation (VEMERS 1.0) to 8 modes of ventilation (VEMERS 2.0) is described. The original VEMERS 1.0 was developed in the midst of the COVID-19 crisis in Chile (April to August 2020) following special but nonetheless strict guidelines specified by local medical associations and national health and scientific ministries. The upgrade to 8 modes of ventilation in VEMERS 2.0 was made possible with minor but transcendental changes to the original architecture. The main contribution of this research is that starting from a functional block diagram of an ICU mechanical ventilator and carrying a systematic analysis, the main function blocks are implemented in such a way that combinations of standard off-the-shelf pneumatic and electronic components can be used. This approach has both economical and technical advantages. No special parts need to be fabricated at all, and because of a wider variety of options, the use of extensively field-proven off-the-shelf commercial components assures better availability and lower costs when compared to that of conventional ICU mechanical ventilators, without sacrificing reliability. Given the promising results obtained with VEMERS 2.0 in the subsequent national certification process, the production of 40 VEMERS 2.0 units was sponsored by the Ministry of Science and the Ministry of Economy. Twenty units have been distributed among hospitals along the country. The purpose of VEMERS 2.0, as a low-cost but very reliable option, is to increase the number of mechanical ventilators available (3,000 for a population of 18,000,000) in the country to eventually reach a ratio similar to that of more developed countries. VEMERS is an open-source project for others to use the knowledge gained.

Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped, cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide (ASO) that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with a nusinersen-like ASO to promote E7 inclusion. Surprisingly, the ASO promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to RNA polymerase II elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the chromatin effects of the ASO, resulting in higher E7 inclusion without large pleiotropic effects. Combined administration of the nusinersen-like ASO and VPA in SMA mice strongly synergizes SMN expression, growth, survival, and neuromuscular function.

Physiological tissue-specific and age-related reduction of mouse TDP-43 levels is regulated by epigenetic modifications.

The cellular level of TDP-43 (also known as TARDBP) is tightly regulated; increases or decreases in TDP-43 have deleterious effects in cells. The predominant mechanism responsible for the regulation of the level of TDP-43 is an autoregulatory negative feedback loop. In this study, we identified an in vivo cause-effect relationship between Tardbp gene promoter methylation and specific histone modification and the TDP-43 level in tissues of mice at two different ages. Furthermore, epigenetic control was observed in mouse and human cultured cell lines. In amyotrophic lateral sclerosis, the formation of TDP-43-containing brain inclusions removes functional protein from the system. This phenomenon is continuous but compensated by newly synthesized protein. The balance between sequestration and new synthesis might become critical with ageing, if accompanied by an epigenetic modification-regulated decrease in newly synthesized TDP-43. Sequestration by aggregates would then decrease the amount of functional TDP-43 to a level lower than those needed by the cell and thereby trigger the onset of symptoms.

Mesenteric Artery Thrombosis, Microvascular Intestinal Endothelitiis, and Guillain-Barrè Syndrome in the Same SARS-CoV-2 Patient.

Coronavirus disease 2019 (COVID-19) in humans is a novel disease that can affect every organ of the body, with life-threatening consequences. Microvascular lesions and thrombosis have been previously reported in the lung, kidney, and brain. We report a case of combined intestinal lesions and Guillain-Barrè Syndrome in a patient suffering from COVID-19 in the absence of clear laboratory predictors of upcoming complications. The patient survived the severe respiratory syndrome but died after virus-related systemic organ failure.

Colangiografía intraoperatoria: curva de aprendizaje en una Residencia de Cirugía General / Intraoperative cholangiography: Learning curve in a General Surgery residency

RESUMEN Antecedentes: el uso de la colangiografía intraoperatoria dinámica (CIOd) durante la colecistectomía laparoscópica (Colelap) sigue siendo un tema en discusión. Objetivos: Este trabajo tiene como objetivo describir y evaluar la curva de aprendizaje y los hallazgos en la CIOd durante las colecistectomías laparoscópicas realizadas por residentes de Cirugía General, incluyéndola como herramienta para una colecistectomía segura, así como entrenamiento para el de sarrollo de habilidades y destrezas. Material y métodos: se incluyeron pacientes con indicación de colecistectomía laparoscópica pro gramada o de urgencia. En las cirugías se realizó tracción según Hunter, visión crítica de seguridad y CIOd sistemática, por un residente mayor y la CIOd por un residente inferior, tutorizado por cirujano de planta. Se evaluaron curva de aprendizaje, tiempos operatorios, relación del tiempo de CIOd con el tiempo de duración de la Colelap (CIO/CX), redisección del cístico y litiasis cística y coledociana. Resultados: se operaron 456 pacientes durante un año (2017-2018). Se observó que, independiente mente de quien realice la CIOd, los residentes pudieron mejorar su curva de aprendizaje, objetiván dose tiempos más cortos para la Colelap, CIOd y la relación CIO/CX. Los coeficientes de aprendizaje fueron mejores en cirugías más complejas en relación con el semestre. El 5,26% presentó litiasis cole dociana (n = 24); de estas, 66,7% tenían litiasis cística (n = 16) y 25% colecistitis (n = 6) asociadas. Todas se resolvieron por vía transcística. No hubo conversiones y se realizó CIOd en el 100%. Conclusión: la CIOd es un procedimiento ideal para ser practicado de manera sistemática durante la Residencia, porque da el entrenamiento necesario para el manejo de la vía transcística, permite evitar una lesión quirúrgica de vía biliar mayor y el diagnóstico de coledocolitiasis.

ABSTRACT Background: The use of dynamic intra-operative cholangiography (dIOC) during laparoscopic cholecystectomy (Lap Chole) remains a topic under discussion. Objectives: This study aims to describe and evaluate the learning curve and findings in the dIOC during laparoscopic cholecystectomies performed by Residents of General Surgery, including it as a tool for a safe cholecystectomy, as well as training for the development of skills and abilities. Material and methods: Patients with indication of scheduled or emergency laparoscopic cholecystectomy were included. In the surgeries, traction was performed according to Hunter, critical safety vision and systematic dIOC, by a senior Resident and the dIOC by a less trained resident, tutored by a staff surgeon. Learning curve, operative times, dIOC time relationship with Lap Chole duration time (IOC/LC), repeated cystic dissection, cystic lithiasis and choledocholithiasis were evaluated. Results: 456 patients were operated for one year (2017-2018). It was observed that regardless of who performs the dIOC, they were able to improve their learning curve, objectifying shorter times for Lap Chole, dIOC and the IOC/LC relationship. The learning coefficients were better in complex surgeries in relation to the semester. 5.26 % had choledocholithiasis (n = 24), of these, 66.7% had cystic lithiasis (n = 16) and 25% associated cholecystitis (n = 6). All were resolved trancystically. There were no conversions and dIOC was performed in 100% of cases. Conclusion: The dIOC is an ideal procedure to be practiced systematically during residency. Because it gives the necessary training for the management of the transcystic pathway, allows avoiding an upper bile duct injury and the diagnosis of choledocholithiasis.

Nuclear role for human Argonaute-1 as an estrogen-dependent transcription coactivator.

In mammals, argonaute (AGO) proteins have been characterized for their roles in small RNA-mediated posttranscriptional and also in transcriptional gene silencing. Here, we report a different role for AGO1 in estradiol-triggered transcriptional activation in human cells. We show that in MCF-7 mammary gland cells, AGO1 associates with transcriptional enhancers of estrogen receptor α (ERα) and that this association is up-regulated by treating the cells with estrogen (E2), displaying a positive correlation with the activation of these enhancers. Moreover, we show that AGO1 interacts with ERα and that this interaction is also increased by E2 treatment, but occurs in the absence of RNA. We show that AGO1 acts positively as a coactivator in estradiol-triggered transcription regulation by promoting ERα binding to its enhancers. Consistently, AGO1 depletion decreases long-range contacts between ERα enhancers and their target promoters. Our results point to a role of AGO1 in transcriptional regulation in human cells that is independent from small RNA binding.

[Cognitive-behavioural group therapy for insomnia: evaluation of the results after its implementation in a health department]. / Terapia grupal cognitivo-conductual para el insomnio: evaluación de resultados tras su introducción en un departamento de salud.

INTRODUCTION: Cognitive-behavioural therapy (CBT) is the preferred treatment in cases of chronic insomnia disorder in adults. PATIENTS AND METHODS: Open pragmatic study of 32 patients after eight sessions of group CBT for insomnia. RESULTS: Remission (insomnia severity index: 0-7 points) and response (insomnia severity index drops to > 8) were 31.3% and 46.9% at one month (n = 32) and 42.8% and 52.4% at one year (n = 21), respectively, with an effect size of 1.9 at one month and 2.3 at one year. At one month, 40.6% met the criteria for a case of insomnia (according to the insomnia symptoms questionnaire), and at one year, 19%, with a significant improvement in the symptoms at night and the consequences during the day. The questions of the Pittsburgh Sleep Quality Index on insomnia and sleep efficiency also improved. The pre-sleep arousal scale (n = 7) showed a shift from significant somatic and cognitive arousal to no arousal at one month. In the sleep diaries, total sleep time increased by an average of 53 minutes at one month (n = 14) and 76 minutes at one year (n = 10), with an increase of more than 10% in 71.4% of patients at one month and at one year, and an average sleep efficiency of more than 85%. The effect size for total sleep time and sleep efficiency was between 0.7 and 1. CONCLUSIONS: Group CBT for insomnia appears to be an effective treatment option in a clinical setting.

TITLE: Terapia grupal cognitivo-conductual para el insomnio: evaluación de resultados tras su introducción en un departamento de salud.Introducción. La terapia cognitivo-conductual (TCC) es el tratamiento de elección en el trastorno de insomnio crónico en adultos. Pacientes y métodos. Estudio pragmático abierto de 32 pacientes tras ocho sesiones de TCC grupal para el insomnio. Resultados. La remisión (índice de gravedad del insomnio: 0-7 puntos) y la respuesta (caída del índice de gravedad del insomnio > 8) fue del 31,3% y 46,9% al mes (n = 32) y del 42,8% y 52,4% al año (n = 21), respectivamente, con un tamaño del efecto de 1,9 al mes y 2,3 al año. Al mes, el 40,6% cumplía criterios de caso de insomnio (según el cuestionario de síntomas de insomnio), y al año, el 19%, con una mejoría significativa de síntomas nocturnos y consecuencias diurnas. También mejoraron las preguntas del índice de calidad de sueño de Pittsburgh sobre el insomnio y la eficiencia del sueño. La escala de activación previa al sueño (n = 7) mostró un trasvase desde activación significativa somática y cognitiva a ausencia de activación al mes. En los diarios de sueño, el tiempo total de sueño aumentó 53 minutos de media al mes (n = 14) y 76 al año (n = 10), con un aumento superior al 10% en el 71,4% de los pacientes al mes y al año, y una eficiencia del sueño media superior al 85%. El tamaño del efecto para el tiempo total de sueño y la eficiencia del sueño estuvo entre 0,7 y 1. Conclusiones. La TCC grupal para el insomnio parece una opción terapéutica eficaz en un entorno clínico.

Utilidad de los estudios de función pulmonar en el niño / Utility of lung function tests in children

Pulmonary function testing in children includes a large number of methods and aspects. Children constitute a very heterogeneous group of individuals, among which are non-collaborative infants and preschoolers who represent a challenge in the development of new methods that do not require collaboration or coordination. This review attempts to achieve a comprehensive approach to pulmonary function tests in children that allow the physician working in pediatrics to get to know: their pathophysiological bases; the reasons for a request for a pulmonary function test taking into account the underlying pathophysiological process that is suspected; the study procedures; the possible clinical findings and their interpretation; the advantages and limitations of several of the tests. Information related to spirometry is developed more specifically, since it is the most widespread, accessible and widely validated methods.

El estudio de la función pulmonar (FP) en niños abarca un gran número de métodos y aspectos. La edad pediátrica en sí constituye un grupo muy heterogéneo de individuos, entre los que se encuentran los de edades más tempranas que son no colaborativos y que representan un desafío en el desarrollo de nuevos métodos que no requieran colaboración ni coordinación. En esta revisión se describirá un enfoque integral de los estudios de FP más utilizados en niños. Se mencionan sus bases fisiopatológicas; los motivos de un pedido de estudio de FP teniendo en cuenta el proceso fisiopatológico subyacente que se sospecha; los posibles hallazgos clínicos y su interpretación y las ventajas y limitaciones de varios de los test.

[Alternative splicing and the cure of spinal muscular atrophy]. / El splicing alternativo y la cura de la atrofia muscular espinal.

Alternative splicing of the messenger RNA plays a fundamental role in the flow of genetic information from DNA to proteins by expanding the coding capacity of the genome. The regulation of alternative splicing is as important as the regulation of transcription to determine the specific characteristics of cells and tissues, the normal functioning of cells and the responses of eukaryotic cells to external signals. Basic knowledge of the pre-mRNA sequences and splicing factors that recognize them has allowed scientists to design a therapeutic synthetic oligonucleotide for spinal muscular atrophy. This is an autosomal recessive inherited disease in which the SMN1 gene is mutated and affects one in 10,000 births. By blocking the binding of a negative splicing factor to the mRNA of a paralogue of the SMN1 gene, called SMN2, the Spinraza oligonucleotide corrects an abnormal alternative splicing event of the SMN2 gene and allows the synthesis of high levels of the SMN protein, constituting the first successful case of cure of a neurodegenerative disease.

El splicing alternativo del ácido ribonucleico mensajero (mRNA) juega un papel fundamental en el flujo de información genética desde el ADN a las proteínas al expandir la capacidad de codificación de los genomas. La regulación del splicing alternativo es tan importante como la regulación de la transcripción para determinar las características específicas de las células y los tejidos, el funcionamiento normal de las células y las respuestas de las células eucarióticas a las señales externas. El conocimiento básico de las secuencias del pre-mRNA y de los factores de splicing que las reconocen ha permitido a científicos diseñar un oligonucleótido sintético terapéutico para la atrofia muscular espinal. ésta es una enfermedad hereditaria autosómica recesiva en que el gen SMN1 se encuentra mutado y que afecta a uno de cada 10 000 nacimientos. Al bloquear la unión de un factor de splicing negativo al mRNA del gen parálogo del gen SMN1, denominado SMN2, el oligonucleótido Spinraza corrige un evento de splicing alternativo anormal del gen SMN2 y permite que se sinteticen altos niveles de la proteína SMN, constituyéndose en el primer caso exitoso de cura de una enfermedad neurodegenerativa.

Population genetic analysis of 23 Y-STR loci in Central Argentine Patagonia.

We analyzed 23 Y-STR haplotypes of 139 unrelated males from Central Argentine Patagonia. A total of 133 different haplotypes (127 singletons) were observed. Haplotype diversity was similar to that previously observed in other Argentine populations and matching probability showed a strong dependence on the sample size. AMOVA carried out with full haplotypes showed significant differences between different regions of the country. The multi-dimensional scaling plot showed Chubut sample in an intermediate position among Europe and other Patagonian populations. These results will contribute to increase the Y-chromosome haplotype reference database and constitute a useful tool for anthropological and forensic researches.

Diferenciar la apendicitis con o sin fecalito ¿puede cambiar el enfoqueterapéutico?: Resultados preliminares / Differentiating between appendicitis with or without fecalith to change the therapeutic approach: Preliminary results

Antecedentes: el manejo de los pacientes con apendicitis aguda fue clásicamente quirúrgico. En la era de los antibióticos se plantean nuevos paradigmas terapéuticos. La diferencia en el origen de la apendicitis podría establecer el tratamiento por elegir. Objetivo: analizar si la presencia de fecalito en una apendicitis puede condicionar un tratamiento quirúrgico o solo con antibióticos. Material y métodos: análisis descriptivo observacional de las diferencias intraoperatorias y anatomopatológicas de los pacientes operados por apendicitis aguda, divididos en 2 grupos según presentaran fecalito o hiperplasia linfoidea como causa de origen. Se utilizó la prueba de Chi2 para la comparación de ambos grupos, tomando un valor de p<0,05. Resultados: el grupo de apendicitis por fecalito presentó un estadio más avanzado de la enfermedad, con líquido libre con más frecuencia (el 67% de los pacientes con apendicitis aguda por fecalito vs. el 18% en el grupo de apendicitis aguda por hiperplasia), en más de una localización (solo el grupo con fecalito presentó líquido en el fondo de saco de Douglas o en el resto del abdomen, en el 50% y 16,7% respectivamente), con características que variaron entre seroso y purulento y anatomopatológicamente presentaron mayor afectación de las capas histológicas (en el grupo hiperplasia la afectación hasta la mucosa fue 63,6% vs. 16,7%, mientras que en el grupo fecalito fue más frecuente la afectación hasta la serosa 66,6% vs. 27,3%). Conclusiones: los pacientes con apendicitis aguda por hiperplasia linfoidea tendrían menos complicaciones intraabdominales en el posoperatorio y podrían ser buenos candidatos a tratamiento médico solo con antibióticos, evitando la cirugía.

Background: Surgery is the traditional approach for patients with acute appendicitis. In the antibiotic era, new therapeutic paradigms are being proposed. The difference in the cause of appendicitis could establish the treatment of choice. Objective: to analyze if the presence of fecalith in an appendicitis can condition a surgical treatment or only with antibiotics. Material and methods: This observational analysis describes the intraoperative and pathological differences between patients undergoing surgery for acute appendicitis, divided into two groups according to the presence of fecalith or lymphoid hyperplasia as cause of the condition. The chi square test was used to compare the fecalith group versus the lymphoid hyperplasia group using a p value < 0.05. Results: The presence of fecaliths was more commonly associated with advanced stage of inflammation, presence of free peritoneal fluid (67% vs. 18% in the lymphoid hyperlasia group) and in more than one site (50% in the Douglas' pouch and 16.7% in the rest of the abdominal cavity). In this group, peritoneal fluid varied between serous and purulent and more appendiceal layers were involved (63.6% of mucous layer involvement in the lymphoid hyperplasia group vs. 16.7%, while serous compromise was more common in the fecalith group: 66.6% vs. 27.3%). Conclusions: Patients with acute appendicitis due to lymphoid hyperplasia could have lower rate of post-operative complications or could be good candidates for medical treatment with antibiotics alone, avoiding surgery.