Grant Application Review: The Case of Transparency

The Legitimacy of Peer Reviewing Transparency Policies at Funding Agencies Incremental Perspective: How to Improve Effectiveness and Robustness Further through Transparency The Radical Perspective: Transformative Potential of Transparency Acknowledgments Reference

ProCMD: a database and 3D web resource for protein C mutants

Background: Activated Protein C (ProC) is an anticoagulant plasma serine protease which also plays an important role in controlling inflammation and cell proliferation. Several mutations of the gene are associated with phenotypic functional deficiency of protein C, and with the risk of developing venous thrombosis. Structure prediction and computational analysis of the mutants have proven to be a valuable aid in understanding the molecular aspects of clinical thrombophilia. Results: We have built a specialized relational database and a search tool for natural mutants of protein C. It contains 195 entries that include 182 missense and 13 stop mutations. A menu driven search engine allows the user to retrieve stored information for each variant, that include genetic as well as structural data and a multiple alignment highlighting the substituted position. Molecular models of variants can be visualized with interactive tools; PDB coordinates of the models are also available for further analysis. Furthermore, an automatic modelling interface allows the user to generate multiple alignments and 3D models of new variants. Conclusion: ProCMD is an up-to-date interactive mutant database that integrates phenotypical descriptions with functional and structural data obtained by computational approaches. It will be useful in the research and clinical fields to help elucidate the chain of events leading from a molecular defect to the related disease. It is available for academics at the URL http://www.itb.cnr.it/procmd/

Pros and cons of NRF2 activation as adjunctive therapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease with an important inflammatory component accompanied by deregulated redox-dependent signaling pathways that are feeding back into inflammation. In this context, we bring into focus the transcription factor NRF2, a master redox regulator that exerts exquisite antioxidant and anti-inflammatory effects. The review does not intend to be exhaustive, but to point out arguments sustaining the rationale for applying an NRF2-directed co-treatment in RA as well as its potential limitations. The involvement of NRF2 in RA is emphasized through an analysis of publicly available transcriptomic data on NRF2 target genes and the findings from NRF2-knockout mice. The impact of NRF2 on concurrent pathologic mechanisms in RA is explained by its crosstalk with major redox-sensitive inflammatory and cell death-related pathways, in the context of the increased survival of pathologic cells in RA. The proposed adjunctive therapy targeted to NRF2 is further sustained by the existence of promising NRF2 activators that are in various stages of drug development. The interference of NRF2 with conventional anti-rheumatic therapies is discussed, including the cytoprotective effects of NRF2 for alleviating drug toxicity. From another perspective, the review presents how NRF2 activation would be decreasing the efficacy of synthetic anti-rheumatic drugs by increasing drug efflux. Future perspectives regarding pharmacologic NRF2 activation in RA are finally proposed.The collaboration of the authors was supported by European COST Action CA20121: Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases (BenBedPhar). Webpage: https://benbedphar.org/about-benbedphar/. GM, EM, CMN, IVN, EMD and AC were supported by the Romanian Ministry of Research, Innovation and Digitization through the European Regional Development Fund, Competitiveness Operational Program 2014–2020 [the REDBRAIN project, ID: P_37_732

Vitamin E–loaded dialyzer resets PBMC-operated cytokine network in dialysis patients

Vitamin E–loaded dialyzer resets PBMC-operated cytokine network in dialysis patients.BackgroundIn hemodialysis patients the activity of stimulated Th1 lymphocytes is depressed, while Th2 cells are constitutively primed. Such phenomena may depend on monocyte activation and altered release of interleukin (IL)-12 and IL-18, which regulate Th cell differentiation. Reactive oxygen species (ROS) activate monocytes; therefore, a hemodialyzer with antioxidant activity would contrast ROS, prevent monocyte activation, reset IL-12 and IL-18 release, and restore Th1/Th2 balance.MethodsTen patients on regular dialysis treatment (RDT) with cellulosic membrane (CM) were shifted to vitamin E–coated dialyzer (VE). During treatment with CM and after 3, 6, and 12months of treatment with VE, peripheral blood mononuclear cells (PBMC) and purified CD4+ cells were isolated, and cultured, resting, mitogen-stimulated, and interferon γ (IFNγ), IL-4, IL-10, IL-12, and IL-18 release was measured. Vitamin E and A plasma levels and the effects of a single dialysis session on peripheral blood NO levels were assayed.ResultsThe constitutive release of IL-4 and IL-10 by CD4+ cells was abated significantly by treatment with VE (nadir -77.8% and -55.3%, respectively, at 12months). INFγ release by mitogen-stimulated CD4+ recovered with VE (zenith +501% at 12months). PBMC constitutive production of IL-12 and IL-18 was significantly reduced by VE (nadir at 12months -64.7% and -51.3%, respectively). VE increased plasma levels of vitamins E and A. NO plasma levels fell after a single dialysis treatment with VE (-17%, P < 0.05) in contrast with CU (+27.1%, P < 0.05).ConclusionThe network of cytokines released by monocytes and Th cells is reset toward normality by treatment with vitamin E–coated dialyzer

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom's macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy

Tricuspid regurgitant velocity elevation in a three-year old child with sickle cell anemia and recurrent acute chest syndromes reversed not by hydroxyurea but by bone marrow transplantation

Elevated Tricuspid Regurgitant Velocity (TRV) has been related to higher mortality in adults and to hemolysis, lower oxygen saturation during 6-minute walk test and acute chest syndrome (ACS) in children with sickle cell disease (SCD). Hydroxyurea (HU) has reduced TRV value in children and adults. We describe a three year old HbSS child with recurrent ACS, hypoperfusion of the left lung, mild hemolysis and persistent TRV elevation. TRV did not normalize after HU, despite improvement in clinical conditions and in baseline laboratory parameters related to hemolysis and blood viscosity, but normalized after bone marrow transplantation (BMT). Our experience suggests that in young patients, TRV reduction can be a positive concomitant effect of BMT

Prevention of Herpesviridae Infections by Cationic PEGylated Carbosilane Dendrimers

Infections caused by viruses from the Herpesviridae family produce some of the most prevalent transmitted diseases in the world, constituting a serious global public health issue. Some of the virus properties such as latency and the appearance of resistance to antiviral treatments complicate the development of effective therapies capable of facing the infection. In this context, dendrimers present themselves as promising alternatives to current treatments. In this study, we propose the use of PEGylated cationic carbosilane dendrimers as inhibitors of herpes simplex virus 2 (HSV-2) and human cytomegalovirus (HCMV)infections. Studies of mitochondrial toxicity, membrane integrity, internalization and viral infection inhibition indicated that G2-SN15-PEG, G3-SN31-PEG, G2-SN15-PEG fluorescein isothiocyanate (FITC) labeled and G3-SN31-PEG-FITC dendrimers are valid candidates to target HSV-2 and HCMV infections since they are biocompatible, can be effectively internalized and are able to significantly inhibit both infections. Later studies (including viral inactivation, binding inhibition, heparan sulphate proteoglycans (HSPG)binding and surface plasmon resonance assays) confirmed that inhibition takes place at first infection stages. More precisely, these studies established that their attachment to cell membrane heparan sulphate proteoglycans impede the interaction between viral glycoproteins and these cell receptors, thus preventing infection. Altogether, our research confirmed the high capacity of these PEGylated carbosilane dendrimers to prevent HSV-2 and HCMV infections, making them valid candidates as antiviral agents against Herpesviridae infections

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance–related processes may be involved in several phenotypes, including the TRD

BDNF Val66Met polymorphism and protein levels in Amniotic Fluid

Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin which plays survival- and growth-promoting activity in neuronal cells and it is involved in cellular plasticity mechanisms as it controls activity dependent synaptic transmission. A functional polymorphism (Val66Met) in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF has been associated with memory and cognitive deficits as well as to an increased susceptibility for several psychiatric disorders especially those with a neurodevelopmental origin. To date, no study has evaluated the influence of the Val66Met polymorphism on BDNF levels in a peripheral system that may reflect fetal neurodevelopment. Therefore we investigated in amniotic fluids (AF) obtained from 139 healthy women during 15-17 week of pregnancy, BDNF protein levels in correlation with the Val66Met polymorphism

Sanidade de Sementes e Emergência de Plântulas de Nabo Forrageiro, Aveia Preta e Centeio Submetidas a Tratamentos com Bioprotetor e Fungicida

The genus Trichoderma is represented by non pathogenic fungithat exercise antagonism to several phytopathogens through the parasitismand/or antibiosis and, have been used as biocontrole agents, growthpromoters and to improve the germination and sanity of seeds. The objectiveof this work was to compare the efficiency of the biological and chemicaltreatment in the sanity of seeds of forrage turnip (Raphanus sativus L.),black oat (Avena strigosa S.), rye (Secale cereale L.) and the emergency ofseedlings of forrage turnip. The evaluation of the sanity was done throughthe method of filter paper, and for evaluation of the emergency and seedlingsdevelopment, using styrofoam trays in the green-house.Were tested: T1 Rhodiauram®SC (500g/Kg of Thiram); T2 - Agrotrich®; T3 Rhodiauram®SC + Agrotrich®; T4 - Rhodiauram® SC (2:00) +Agrotrich® and T5 - Control. The treatments that controlled 100% theincidence of the fungi of the seeds of black oat were T1 and T4; of ryewere the treatments T1, T2, T4; and of forrage turnip the treatments T2and T4. The seeds of black oat and rye did not germinate due to physiologicproblems. For the forrage turnip, significant difference was not verifiedamong the treatments for the emergency test and emergency speed, andthe treatments T2, T3 and T4 presented the largest seedlings heights. Thebiocontrol product Agrotrich® alone or in combination with chemicalcontrol improved the sanity of forrage turnip, black oat, and rye and theheight of forrage turnip seedlings.O gênero Trichoderma é representado por fungos não patogênicosque exercem antagonismo a vários fitopatógenos através do parasitismo e/ou antibiose e, por isso, têm sido utilizados como agentes de biocontrole,promotores de crescimento e na melhoria da germinação e sanidade de sementes.O objetivo deste trabalho foi comparar a eficiência do tratamentobiológico e químico na sanidade de sementes de nabo forrageiro (Raphanussativus L.), aveia preta (Avena strigosa S.), centeio (Secale cereale L.) e aemergência de plântulas de nabo forrageiro. A avaliação da sanidade, foirealizada usando-se o método do papel filtro e para avaliação da emergênciae desenvolvimento de plântulas, em bandejas de isopor na casa de vegetação. Foram testados os tratamentos: T1- Rhodiauram® SC (500g/Kg deThiram); T2- Agrotrich®; T3- Rhodiauram® SC + Agrotrich®; T4-Rhodiauram® SC (2h) + Agrotrich® e T5- Testemunha. Os tratamentosque controlaram 100% a incidência de fungos nas sementes de aveia pretaforam T1 e T4; no centeio foram os tratamentos T1, T2, T4; e no naboforrageiro os tratamentos T2 e T4. As sementes de aveia preta e centeionão germinaram devido à problemas fisiológicos. No nabo forrageiro, nãofoi constatada diferença significativa entre os tratamentos para o teste deemergência e velocidade de emergência; os tratamentos T2, T3 e T4 apresentaramas maiores alturas de plântulas. O bioprotetor Agrotrich® isoladoou associado ao controle químico favorece a sanidade das sementes denabo forrageiro, aveia preta e centeio e a altura de plântulas de naboforrageiro