An Approach to Acute SARS-CoV-2 Management with Complementary Neuraltherapeutic Medicine: A Case Report.

Background: It has been proposed that the immunomodulatory capacity of neuraltherapeutic medicine (NTM) functions by means of stimuli to the nervous system, which influences the self-regulatory and plastic capacity of the nervous system, especially through the autonomic balance between the sympathetic and parasympathetic nervous systems. Several studies report the usefulness of NTM in inflammatory pathologies. Case presentation: A case report through a retrospective review of the medical history of an 82-year-old male patient with a diagnosis of acute SARS-CoV-2 who received a therapeutic intervention of NTM at the beginning of his hospitalization and presented satisfactory clinical evolution, with a follow-up for 18 months without post-COVID sequelae. A patient diagnosed with acute pneumonia for SARS-CoV-2, and mild ARDS, with markers of severity given by the history of COPD, advanced age, and elevation of LDH, ferritin, and CRP. On the third day of hospitalization, he presented an episode of pulmonary thromboembolism. He presented significant clinical improvement with in-hospital management for 9 days and underwent out-patient control with no post-COVID sequelae. Conclusions: NTM could be useful for the management of acute inflammatory diseases, including viral diseases such as SARS-CoV-2, in a mild or severe state of inflammation, when added to allopathic medicine, and it can improve clinical evolution and long-term sequelae. More studies are needed to validate this information.

Environmental Factors Modulate the Role of orf21 Sigma Factor in Clavulanic Acid Production in Streptomyces Clavuligerus ATCC27064.

Sigma factors and sigma factor-related mechanisms control antibiotic production in Streptomyces. In this contribution, the orf21 gene was overexpressed in the wild-type strain of Streptomyces clavuligerus ATCC2764, yielding S. clavuligerus/pIORF21, to further evaluate its regulatory effect on clavulanic acid (CA) biosynthesis under different culture medium conditions. The orf21 overexpression, regulated under the constitutive promoter ermE*, led to 2.6-fold increase in CA production in GSPG medium, and a 1.8-fold decrease using ISP medium. As for GYM and MYM media, S. clavuligerus/pIORF21 strain showed higher aerial mycelium production compared to control. Glycerol uptake rate profile was affected by orf21 overexpression. Furthermore, in GSPG, S. clavuligerus/pIORF21 slightly increased the expression of adpA and gcas genes, whilst, in ISP, the claR gene expression was drastically reduced, which is consistent with a decreased CA production, observed in this medium. These findings suggest the protein encoded by the orf21 gene plays a role in the regulation of CA biosynthesis as a response to the nutritional composition of the medium.

Hypoxia Signaling in Parkinson's Disease: There Is Use in Asking "What HIF?"

Hypoxia is a condition characterized by insufficient tissue oxygenation, which results in impaired oxidative energy production. A reduction in cellular oxygen levels induces the stabilization of hypoxia inducible factor α (HIF-1α), master regulator of the molecular response to hypoxia, involved in maintaining cellular homeostasis and driving hypoxic adaptation through the control of gene expression. Due to its high energy requirement, the brain is particularly vulnerable to oxygen shortage. Thus, hypoxic injury can cause significant metabolic changes in neural cell populations, which are associated with neurodegeneration. Recent evidence suggests that regulating HIF-1α may ameliorate the cellular damage in neurodegenerative diseases. Indeed, the hypoxia/HIF-1α signaling pathway has been associated to several processes linked to Parkinson's disease (PD) including gene mutations, risk factors and molecular pathways such as mitochondrial dysfunction, oxidative stress and protein degradation impairment. This review will explore the impact of hypoxia and HIF-1α signaling on these specific molecular pathways that influence PD development and will evaluate different novel neuroprotective strategies involving HIF-1α stabilization.

Comparative Analysis of Strategies for De Novo Transcriptome Assembly in Prokaryotes: Streptomyces clavuligerus as a Case Study.

The performance of software tools for de novo transcriptome assembly greatly depends on the selection of software parameters. Up to now, the development of de novo transcriptome assembly for prokaryotes has not been as remarkable as that for eukaryotes. In this contribution, Rockhopper2 was used to perform a comparative transcriptome analysis of Streptomyces clavuligerus exposed to diverse environmental conditions. The study focused on assessing the incidence of software parameters on software performance for the identification of differentially expressed genes as a final goal. For this, a statistical optimization was performed using the Transrate Assembly Score (TAS). TAS was also used for evaluating the software performance and for comparing it with related tools, e.g., Trinity. Transcriptome redundancy and completeness were also considered for this analysis. Rockhopper2 and Trinity reached a TAS value of 0.55092 and 0.58337, respectively. Trinity assembles transcriptomes with high redundancy, with 55.6% of transcripts having some duplicates. Additionally, we observed that the total number of differentially expressed genes (DEG) and their annotation greatly depends on the method used for removing redundancy and the tools used for transcript quantification. To our knowledge, this is the first work aimed at assessing de novo assembly software for prokaryotic organisms.

Comparative Transcriptome Analysis of Streptomyces Clavuligerus in Response to Favorable and Restrictive Nutritional Conditions.

Background: Clavulanic acid (CA), a ß-lactamase inhibitor, is industrially produced by the fermentation of Streptomyces clavuligerus. The efficiency of CA production is associated with media composition, culture conditions and physiological and genetic strain characteristics. However, the molecular pathways that govern CA regulation in S. clavuligerus remain unknown. Methods and Results: Here we used RNA-seq to perform a comparative transcriptome analysis of S. clavuligerus ATCC 27064 wild-type strain grown in both a favorable soybean-based medium and in limited media conditions to further contribute to the understanding of S. clavuligerus metabolism and its regulation. A total of 350 genes were found to be differentially expressed between conditions; 245 genes were up-regulated in favorable conditions compared to unfavorable. Conclusion: The up-regulated expression of many regulatory and biosynthetic CA genes was positively associated with the favorable complex media condition along with pleiotropic regulators, including proteases and some genes whose biological function have not been previously reported. Knowledge from differences between transcriptomes from complex/defined media represents an advance in the understanding of regulatory paths involved in S. clavuligerus' metabolic response, enabling the rational design of future experiments.

An enhanced genome-scale metabolic reconstruction of Streptomyces clavuligerus identifies novel strain improvement strategies.

In this work, we expanded and updated a genome-scale metabolic model of Streptomyces clavuligerus. The model includes 1021 genes and 1494 biochemical reactions; genome-reaction information was curated and new features related to clavam metabolism and to the biomass synthesis equation were incorporated. The model was validated using experimental data from the literature and simulations were performed to predict cellular growth and clavulanic acid biosynthesis. Flux balance analysis (FBA) showed that limiting concentrations of phosphate and an excess of ammonia accumulation are unfavorable for growth and clavulanic acid biosynthesis. The evaluation of different objective functions for FBA showed that maximization of ATP yields the best predictions for cellular behavior in continuous cultures, while the maximization of growth rate provides better predictions for batch cultures. Through gene essentiality analysis, 130 essential genes were found using a limited in silico media, while 100 essential genes were identified in amino acid-supplemented media. Finally, a strain design was carried out to identify candidate genes to be overexpressed or knocked out so as to maximize antibiotic biosynthesis. Interestingly, potential metabolic engineering targets, identified in this study, have not been tested experimentally.

Evaluación probabilista de la dinámica cardiaca arrítmica con y sin metoprolol / Probabilistic evaluation of arrhythmic cardiac dynamics with and without metoprolol

Resumen Introducción: A partir de la teoría de los sistemas dinámicos y de la teoría de la probabilidad se han desarrollado metodologías altamente sensibles de aplicación clínica que permiten diferenciar normalidad, enfermedad y evolución hacia la enfermedad cardiaca. Métodos: Se seleccionaron los registros Holter de siete casos normales y 73 con diagnóstico de arritmia con y sin tratamiento terapéutico de metoprolol. Se aplicaron medidas de probabilidad establecidas previamente para evaluar la frecuencia cardiaca máxima, mínima y promedio, así como el número de latidos por hora. Resultados: Casi la mitad de los casos con arritmias y sin tratamiento presentaron medidas matemáticas de enfermedad y de evolución hacia la enfermedad, mientras que en el grupo con tratamiento con metoprolol, tres cuartas partes cumplieron con estas características. Conclusiones: Se lograron distinciones matemáticas más objetivas entre dinámicas cardiacas tratadas con y sin metoprolol, las cuales pueden ser de gran utilidad para realizar seguimiento individual.

Abstract Introduction: Based on the theory of dynamic systems and probability theory, highly sensitive clinical methodologies have been developed to differentiate normality, disease and evolution towards cardiac disease. Methods: Holter recordings, 7 normal and 73 with arrhythmia diagnosis with and without therapeutic treatment of Metoprolol, were selected. Probability measures, established in a previous work, were applied for assessing maximum, minimal and average heart rate and beats per hour. Results: It was found that almost a half of the cases with arrhythmias without beta-blocker therapy exhibited mathematical measures of illness and evolution towards disease, whereas in the treatment group with Metoprolol, three quarters accomplished these features. Conclusions: More objective mathematical distinctions were achieved between cardiac dynamics treated with and without metoprolol, which is very useful for individual follow-up.

Los aportes de Henry Head a las basesneuroanatómicas y fisiológicas de la terapia de segmento / The contributions of Henry Head to neuroanatomical and physiological bases of therapy segment

Henry Head, neurólogo británico, ha pasado a la historia de la medicina occidental por su contribución a la creación de los mapas de dermatomas. Una modalidad terapéutica dentro de la medicina neuralterapéutica es la terapia de segmento y, dentro del estudio del marco de sustentación teórica y experimental de su utilidad se encuentra este artículo. Las hipótesis planteadas por Head en cuanto a la asociación e interrelación de sensibilidad cutánea y visceral, pueden constituirse en un aporte para las bases neuroanatómicas y fisiológicas de la neuralterapia y la medicina en general. Se realiza una revisión histórica de una parte de su trabajo menos difundida, dedicada al dolor referido en la enfermedad visceral y en los cambios mentales asociados a la misma...

Henry Head, a British neurologist, carved a name for himself in the Western Medicine Annals for his contribution to the creation of dermatome maps. Segment therapy stands as one of the therapeutic modalities making up neural-therapeutic medicine, and this paper is within the theoretical and experimental support frame of the study of its utilization. The hypotheses proposed by Head in terms of association and interrelation of cutaneous and visceral sensitivity can be deemed as a contribution to the neural-anatomic physiologic grounds for not only neural-therapy, but also general medicine. This paper constitutes a historic review of one of the least known parts of his work, devoted to visceral-disease-referred pain and visceral-disease-associated mental changes...