New echocardiographic techniques in the evaluation of left ventricular function in obesity

Objective:

Obesity has reached global epidemic proportions and is associated with numerous comorbidities, including major cardiovascular (CV) diseases.

Design and Methods:

It has many adverse effects on hemodynamics and CV structure and function: it increases total blood volume and cardiac output, and the cardiac workload is greater. Typically, obese patients have a higher cardiac output but a lower level of total peripheral resistance at any given level of arterial pressure. Most of the increase in cardiac output in obesity is caused by stroke volume, although heart rate typically mildly increases also due to enhanced sympathetic activation.

Results:

Over the last few years, experimental investigations have unraveled some important pathogenetic mechanisms that may underlie a specific form of “obesity cardiomyopathy.” Bariatric surgery represents an effective alternative to treat obesity when nonsurgical weight loss programs (diet + behavior modifications + regular exercise) have failed. A great numbers of questions are still open in the global comprehension of the pathophysiological interactions between obesity and heart.

Conclusion:

Conventional two‐dimensional Doppler echocardiography, integrated by relative new technological ultrasonic approaches, represents the reference technique to study and possibly clarify both the very complex hemodynamic changes induced by obesity and those relative to obesity treatment.     

MALDI–MS Profiling to Address Honey Bee Health Status under Bacterial Challenge through Computational Modeling

Honey bees play a critical role in the maintenance of plant biodiversity and sustainability of food webs. In the past few decades, bees have been subjected to biotic and abiotic threats causing various colony disorders. Therefore, monitoring solutions to help beekeepers to improve bee health are necessary. Matrix‐assisted laser desorption ionization–mass spectrometry (MALDI–MS) profiling has emerged within this decade as a powerful tool to identify in routine micro‐organisms and is currently used in real‐time clinical diagnosis. MALDI BeeTyping is developed to monitor significant hemolymph molecular changes in honey bees upon infection with a series of entomopathogenic Gram‐positive and ‐negative bacteria. A Serratia marcescens strain isolated from one naturally infected honey bee collected from the field is also considered. A series of hemolymph molecular mass fingerprints is individually recorded and to the authors' knowledge, the first computational model harboring a predictive score of 97.92% and made of nine molecular signatures that discriminate and classify the honey bees’ systemic response to the bacteria is built. Hence, the model is challenged by classifying a training set of hemolymphs and an overall recognition of 91.93% is obtained. Through this work, a novel, time and cost saving high‐throughput strategy that addresses honey bee health on an individual scale is introduced.     

Accelerated bio‐cognitive aging in Down syndrome: State of the art and possible deceleration strategies

Down syndrome (DS) has been proposed by George Martin as a segmental progeroid syndrome since 1978. In fact, DS persons suffer from several age‐associated disorders much earlier than euploid persons. Furthermore, a series of recent studies have found that DS persons display elevated levels of age biomarkers, thus supporting the notion that DS is a progeroid trait. Nowadays, due to the progressive advancements in social inclusion processes and medical assistance, DS persons live much longer than in the past; therefore, the early‐onset health problems of these persons are becoming an urgent and largely unmet social and medical burden. In particular, the most important ailment of DS persons is the accelerated cognitive decline that starts when they reach about 40 years of age. This decline can be at least in part counteracted by multi‐systemic approaches including early‐onset cognitive training, physical activity, and psychosocial assistance. However, no pharmacological treatment is approved to counteract this decline. According to the most advanced conceptualization of Geroscience, tackling the molecular mechanisms underpinning the aging process should be a smart/feasible strategy to combat and/or delay the great majority of age‐related diseases, including cognitive decline. We think that a debate is needed urgently on if (and how) this strategy could be integrated in protocols to face DS‐associated dementia and overall unhealthy aging. In particular we propose that, on the basis of data obtained in different clinical settings, metformin is a promising candidate that could be exploited to counteract cognitive decline in DS.     

Catalytic domain of MMP20 (Enamelysin) - the NMR structure of a new matrix metalloproteinase

The solution structure of the catalytic domain of MMP-20, a member of the matrix metalloproteinases family not yet structurally characterized, complexed with N-Isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid (NNGH), is here reported and compared with other MMPs-NNGH adducts. The backbone dynamic has been characterized as well. We have found that, despite the same fold and very high overall similarity, the present structure experiences specific structural and dynamical similarities with some MMPs and differences with others, around the catalytic cavity. The present solution structure, not only contributes to fill the gap of structural knowledge on human MMPs, but also provides further information to design more selective and efficient inhibitors for a specific member of this class of proteins.     

Quantitative profiling of the pathological prion protein allotypes in bank voles by liquid chromatography-mass spectrometry

The conversion of the cellular prion protein (PrP(C)) into a misfolded isoform (PrP(TSE)) that accumulates in the brain of affected individuals is the key feature of transmissible spongiform encephalopaties (TSEs). Susceptibility to TSEs is influenced by polymorphisms of the prion gene suggesting that the presence of certain amino acid residues may facilitate the pathological conversion. In this work, we describe a quantitative, fast and reliable HPLC-MS method that allowed to demonstrate that in the brain of 109(Met/Ile) heterozygous bank voles infected with the mouse adapted scrapie strain 139A, there are comparable amounts of PrP(TSE) with methionine or isoleucine in position 109, suggesting that in this TSE model the two allotypes have similar rates of accumulation. This method can be easily adapted for the quantitative determination of PrP allotypes in the brain of other natural or experimental TSE models.     

Global distribution of plasmid-mediated colistin resistance mcr gene in Salmonella: A systematic review

This systematic review focuses on obtaining the most relevant information from multiple studies that detected a mobilized colistin resistance mcr gene in Salmonella for a better comprehension of its global distribution. A group of strategic and systematic keywords were combined to retrieve research data on the detection frequency of the mcr gene globally from four database platforms (Google Scholar, Science Direct, PubMed and Scielo). Forty-eight studies attended all the eligibility criteria and were selected. China was the country with the highest frequency of Salmonella strains with the mcr gene, and Europe exhibited a wide diversity of countries with positive mcr strains. In addition, animals and humans carried the highest frequency of positive strains for the mcr gene. Salmonella Typhimurium was the most frequent serovar carrying the mcr gene. Apparently, colistin overuse in animal husbandry has increased the selective pressure of antimicrobial resistance, resulting in the emergence of a plasmid-mediated colistin resistance mcr gene in China. The mcr-positive Salmonella strains are recently predominant worldwide, which is probably due to the capacity of this gene to be swiftly horizontally transmissible. The transmission ability of mcr-positive Salmonella strains to humans through the consumption of contaminated animal-based food is a public health concern.     

Immunotoxins containing recombinant anti-CTLA-4 single-chain fragment variable antibodies and saporin: in vitro results and in vivo effects in an acute rejection model

Immunotoxins containing recombinant human-derived single-chain fragment variable (scFv) reagents (83 and 40) against CTLA-4 (CD152) linked to saporin, a ribosome-inactivating protein, were prepared and tested on CD3/CD28-activated T lymphocytes, MLRs, CTLA-4-positive cell lines, and hemopoietic precursors. Immunotoxins induced apoptosis in activated T lymphocytes and were able to specifically inhibit MLR between T lymphocytes and dendritic cells. The 83-saporin immunotoxin also inhibited the T cell activation in an MLR between T lymphocytes and an EBV-positive lymphoblastoid B cell line. Toxicity tests on hemopoietic precursors showed little or no effects in inhibiting colonies' growth. As the 83 scFv Ab was reactive also with activated mouse T lymphocytes, 83-saporin was tested in a model of tumor rejection consisting of C57BL/6 mice bearing a murine H.end endothelioma cell line, derived from DBA/2 mice. The lymphoid infiltration due to the presence of the tumor was reduced to a high extent, demonstrating that the immunotoxin was actually available and active in vivo. Thus, taking the results altogether, this study might represent a new breakthrough for immunotherapy, showing the possibility of targeting CTLA-4 to kill activated T cells, using conjugates containing scFv Abs and type 1 ribosome-inactivating protein.     

Tick-borne diseases in ruminants of Central and Southern Italy: epidemiology and case reports

Sera and blood from cattle and sheep were examined for the presence of Babesia and Theileria spp by microscopy and serology at the Parasitology Department of the Istituto Zooprofilattico Sperimentale of Abruzzo and Molise (IZSAM). Of the 47 bovine herds (323 animals) tested, 15 were found positive for Babesia bigemina and 1 for Babesia bovis. Two outbreaks occurred, one caused by B. bigemina and one by B. bovis. The B. bigemina outbreak occurred in Abruzzo and has been followed for two years. The isolate of B. bigemina was very pathogenic leading to the death of two cows out of 57. The vector responsible of the transmission appeared to be Rhipicephalus bursa. Parasites were observed in the erythrocytes for 30 days whereas sera were positive to indirect immunofluorescence (IFA) for at least one year. The B. bovis outbreak occurred in the province of Mantova (Northern Italy) in a group of 70 beef cattle imported from France. The infection resulted in the death of 5 animals and severe illness in another 6. In contrast with what occurred for Babesia infection, no clinical cases were recorded in cattle when species of Theileria were detected by microscopy. Of the 24 bovine herds (252 animals) tested for Theileria, 21 were found positive for the T. "sergenti"/buffeli/orientalis group. Single and mixed infection of T. "sergenti" and T. buffeli/orientalis were detected in herds of cross-bred cattle from Abruzzo and Marche. The parasites were identified by using a polymerase chain reaction which amplified DNA encoding p32/34. Most of the collected ticks (90%) were adults of R. bursa whereas the others were adults of Hyalomma detritum. During the period the animals have been observed (18 months), no clinical cases have been recorded and no associations have been found between blood abnormalities and animals found infected with Theileria. Prevalences of subclinically infected carriers increased from February till December (95.4%) even if the animals were indoors and no ticks were present. The prevalence then dropped dramatically six months later (76.7%). In calves less than 1 year old, the prevalence of infection significantly (p<0.05) increased with age, however intraerythrocytic stages of Theileria were found in the blood of three newborn calves (<7 days of age). Of the 18 ovine flocks tested for Babesia spp. (150 animals examined), 1 was positive for B. ovis and 2 for B. motasi. B. motasi infection was not associated with symptoms, while an outbreak of babesiosis caused by B. ovis occurred in Abruzzo. The infection resulted in the death of 3 animals (0.75% of the flock), two rams (20% of the total number) and a ewe, and severe illness in another 5 ewes (2% of the flock). Specimens of R. bursa and R. turanicus were collected from the infected animals. Of the 18 flocks (150 animals) examined, 12 were microscopically positive for Theileria spp. No clinical cases were recorded and identification at species level was not possible on the basis of morphological criteria. The prevalence distribution of infected herds and infected animals within herds and flocks have been calculated by a Monte Carlo simulation model, running 10,000 iterations. The most likely levels of prevalence of infected herds and infected animals within herds found for the species observed were as follows: 20% for B. bigemina with a prevalence within herd of 27%, 11% for B. bovis (18% within herd), 10% for Babesia ovis (19% within herd), 10% for B. motasi (17.5% within herd), 63% for Theileria in cattle (66% within herd) and 51% for Theileria in sheep (55% within herd).     

Saposins and Their Interaction with Lipids

The lysosomal degradation of several sphingolipids requires the presence of four small glycoproteins called saposins, generated by proteolytic processing of a common precursor, prosaposin. Saposins share several structural properties, including six similarly located cysteines forming three disulfide bridges with the same cysteine pairings. Recently it has been noted that also other proteins have the same polypeptide motif characterized by the similar location of six cysteines. These saposin-like (SAPLIP) proteins are surfactant protein B (SP-B), Entamoeba histolytica poreforming peptide, NK-lysin, acid sphingomyelinase and acyloxyacyl hydrolase. The structural homology and the conserved disulfide bridges suggest for all SAPLIPs a common fold, called saposin fold. Up to now a precise fold, comprising five -helices, has been established only for NK-lysin. Despite their similar structure each saposin promotes the degradation of specific sphingolipids in lysosomes, e.g. Sap B that of sulfatides and Sap C that of glucosylceramides. The different activities of the saposins must reside within the module of the -helices and/or in additional specific regions of the molecule. It has been reported that saposins bind to lysosomal hydrolases and to several sphingolipids. Their structural and functional properties have been extensively reviewed and hypotheses regarding their molecular mechanisms of action have been proposed. Recent work of our group has evidenced a novel property of saposins: some of them undergo an acid-induced change in hydrophobicity that triggers their binding to phospholipid membranes. In this article we shortly review recent findings on the structure of saposins and on their interactions with lipids, with special attention to interactions with phospholipids. These findings offer a new approach for understanding the physiological role of saposins in lysosomes.