MEA-NAP compares microscale functional connectivity, topology, and network dynamics in organoid or monolayer neuronal cultures.

Microelectrode array (MEA) recordings are commonly used to compare firing and burst rates in neuronal cultures. MEA recordings can also reveal microscale functional connectivity, topology, and network dynamics-patterns seen in brain networks across spatial scales. Network topology is frequently characterized in neuroimaging with graph theoretical metrics. However, few computational tools exist for analyzing microscale functional brain networks from MEA recordings. Here, we present a MATLAB MEA network analysis pipeline (MEA-NAP) for raw voltage time-series acquired from single- or multi-well MEAs. Applications to 3D human cerebral organoids or 2D human-derived or murine cultures reveal differences in network development, including topology, node cartography, and dimensionality. MEA-NAP incorporates multi-unit template-based spike detection, probabilistic thresholding for determining significant functional connections, and normalization techniques for comparing networks. MEA-NAP can identify network-level effects of pharmacologic perturbation and/or disease-causing mutations and, thus, can provide a translational platform for revealing mechanistic insights and screening new therapeutic approaches.

Extracellular Vesicles as Drug Delivery Systems in Organ Transplantation: The Next Frontier.

Extracellular vesicles are lipid bilayer-delimited nanoparticles excreted into the extracellular space by all cells. They carry a cargo rich in proteins, lipids and DNA, as well as a full complement of RNA species, which they deliver to recipient cells to induce downstream signalling, and they play a key role in many physiological and pathological processes. There is evidence that native and hybrid EVs may be used as effective drug delivery systems, with their intrinsic ability to protect and deliver a functional cargo by utilising endogenous cellular mechanisms making them attractive as therapeutics. Organ transplantation is the gold standard for treatment for suitable patients with end-stage organ failure. However, significant challenges still remain in organ transplantation; prevention of graft rejection requires heavy immunosuppression and the lack of donor organs results in a failure to meet demand, as manifested by growing waiting lists. Pre-clinical studies have demonstrated the ability of EVs to prevent rejection in transplantation and mitigate ischemia reperfusion injury in several disease models. The findings of this work have made clinical translation of EVs possible, with several clinical trials actively recruiting patients. However, there is much to be uncovered, and it is essential to understand the mechanisms behind the therapeutic benefits of EVs. Machine perfusion of isolated organs provides an unparalleled platform for the investigation of EV biology and the testing of the pharmacokinetic and pharmacodynamic properties of EVs. This review classifies EVs and their biogenesis routes, and discusses the isolation and characterisation methods adopted by the international EV research community, before delving into what is known about EVs as drug delivery systems and why organ transplantation represents an ideal platform for their development as drug delivery systems.

Meta-Analysis of Heifer Traits Identified Reproductive Pathways in Bos indicus Cattle.

Fertility traits measured early in life define the reproductive potential of heifers. Knowledge of genetics and biology can help devise genomic selection methods to improve heifer fertility. In this study, we used ~2400 Brahman cattle to perform GWAS and multi-trait meta-analysis to determine genomic regions associated with heifer fertility. Heifer traits measured were pregnancy at first mating opportunity (PREG1, a binary trait), first conception score (FCS, score 1 to 3) and rebreeding score (REB, score 1 to 3.5). The heritability estimates were 0.17 (0.03) for PREG1, 0.11 (0.05) for FCS and 0.28 (0.05) for REB. The three traits were highly genetically correlated (0.75-0.83) as expected. Meta-analysis was performed using SNP effects estimated for each of the three traits, adjusted for standard error. We identified 1359 significant SNPs (p-value < 9.9 × 10-6 at FDR < 0.0001) in the multi-trait meta-analysis. Genomic regions of 0.5 Mb around each significant SNP from the meta-analysis were annotated to create a list of 2560 positional candidate genes. The most significant SNP was in the vicinity of a genomic region on chromosome 8, encompassing the genes SLC44A1, FSD1L, FKTN, TAL2 and TMEM38B. The genomic region in humans that contains homologs of these genes is associated with age at puberty in girls. Top significant SNPs pointed to additional fertility-related genes, again within a 0.5 Mb region, including ESR2, ITPR1, GNG2, RGS9BP, ANKRD27, TDRD12, GRM1, MTHFD1, PTGDR and NTNG1. Functional pathway enrichment analysis resulted in many positional candidate genes relating to known fertility pathways, including GnRH signaling, estrogen signaling, progesterone mediated oocyte maturation, cAMP signaling, calcium signaling, glutamatergic signaling, focal adhesion, PI3K-AKT signaling and ovarian steroidogenesis pathway. The comparison of results from this study with previous transcriptomics and proteomics studies on puberty of the same cattle breed (Brahman) but in a different population identified 392 genes in common from which some genes-BRAF, GABRA2, GABR1B, GAD1, FSHR, CNGA3, PDE10A, SNAP25, ESR2, GRIA2, ORAI1, EGFR, CHRNA5, VDAC2, ACVR2B, ORAI3, CYP11A1, GRIN2A, ATP2B3, CAMK2A, PLA2G, CAMK2D and MAPK3-are also part of the above-mentioned pathways. The biological functions of the positional candidate genes and their annotation to known pathways allowed integrating the results into a bigger picture of molecular mechanisms related to puberty in the hypothalamus-pituitary-ovarian axis. A reasonable number of genes, common between previous puberty studies and this study on early reproductive traits, corroborates the proposed molecular mechanisms. This study identified the polymorphism associated with early reproductive traits, and candidate genes that provided a visualization of the proposed mechanisms, coordinating the hypothalamic, pituitary, and ovarian functions for reproductive performance in Brahman cattle.

Patología pulmonar obstructiva incipiente: relación entre capacidad vital forzada y curva flujo volumen / Incipient obstructive pulmonar disease: relation between forced vital capacity and flow volumen curve

Se revisan y correlacionan 92 pacientes a los cuales se les practicó capacidad vital forzada (CVF) y curva flujo volumen (VV). Como veremos en el análisis de los diferentes parámetros, concluimos que la CVF constituye una prueba confiable para determinar enfermedad pulmonar obstructiva incipiente

Los objetivos de la educación médica / The objectives of medical education

The author supports the thesis that it is important to train a physician who, above all, knows the fundamentals of medicine and knows how to apply them in a wise and disciplined manner as the occasion demands; who, with critical acumen, according to the signs and symptoms of the case, knows how to make use of laboratory data or information from clinical books and periodicals; who knows how to convey his ideas and his experience to the patient and his relatives, to the nurse and the others who work closely with him, and to an assembly of experts on matters of his specialty; and who, further, is understanding, generous, and sensitive to the suffering of others; who knows the duties inherent in his profession and who, finally, is a citizen par excellence and, for that very reason, is willing to put his talent and his energy at the service of his neighbors and fellow citizens. More than a mere file cabinet of information, news, details, and knowledge - which will always be limited in relation to the growing accumulation of medical knowledge - he must be a cultivated, capable person, abreast of the general progress of medicine and willing to fill all lacunae he may encounter in the performance of his professional duties

Los objetivos de la educación médica / The objectives of medical education

The author supports the thesis that it is important to train a physician who, above all, knows the fundamentals of medicine and knows how to apply them in a wise and disciplined manner as the occasion demands; who, with critical acumen, according to the signs and symptoms of the case, knows how to make use of laboratory data or information from clinical books and periodicals; who knows how to convey his ideas and his experience to the patient and his relatives, to the nurse and the others who work closely with him, and to an assembly of experts on matters of his specialty; and who, further, is understanding, generous, and sensitive to the suffering of others; who knows the duties inherent in his profession and who, finally, is a citizen par excellence and, for that very reason, is willing to put his talent and his energy at the service of his neighbors and fellow citizens. More than a mere file cabinet of information, news, details, and knowledge - which will always be limited in relation to the growing accumulation of medical knowledge - he must be a cultivated, capable person, abreast of the general progress of medicine and willing to fill all lacunae he may encounter in the performance of his professional duties

Publicado en inglés con el título "The Objectives of Undergraduate Medical Education" en el Journal of Medical Education 35:895-902, 1960