Analisi dei profili di espressione dei microRNA: identificazione di biomarker nel suicidio

MicroRNAs (miRNAs) are small non-coding RNAs playing an important role as post-transcriptional regulators of gene expression. A growing body of evidence has shown that alterations in miRNA expression pattern are associated with several pathological processes. In particular, post-mortem brain studies support miRNA involvement in the pathophysiology of psychiatric disorders but their role as peripheral biomarkers or targets of pharmacological treatments has been scarcely investigated. Our purpose was to identify potential biological correlates of suicide and to evaluate their role in the pathogenesis and pharmacotherapy of suicide. We conducted a high-throughput profiling of miRNAs in lymphoblastoid cell lines (LCLs), not-treated or treated with lithium in vitro, derived from bipolar suicide completers (S, n=7) and non-suicidal bipolar patients (NS, n=12). Global miRNA expression was measured using nCounter® miRNA expression Assay (NanoString Technologies). In total, 28 miRNAs were differentially expressed or regulated by lithium between the two groups at a false discovery rate of 0.1. Two miRNAs were validated with quantitative Real Time-PCR (qRT-PCR): miR-4286, up-regulated in non-treated LCLs from S versus NS, and miR-186-5p, down-regulated in lithium-treated LCLs from S versus NS. Treatment of human neural progenitor cells with lithium down-regulated both miRNAs. Then, we evaluated the expression of these miRNAs in post-mortem brains from 12 suicidal bipolar subjects (Sbrain) and 13 healthy controls (Cbrain), showing an under-expression of miR-4286 in Sbrain and no differences for miR-186-5p. Finally, we performed a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to clarify the possible role of the identified miRNAs in biological mechanisms involved in suicide. Results from GO analysis indicated that miR-4286 and miR-186-5p regulate the expression of key genes involved in neuronal processes as neurogenesis and synaptic plasticity. Whereas, KEGG pathway analysis showed that both miRNAs are involved in several biological pathways that could be related to suicide, such as TGF-beta signaling pathway and long-term potentiation pathway. In conclusion, our study suggests that miR-4286 and miR-186-5p could constitute potential biomarkers of suicide and be involved in the mechanism of action of lithium

An integrated single-cell analysis of human adrenal cortex development

The adrenal glands synthesize and release essential steroid hormones such as cortisol and aldosterone, but many aspects of human adrenal gland development are not well understood. Here, we combined single-cell and bulk RNA sequencing, spatial transcriptomics, IHC, and micro-focus computed tomography to investigate key aspects of adrenal development in the first 20 weeks of gestation. We demonstrate rapid adrenal growth and vascularization, with more cell division in the outer definitive zone (DZ). Steroidogenic pathways favored androgen synthesis in the central fetal zone, but DZ capacity to synthesize cortisol and aldosterone developed with time. Core transcriptional regulators were identified, with localized expression of HOPX (also known as Hop homeobox/homeobox-only protein) in the DZ. Potential ligand-receptor interactions between mesenchyme and adrenal cortex were seen (e.g., RSPO3/LGR4). Growth-promoting imprinted genes were enriched in the developing cortex (e.g., IGF2, PEG3). These findings reveal aspects of human adrenal development and have clinical implications for understanding primary adrenal insufficiency and related postnatal adrenal disorders, such as adrenal tumor development, steroid disorders, and neonatal stress

Pathogenic variants in the human m(6)A reader YTHDC2 are associated with primary ovarian insufficiency

Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: C. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosisassociated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377*variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI

Guidelines on the diagnosis, treatment and management of visceral and renal arteries aneurysms: a joint assessment by the Italian Societies of Vascular and Endovascular Surgery (SICVE) and Medical and Interventional Radiology (SIRM)

: The objective of these Guidelines is to provide recommendations for the classification, indication, treatment and management of patients suffering from aneurysmal pathology of the visceral and renal arteries. The methodology applied was the GRADE-SIGN version, and followed the instructions of the AGREE quality of reporting checklist. Clinical questions, structured according to the PICO (Population, Intervention, Comparator, Outcome) model, were formulated, and systematic literature reviews were carried out according to them. Selected articles were evaluated through specific methodological checklists. Considered Judgments were compiled for each clinical question in which the characteristics of the body of available evidence were evaluated in order to establish recommendations. Overall, 79 clinical practice recommendations were proposed. Indications for treatment and therapeutic options were discussed for each arterial district, as well as follow-up and medical management, in both candidate patients for conservative therapy and patients who underwent treatment. The recommendations provided by these guidelines simplify and improve decision-making processes and diagnostic-therapeutic pathways of patients with visceral and renal arteries aneurysms. Their widespread use is recommended

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Cambios en la conducta del consumidor en época de pandemia y el gran reto del marketing para retener a los clientes de la ciudad de Cuenca, Ecuador

El presente estudio tiene como propósito analizar el cambio del comportamiento del consumidor cuencano ocasionado por el COVID-19 debido a las repercusiones en la salud y economía generadas por el mismo, ante esto es imprescindible conocer cuál es el reto del marketing para retener a los clientes ya que, es uno de los aliados para las empresas frente a la constante disminución de los ingresos.The purpose of this study is to analyze the change in consumer behavior in Cuenca caused by COVID-19 due to the repercussions on health and economy generated by it, given this, it is essential to know what the marketing challenge is to retain customers since, it is one of the allies for companies facing the constant decrease in income

Cosmetic surgery: medicolegal considerations

Cosmetic surgery is one of the two branches of plastic surgery. The characteristic of non-necessity of this surgical speciality implies an increased severity in the evaluation of the risk-benefit balance. Therefore, great care must be taken in providing all the information necessary in order to obtain valid consent to the intervention. The receipt of valid, informed consent is of absolute importance not only to legitimise the medical- surgical act, but it also represents the key element in the question concerning the existence of an obligation to achieve certain results/use of certain methods in the cosmetic surgery

Voluntary termination of pregnancy (medical or surgical abortion): forensic medicine issues

In Italy, Law 194 of 22 May 1978 provides for and regulates the voluntary termination of pregnancy (VTP). Medical abortion became popular nationwide after Mifepristone (RU-486) was authorized for the market by AIFA (Italian Drug Agency) in July 2009. We searched articles in medical literature database with these terms: “medical abortion”, “RU486”, “surgical abortion”. We also searched laws and judgments concerning abortion in national legal databases. Ministerial guidelines were searched on official website of Italian Ministry of Health. We found many medical studies about medical and surgical abortion. We found also ministerial and regional guidelines, which were analyzed. From the point of view of legal medicine, the issues related to abortion with the pharmacological method consist in verifying compatibility and consistency with the safety principles and the parameters imposed by Law n. 194 of 1978, using off-label Misoprostol, what inpatient care should be used and informed consent. The doctor’s job is to provide the patient with comprehensive and clear information about how the procedure will be performed, any complications and the time period needed for both procedures

Voluntary termination of pregnancy (medical or surgical abortion): forensic medicine issues

In Italy, Law 194 of 22 May 1978 provides for and regulates the voluntary termination of pregnancy (VTP). Medical abortion became popular nationwide after Mifepristone (RU-486) was authorized for the market by AIFA (Italian Drug Agency) in July 2009. From the point of view of legal medicine, the issues related to abortion with the pharmacological method consist in verifying compatibility and consistency with the safety principles and the parameters imposed by Law n. 194 of 1978, using off-label Misoprostol, what inpatient care should be used and informed consent. The doctor’s job is to provide the patient with comprehensive and clear information about how the procedure will be performed, any complications and the time period needed for both procedures