Age-Related Differences in the Expression of Most Relevant Mediators of SARS-CoV-2 Infection in Human Respiratory and Gastrointestinal Tract

Background: Clinical features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seem to differ in children compared to that in adults. It has been hypothesized that the lower clinical severity in children could be influenced by differential expression of the main host functional receptor to SARS-CoV-2, the angiotensin-converting enzyme 2 (ACE2), but data are still conflicting. To explore the origin of age-dependent clinical features of coronavirus disease 2019 (COVID-19), we comparatively evaluated the expression in children and adult subjects of the most relevant mediators of the SARS-CoV-2 infection: ACE2, angiotensin-converting enzyme 1 (ACE1), transmembrane serine protease-2 (TMPRSS2), and neuropilin-1 (NRP1), at upper respiratory tract and small intestine level. Methods: The expression of ACE2, ACE1, TMPRSS2, and NRP1 in nasal epithelium and in small intestine epithelium was investigated by quantitative real-time PCR analysis. Results: We found no differences in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium comparing children and adult subjects. In contrast, nasal epithelium NRP1 expression was lower in children compared to that in adults. Intestinal ACE2 expression was higher in children compared to that in adults, whereas intestinal ACE1 expression was higher in adults. Intestinal TMPRSS2 and NRP1 expression was similar comparing children and adult subjects. Conclusions: The lower severity of SARS-CoV-2 infection observed in children may be due to a different expression of nasal NRP1, that promotes the virus interaction with ACE2. However, the common findings of intestinal symptoms in children could be due to a higher expression of ACE2 at this level. The insights from these data will be useful in determining the treatment policies and preventive measures for COVID-19

Comparative Evaluation of Nasal and Small Intestine Expression of ACE2, TMPRSS2 and ACE1 and in Children and in Adults

Importance: Clinical severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seems to be lower in children compared to that in adults. Defining the pathophysiological mechanisms of such disease patterns maybe relevant for development of effective public health strategies. It has been hypothesised that the lower severity of SARS-CoV-2 infection in children could be due to the differential expression of angiotensin-converting enzyme 2 (ACE2), which serves as a virus receptor. Objective: To evaluate the expression of ACE2, ACE1, and TMPRSS2 genes at the level of the two most relevant entry sites for SARS-CoV-2, the upper respiratory tract and small intestine, in healthy children and adult subjects. Design, Setting, and Participants: This prospective study included healthy individuals of both sexes, aged 1-10 years in the paediatric population (n=30) and 20-80 years in the adult population (n=30). The participants were consecutively evaluated at two tertiary centres for paediatrics, gastroenterology, and otolaryngology. Main Measures: Expression of ACE2, ACE1, and TMPRSS2 genes in samples collected from the upper respiratory tract and small intestine. Results: We found no difference in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium between children and adult subjects. ACE2 expression was more abundant in the small intestine of children compared to that in adults. ACE1 expression was higher in the small intestine of adults compared to that in children. Intestinal TMPRSS2 expression was similar in the two study populations. Conclusions and Relevance: The general lower severity of SARS-CoV-2 infection in children does not seem to be related to a lower expression of ACE2 and/or TMPRSS2 in the respiratory tract or in the gastrointestinal tract. Other co-factors may confer protection against SARS-CoV-2 in children. The exploration of such factors is of pivotal importance for development of innovative protective strategies against SARS-CoV-2. Funding Statement: This work was supported in part by a grant of Regione Campania POR FESR 2014/2020, Task Force Covid-19 DGR 140 – 17 March 2020. Declaration of Interests: The authors have no other conflict of interests that are directly relevant to the content of this manuscript, which remains their sole responsibility. Ethics Approval Statement: The study was approved by the Ethics Committee of the University Federico II of Naples, Italy. Written informed consent was obtained from the adult participants and from the parents/tutors of minors

Insulin Resistance in Women Correlates with Chromatin Histone Lysine Acetylation, Inflammatory Signaling, and Accelerated Aging

BackgroundEpigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top "hit" was chromatin opening at H3K9ac.MethodsBuilding on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women.ResultsChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women.ConclusionsThis study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer

Insulin Resistance in Women Correlates with Chromatin Histone Lysine Acetylation, Inflammatory Signaling, and Accelerated Aging

BACKGROUND: Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top hit was chromatin opening at H3K9ac. METHODS: Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women. RESULTS: ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women. CONCLUSIONS: This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Clara: mujer y marginalidad Proposta di traduzione di una parte di Hay que sonreir di Luisa Valenzuela

Il mio lavoro di tesi magistrale si propone di presentare la figura di Luisa Valenzuela, rinomata scrittrice argentina, e la traduzione di una parte del suo primo romanzo, Hay que sonreír. In un capitolo introduttivo ho fornito alcuni dati circa la vita e la produzione letteraria della scrittrice, focalizzando l’attenzione sui principali aspetti della sua scrittura. In un ulteriore capitolo, ho fornito un’analisi del romanzo oggetto della mia traduzione concentrando lo sguardo sulla voce narrante e sulla struttura tripartita del romanzo. Infine, l’ultima parte di tesi prevede il commento alla traduzione del romanzo di Luisa Valenzuela. In esso ho scelto di presentare le principali soluzioni traduttive e ho dedicato parte del commento alle caratteristiche linguistiche e morfosintattiche del romanzo, in particolare, i culturemi. Questi ultimi sono elementi culturali specifici di una lingua e, pertanto, sono difficilmente traducibili in una diversa lingua e cultura o, a volte, non possiedono elementi equivalenti nella cultura e lingua d’arrivo. Il mio approccio ad essi è stato differente in vari punti della traduzione e ho scelto di classificarli nel commento, secondo il modello della studiosa Lucía Molina, in quattro categorie: elementi naturali, il patrimonio culturale, cultura sociale e cultura linguistica

Protein engineering of multi-modular transcription factor alcohol dehydrogenase repressor 1 (adr1p), a tool for dissecting in vitro transcription activationviocyte co-culture system

Studying transcription machinery assembly in vitro is challenging because of long intrinsically disordered regions present within the multi-modular transcription factors. One example is alcohol dehydrogenase repressor 1 (Adr1p) from fermenting yeast, responsible for the metabolic switch from glucose to ethanol. The role of each individual transcription activation domain (TAD) has been previously studied, but their interplay and their roles in enhancing the stability of the protein is not known. In this work, we designed five unique miniAdr1 constructs containing either TADs I-II-III or TAD I and III, connected by linkers of different sizes and compositions. We demonstrated that miniAdr1-BL, containing only PAR-TAD I+III with a basic linker (BL), binds the cognate DNA sequence, located in the promoter of the ADH2 (alcohol dehydrogenase 2) gene, and is necessary to stabilize the heterologous expression. In fact, we found that the sequence of the linker between TAD I and III affected the solubility of free miniAdr1 proteins, as well as the stability of their complexes with DNA. miniAdr1-BL is the stable unit able to recognize ADH2 in vitro, and hence it is a promising tool for future studies on nucleosomal DNA binding and transcription machinery assembly in vitro

Application of Biobased Solvents in Asymmetric Catalysis

The necessity of more sustainable conditions that follow the twelve principles of Green Chemistry have pushed researchers to the development of novel reagents, catalysts and solvents for greener asymmetric methodologies. Solvents are in general a fundamental part for developing organic processes, as well as for the separation and purification of the reaction products. By this reason, in the last years, the application of the so-called green solvents has emerged as a useful alternative to the classical organic solvents. These solvents must present some properties, such as a low vapor pressure and toxicity, high boiling point and biodegradability, and must be obtained from renewable sources. In the present revision, the recent application of these biobased solvents in the synthesis of optically active compounds employing different catalytic methodologies, including biocatalysis, organocatalysis and metal catalysis, will be analyzed to provide a novel tool for carrying out more ecofriendly organic processes

Hb(\u3b1\u3b1,\u3b2\u3b2): a novel fusion construct for a dimeric, four domain hemoglobin

Hemoglobin-based blood substitutes are one of the options available to derive a resuscitating fluid taking into account clinical and physiological demands. In this paper we investigated a novel protein, Hb(\u3b1\u3b1,\u3b2\u3b2) obtained as a combination of two homodimers \u3b12 and \u3b22 both derived from a fusion gene containing two alfa chains or two beta chains respectively coupled via a specific linker. The construct here described is thus a novel heterodimeric hemoglobin carrying four heme groups. The protein cannot dissociate into dimers, as demonstrated by its absence of reactivity versus haptoglobin, and is expected to have a relatively long circulating half-life. The modification does not increase the autoxidation rate, but increases the oxygen affinity, due to a destabilization of the T quaternary state. Characterization of the biochemical properties of this protein in comparison with HbA is reported