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Martina Trentini,1,* Ugo D’Amora,2,* Alfredo Ronca,2 Luca Lovatti,2 José Luis Calvo-Guirado,3 Danilo Licastro,4 Simeone Dal Monego,4 Lucia Gemma Delogu,5 Mariusz R Wieckowski,6 Shlomo Barak,7 Oleg Dolkart,7 Barbara Zavan1 1Translational Medicine Department, University of Ferrara, Ferrara, 44121, Italy; 2Institute of Polymers, Composites and Biomaterials - National Research Council (IPCB-CNR), Naples, 80125, Italy; 3Faculty of Health Sciences, Universidad Autonoma de Chile, Santiago de Chile, 7500912, Chile; 4AREA Science Park, Trieste, 34149, Italy; 5Biomedical Science Department University of Padova, Padova, Italy; 6Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland; 7Magdent B.S.R. 3, Bnei Brak, Tel Aviv, Israel*These authors contributed equally to this workCorrespondence: Alfredo Ronca; Barbara Zavan, Email alfredo.ronca@cnr.it; barbara.zavan@unife.itIntroduction: In the process of bone regeneration, a prominent role is played by macrophages involved in both the initial inflammation and the regeneration/vascularization phases, due to their M2 anti-inflammatory phenotype. Together with osteoclasts, they participate in the degradation of the bone matrix if the inflammatory process does not end. In this complex scenario, recently, much attention has been paid to extracellular communication mediated by nanometer-sized vesicles, with high information content, called exosomes (EVs). Considering these considerations, the purpose of the present work is to demonstrate how the presence of a pulsed electromagnetic field (PEMF) can positively affect communication through EVs.Methods: To this aim, macrophages and osteoclasts were treated in vitro with PEMF and analyzed through molecular biology analysis and by electron microscopy. Moreover, EVs produced by macrophages were characterized and used to verify their activity onto osteoclasts.Results: The results confirmed that PEMF not only reduces the inflammatory activity of macrophages and the degradative activity of osteoclasts but that the EVS produced by macrophages, obtained from PEMF treatment, positively affect osteoclasts by reducing their activity.Discussion: The co-treatment of PEMF with M2 macrophage-derived EVs (M2-EVs) decreased osteoclastogenesis to a greater degree than separate treatments. Keywords: PEMF, exosomes, macrophages, bone, osteoclast

We present the current status of the Next-to-Next-to-Leading Order QED contribution to the µescattering. Particular focus is given to the techniques involved to tackle the virtual amplitude and their automatic implementation. Renormalization of the amplitude will be also discuss in details.

Intermolecular van der Waals interactions are central to chemical and physical phenomena ranging from biomolecule binding to soft-matter phase transitions. In this work, we demonstrate that strong light-matter coupling can be used to control the thermodynamic properties of many-molecule systems. Our analyses reveal orientation dependent single molecule energies and interaction energies for van der Waals molecules. For example, we find intermolecular interactions that depend on the distance between the molecules R as R-3 and R0. Moreover, we employ ab initio cavity quantum electrodynamics calculations to develop machine-learning-based interaction potentials for molecules inside optical cavities. By simulating systems ranging from 12 H2 to 144 H2 molecules, we observe varying degrees of orientational order because of cavity-modified interactions, and we explain how quantum nuclear effects, light-matter coupling strengths, number of cavity modes, molecular anisotropies, and system size all impact the extent of orientational order.

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the RXSCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ ).

Attentional deficits have tragic consequences on road safety. These deficits are not solely caused by distraction, since they can also arise from other mental impairments such as, most frequently, mental fatigue. Fatigue is among the most prevalent impairing conditions while driving, degrading drivers’ cognitive and physical abilities. This issue is particularly relevant for professional drivers, who spend most of their time behind the wheel. While scientific literature already documented the behavioral effects of driving fatigue, most studies have focused on drivers under sleep deprivation or anyhow at severe fatigue degrees, since it is difficult to recognize the onset of fatigue. The present study employed an EEG-driven approach to detect early signs of fatigue in professional drivers during a simulated task, with the aim of studying visual attention as fatigue begins to set in. Short-range and long-range professional drivers were recruited to take part in a 45-min-long simulated driving experiment. Questionnaires were used to validate the experimental protocol. A previously validated EEG index, the MDrow, was adopted as the benchmark measure for identifying the “fatigued” spans. Results of the eye-tracking analysis showed that, when fatigued, professional drivers tended to focus on non-informative portions of the driving environment. This paper presents evidence that an EEG-driven approach can be used to detect the onset of fatigue while driving and to study the related visual attention patterns. It was found that the onset of fatigue did not differentially impact drivers depending on their professional activity (short- vs. long-range delivery).

Objectives. An epidemiological study to identify the most represented pathogens isolated from blood and to evaluate their antibiotic susceptibility patterns, was conducted. Methods. Seven clinical microbiology laboratories, homogeneously distributed in the Ligurian area,were required to collected all consecutive non-duplicates strains isolated froom blood cultures during January 2010 to April 2010. The strains were sent to the reference laboratory (Sezione di Microbiologia del DISC, University of Genoa, Italy). Results. A total of 277 microorganisms were enrolled, including 155 Gram positive and 122 Gram negative.The most represented pathogens were: Escherichia coli (68), Staphylococcus aureus (57), Staphylococcus epidermidis (32), Staphylococcus hominis (17), Pseudomonas aeruginosa (15), Klebsiella pneumoniae (15), Enterococcus faecalis (11). Samples were collected mainly from medicine (66, 33.3%, of this number was determined by E. coli), intensive care units (33, 18.2% of this number consisted of S. epidermidis), surgery (24, 33.3% consisted of E. coli) and infectious diseases (20, of which S. aureus, E. coli and S. epidermidis equally represented 20.0%).Among the Staphylococci the most active molecules were: vancomycin and teicoplanin (100% of susceptible strains), chloramphenicol (92.3%) and trimethoprim-sulfamethoxazole (89.8%). Among the OXA-R Staphylococci (81/123, 65.9%) the most active molecules were: vancomycin and teicoplanin (100% of susceptible strains), chloramphenicol (93.8%) and trimethoprim-sulfamethoxazole (84.8%). Enterococci showed rates of resistance to vancomycin of 5.9%. Enterobacteriaceae exhibited resistance to ampicillin (77.5%), trimethoprim-sulfamethoxazole (42.6%), ciprofloxacin (41.2%), ceftriaxone (37.5%), ceftazidime (28.2%), cefepime (26.7%), cefoxitin (22.1%), piperacillintazobactam (20.4%), imipenem (4.7%) and amikacin (2.9%). The Gram negative non-Enterobacteriaceae showed rates of resistance of 100% to ceftriaxone, 81.3% to trimethoprim-sulfamethoxazole, 42.1% to ciprofloxacin and piperacillin-tazobactam, 33.3% to ceftazidime, 31.6% to cefepime, 27.8% to imipenem, 26.3 % to amikacin. Conclusions. The data show a higher incidence of Gram positive (56%) in comparison to Gram negative (44%).This confirms the high incidence of oxacillino-resistance in Staphylococci in our geographic area.Against Enterobacteriaceae rates of resistance were observed in excess of 20% for all drugs tested except imipenem (4.7%) and amikacin (2.9%). The proportion of imipenem-resistant isolates was constituted of strains of K. pneumoniae carbapenemase producers.

Advancement in proteomics methods for interrogating biological samples has helped identify disease biomarkers for early diagnostics and unravel underlying molecular mechanisms of disease. Herein, we examined the serum proteomes of 23 study participants presenting with one of two common arthropod-borne infections: Lyme disease (LD), an extracellular bacterial infection or West Nile virus infection (WNV), an intracellular viral infection. The LC/MS based serum proteomes of samples collected at the time of diagnosis and during convalescence were assessed using a depletion-based high-throughput shotgun proteomics (dHSP) pipeline as well as a non-depleting blotting-based low-throughput platform (MStern). The LC/MS integrated analyses identified host proteome responses in the acute and recovery phases shared by LD and WNV infections, as well as differentially abundant proteins that were unique to each infection. Notably, we also detected proteins that distinguished localized from disseminated LD and asymptomatic from symptomatic WNV infection. The proteins detected in both diseases with the dHSP pipeline identified unique and overlapping proteins detected with the non-depleting MStern platform, supporting the utility of both detection methods. Machine learning confirmed the use of the serum proteome to distinguish the infection from healthy control sera but could not develop discriminatory models between LD and WNV at current sample numbers. Our study is the first to compare the serum proteomes in two arthropod-borne infections and highlights the similarities in host responses even though the pathogens and the vectors themselves are different.

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [Ki] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (Ki = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (Ki = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets.

Abstract Background The Anopheles gambiae gSG6 is an anopheline-specific salivary protein which helps female mosquitoes to efficiently feed on blood. Besides its role in haematophagy, gSG6 is immunogenic and elicits in exposed individuals an IgG response, which may be used as indicator of exposure to the main African malaria vector A. gambiae. However, malaria transmission in tropical Africa is sustained by three main vectors (A. gambiae, Anopheles arabiensis and Anopheles funestus) and a general marker, reflecting exposure to at least these three species, would be especially valuable. The SG6 protein is highly conserved within the A. gambiae species complex whereas the A. funestus homologue, fSG6, is more divergent (80% identity with gSG6). The aim of this study was to evaluate cross-reactivity of human sera to gSG6 and fSG6. Methods The A. funestus SG6 protein was expressed/purified and the humoral response to gSG6, fSG6 and a combination of the two antigens was compared in a population from a malaria hyperendemic area of Burkina Faso where both vectors were present, although with a large A. gambiae prevalence (>75%). Sera collected at the beginning and at the end of the high transmission/rainy season, as well as during the following low transmission/dry season, were analysed. Results According to previous observations, both anti-SG6 IgG level and prevalence decreased during the low transmission/dry season and showed a typical age-dependent pattern. No significant difference in the response to the two antigens was found, although their combined use yielded in most cases higher IgG level. Conclusions Comparative analysis of gSG6 and fSG6 immunogenicity to humans suggests the occurrence of a wide cross-reactivity, even though the two proteins carry species-specific epitopes. This study supports the use of gSG6 as reliable indicator of exposure to the three main African malaria vectors, a marker which may be useful to monitor malaria transmission and evaluate vector control measures, especially in conditions of low malaria transmission and/or reduced vector density. The Anopheles stephensi SG6 protein also shares 80% identity with gSG6, suggesting the attractive possibility that the A. gambiae protein may also be useful to assess human exposure to several Asian malaria vectors.

Abstract Introduction Skin metastasis from internal carcinoma rarely occurs. It has an incidence of 0.7 to 9% and it may be the first sign of an unknown malignancy. However, it can also occur during follow-up. Case presentation A 90-year-old female patient was admitted to our surgical division with a diagnosis of anemia from a bleeding gastric adenocarcinoma. She underwent a gastric resection and Billroth II retrocolic Hofmeister/Finsterer reconstruction. She developed an enteric fistula, which needed a permanent abdominal drain until the 60th postoperative day. After 12 months she was readmitted to our division with subacute small bowel obstruction and an erythematous swelling on the right side of the abdomen. Biopsies characterized it as a cutaneous metastasis from the gastric adenocarcinoma. No surgical therapy was performed given her poor clinical condition. Conclusion Skin metastasis from carcinomas of the upper gastrointestinal tract is very rare. Persisting erythematous nodules must be biopsied in order to diagnose cutaneous metastases and to recognize them early and start prompt therapy with anti-tumour agents before the occurrence of massive visceral metastases.