Prophylaxis and Treatment against Klebsiella pneumoniae: Current Insights on This Emerging Anti-Microbial Resistant Global Threat

Klebsiella pneumoniae (Kp) is an opportunistic pathogen and the leading cause of healthcare-associated infections, mostly affecting subjects with compromised immune systems or suffering from concurrent bacterial infections. However, the dramatic increase in hypervirulent strains and the emergence of new multidrug-resistant clones resulted in Kp occurrence among previously healthy people and in increased morbidity and mortality, including neonatal sepsis and death across low- and middle-income countries. As a consequence, carbapenem-resistant and extended spectrum β-lactamase-producing Kp have been prioritized as a critical anti-microbial resistance threat by the World Health Organization and this has renewed the interest of the scientific community in developing a vaccine as well as treatments alternative to the now ineffective antibiotics. Capsule polysaccharide is the most important virulence factor of Kp and plays major roles in the pathogenesis but its high variability (more than 100 different types have been reported) makes the identification of a universal treatment or prevention strategy very challenging. However, less variable virulence factors such as the O-Antigen, outer membrane proteins as fimbriae and siderophores might also be key players in the fight against Kp infections. Here, we review elements of the current status of the epidemiology and the molecular pathogenesis of Kp and explore specific bacterial antigens as potential targets for both prophylactic and therapeutic solutions.     

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.     

Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.     

The AFLATOX® Project: Approaching the Development of New Generation,Natural-Based Compounds for the Containment of the Mycotoxigenic Phytopathogen Aspergillus flavus and Aflatoxin Contamination

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre- and post-harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role; however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox^® Project was aimed at the development of new-generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti-aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi-genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem.     

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Cardiac connexins (Cxs) are proteins responsible for proper heart function. They form gap junctions that mediate electrical and chemical signalling throughout the cardiac system, and thus enable a synchronized contraction. Connexins can also individually participate in many signal transduction pathways, interacting with intracellular proteins at various cellular compartments. Altered connexin expression and localization have been described in diseased myocardium and the aim of this study is to assess the involvement of Cx43, Cx26, and some related molecules in ponatinib-induced cardiac toxicity. Ponatinib is a new multi-tyrosine kinase inhibitor that has been successfully used against human malignancies, but its cardiotoxicity remains worrisome. Therefore, understanding its signaling mechanism is important to adopt potential anti cardiac damage strategies. Our experiments were performed on hearts from male and female mice treated with ponatinib and with ponatinib plus siRNA-Notch1 by using immunofluorescence, Western blotting, and proteomic analyses. The altered cardiac function and the change in Cxs expression observed in mice after ponatinib treatment, were results dependent on the Notch1 pathway and sex. Females showed a lower susceptibility to ponatinib than males. The downmodulation of cardiac Cx43, Cx26 and miR-122, high pS368-Cx43 phosphorylation, cell viability and survival activation could represent some of the female adaptative/compensatory reactions to ponatinib cardiotoxicity.     

Sulfur containing polymers

Summary Copolymers containing -S-CO-S-and/or -O-CO-S-groups have been synthesized mainly by interfacial polycondensation.Different chemical structures were obtained by reacting 1,3-benzene dithiol (BDT) respectively with phosgene alone, phosgene and bisphenol-A (BPA), bischloroformate of BPA, BPA polycarbonate oligomers and by reacting phosgene with the products of BPA polycarbonate degraded with BDT. The chemical structures of the copolymers were investigated by IR, ¹H-NMR and ¹³C-NMR; molecular weights were determined by viscometry and vapor pressure osmometry. Although no attempt was made to find the optimum conditions for high molecular weight, some copolymers with fairly high mol. weight were obtained.     

Synchronization in complex networks of phase oscillators: A survey

The emergence of synchronization in a network of coupled oscillators is a fascinating subject of multidisciplinary research. This survey reviews the vast literature on the theory and the applications of complex oscillator networks. We focus on phase oscillator models that are widespread in real-world synchronization phenomena, that generalize the celebrated Kuramoto model, and that feature a rich phenomenology. We review the history and the countless applications of this model throughout science and engineering. We justify the importance of the widespread coupled oscillator model as a locally canonical model and describe some selected applications relevant to control scientists, including vehicle coordination, electric power networks, and clock synchronization. We introduce the reader to several synchronization notions and performance estimates. We propose analysis approaches to phase and frequency synchronization, phase balancing, pattern formation, and partial synchronization. We present the sharpest known results about synchronization in networks of homogeneous and heterogeneous oscillators, with complete or sparse interconnection topologies, and in finite-dimensional and infinite-dimensional settings. We conclude by summarizing the limitations of existing analysis methods and by highlighting some directions for future research.     

Protein ultrafiltration: an experimental study

An experimental study was carried out on the ultrafiltration (UF) of protein-containing solutions under different conditions, as compared with a solution of a linear synthetic polymer. Three different fluidynamic regimes were investigated, namely, unstirred batch system, stirred batch system, and recirculating system. The results obtained substantially agree with the predictions of the gel polarization model. A significant effect of the electrolytes on the UF flux has been observed, which can be attributed to solute–solute interaction. The influence of different UF membranes has also been investigated.     

Robust event discovery from photo collections using Signature Image Bases (SIBs)

Analyzing personal photo albums for understanding the related events is an emerging trend. A reliable event recognition tool could suggest appropriate annotation of pictures, provide the context for single image classification and tagging, achieve automatic selection and summarization, ease organization and sharing of media among users. In this paper, a novel method for fast and reliable event-type classification of personal photo albums is presented. Differently from previous approaches, the proposed method does not process photos individually but as a whole, exploiting three main features, namely Saliency, Gist, and Time, to extract an event signature, which is characteristic for a specific event type. A highly challenging database containing more than 40.000 photos belonging to 19 diverse event-types was crawled from photo-sharing websites for the purpose of modeling and performance evaluation. Experimental results showed that the proposed approach meets superior classification accuracy with limited computational complexity.     

Regional Climate Simulations on EU-INDIA Grid Infrastructures: Methodologies and Performance

In this paper, we present a possible approach to use different Grid infrastructures across Europe and India for regional climate simulations and discuss in details the advantages and limitations in using them. The application taken into consideration is the Regional Climate Model RegCM4, which has been recently re-written for making it more efficient and easier to be fully exploited on any kind of computational infrastructure. We describe here the methods applied to port this package on the Grid infrastructures made available by the EU-IndiaGrid project. We also discuss different approaches, the way to run the model on both European and Indian infrastructures and our promising approach to deal with data management issues. Use of RegCM on Grid infrastructure has further been compared with that on HPC resources. The domain worked upon for these tests is the South-Asia CORDEX domain, which is of great importance for the Indian Summer Monsoon. Our final conclusion is that, for certain class of experiments, RegCM4 model can be efficiently and easily integrated on Grid infrastructures, by means of the procedures described in this paper.