Hematopoietic Stem/Progenitor Cells Express Functional Mitochondrial Energy-Dependent Cystic Fibrosis Transmembrane Conductance Regulator

Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine. Cystic fibrosis (CF) is one of the diseases whose hope of cure relies on the successful application of cell-based gene therapy. This study was aimed at characterizing murine HSPCs on the basis of their bioenergetic competence and CF transmembrane conductance regulator (CFTR) expression. Positively immunoselected Sca-1(+) HSPCs encompassed 2 populations distinguished by their different size, Sca-1 expression and mitochondrial content. The smaller were the cells, the higher was Sca-1 expression and the lower was the intracellular density of functional mitochondria. Reverse transcription-polymerase chain reaction and western blotting revealed that HSPCs expressed CFTR mRNA and protein, which was also functional, as assessed by spectrofluorimetric and patch-clamp techniques. Inhibition of mitochondrial oxidative phosphorylation by oligomycin resulted in a 70% decrease of both the intracelluar adenosine triphosphate content and CFTR-mediated channel activity. Finally, HSPCs with lower Sca-1 expression and higher mitochondrial content displayed higher CFTR levels. Our findings identify 2 subpopulations in HSPCs and unveil a so-far unappreciated relationship between bioenergetic metabolism and CFTR in HSPC biology

Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Identity and externalities toward sustainability

This chapter describes a case study referring to a project named DIscourse in COmmunity of practices through TEcnologies (DI.CO.TE.)1. The project takes place in Southern Italy from 2009 through 2012; it involves 60 Small and Medium Enterprises (SMEs). Within a psychological point of view and a socio-constructivist approach, the main scope of the project is to introduce "externality" as a concept able to introduce and develop innovative practices for SMEs for environmental, economic, and social sustainability. Two focus group discussions involving 14 entrepreneurs and 106 questionnaires administered to employees were analyzed to explore various parameters of externalities, such as: (1) how externality is conceived; (2) the interplay between a sense of community and a re-definition and negotiation of identity; (3) the role of technology; the sense of belonging, and (4) the propensity to collaborate. Data are analyzed through both thematic discourse analysis and quantitative frequencies analysis. Results show that entrepreneurs hold a multidimensional definition of externality, meditated by their professional and private experience. Ultimately, the reflection on externalities sustains a sense of innovation connected to multi-membership and to re-negotiation of the sense of identity. Within this framework, technology is conceived as a tool supporting the appropriation and sharing of externalities. © 2012, IGI Global

CONFRONTO TRA PRAVASTATINA E DIETA NEL TRATTAMENTO DELLE IPERCOLESTEROLEMIE. [Comparison of pravastatin and diet in the treatment of hypercholesterolemia].

Abstract Aim of this study is to point out a correct therapy for the treatment of poligenic hypercholesterolemia resistant to dietetic treatment. There have been studied 40 patients which, after repeated haematochemical controls, resulted affected by dyslipidaemia with prevalent increase of the cholesterol levels. After 30 days of standard hypo-caloric dietetic treatment were enrolled 23 patients, 13 males and 10 females, who presented a plasmatic cholesterol level superior to 250 mg% and LDL superior to 160 mg%. All the patients continued the dietetic treatment; 10 patients began pravastatin therapy at a dose of 20 mg/die while to the rest of them was given placebo. The 30th, 60th, 120th day were controlled the following haematochemical parameters: lipidic frame haematology, hepatic and renal function, glycemia and CPK. After 4 months of treatment the average plasmatic levels of cholesterol resulted different in the two groups: mg% (p < 0.001) in the pravastatin group and 262 mg% (P = ns) in the control group. Then, the pravastatin therapy was suspended and all 23 patients continued for 30 days, dietetic treatment and placebo. After 6 months a new control of the lipidic frame was performed. Our results showed that the hypocholesterolic therapy must be continued for ever. In fact, the suspension of the treatment is followed by an immediate rebound of the dislipidaemia which plasmatic cholesterol levels even superior to the basic levels with probable negative repercussion on the cardiovascular syste

[Evaluation of diastolic function of in patients addicted to recreational cocaine].

Abstract BACKGROUND AND AIMS: The recreational use of cocaine is associated with cardiovascular pathologies, such as ischemic cardiopathy, myocarditis and cardiomyopathies, owing to the increased catecholamine stimulus, a propensity to coronary spasm, increased coagulative activity and inflammatory and degenerative phenomena of myocardiac cells. Early alterations of the diastolic phase may be visualised by evaluating the diastolic Doppler pattern of left ventricular filling. METHODS: For this purpose the authors compared blood pressure, heart rate, heart mass, protodiastolic (E wave) and telediastolic (A wave) filling rate and their ratio (E/A) on the Dopper mitral diastolic profile in a group of 10 patients addicted to the recreational use of cocaine (mean age 33 +/- 7) with those of 10 normal subjects (mean age 34 +/- 2). RESULTS: Patients using cocaine presented mean systolic arterial blood pressures of 130 +/- 12 versus 127 +/- 8 in control subjects (p = ns); mean heart rate was statistically significant with 98 +/- 14 versus 76 +/- 12 in controls (p < 0.05). There were no differences in cardiac mass between the two groups. In cocaine addicts the speed of the E wave was significantly slower: 58.4 +/- 8.6 versus 73 +/- 7.4 cm/sec (p < 0.05), and the speed of the A wave was significantly higher: 70.5 +/- 10.5 versus 62.6 +/- 4.3 cm/sec (p < 0.05), when compared with normal controls subjects; the E/A ratio of cocaine addicts was lower (0.75 +/- 0.34) compared to normal subjects (1.07 +/- 0.7), (p < 0.05). CONCLUSIONS: These data show that patients addicted to the recreational use of cocaine show preclinical alterations of the left ventricular diastolic phase prior to the onset of clinically evident pathologie

Heparin treatment and resolution of left ventricular thrombosis.

Abstract In a 70-year-old man admitted to our hospital because of repeated episodes of transient disorientation, an ECG showed a recent inferior myocardial infarction. A two-dimensional echocardiography detected hypo-akinesia in the apex region, where a hyperechogenic oval and pedunculated mass with a maximum diameter of 1.5 cm, attributable to an organized thrombus, was located. After 20 days of therapy with calcium-heparin at a dose of 12,500 IU every 8 h, a two-dimensional echocardiography showed the complete disappearance of the mass. This and other recent reports confirm the thrombolytic activity of the drug and the possibility of postponing the immediate surgical removal of intraventricular thrombi in favour of heparin treatment