Subcompartmentalisation of Proteins in the Rhoptries Correlates with Ordered Events of Erythrocyte Invasion by the Blood Stage Malaria Parasite

Host cell infection by apicomplexan parasites plays an essential role in lifecycle progression for these obligate intracellular pathogens. For most species, including the etiological agents of malaria and toxoplasmosis, infection requires active host-cell invasion dependent on formation of a tight junction - the organising interface between parasite and host cell during entry. Formation of this structure is not, however, shared across all Apicomplexa or indeed all parasite lifecycle stages. Here, using an in silico integrative genomic search and endogenous gene-tagging strategy, we sought to characterise proteins that function specifically during junction-dependent invasion, a class of proteins we term invasins to distinguish them from adhesins that function in species specific host-cell recognition. High-definition imaging of tagged Plasmodium falciparum invasins localised proteins to multiple cellular compartments of the blood stage merozoite. This includes several that localise to distinct subcompartments within the rhoptries. While originating from the same organelle, however, each has very different dynamics during invasion. Apical Sushi Protein and Rhoptry Neck protein 2 release early, following the junction, whilst a novel rhoptry protein PFF0645c releases only after invasion is complete. This supports the idea that organisation of proteins within a secretory organelle determines the order and destination of protein secretion and provides a localisation-based classification strategy for predicting invasin function during apicomplexan parasite invasion. © 2012 Zuccala et al

A New Approach to Analyzing Patterns of Collaboration in Co-authorship Networks - Mesoscopic Analysis and Interpretation

This paper focuses on methods to study patterns of collaboration in co-authorship networks at the mesoscopic level. We combine qualitative methods (participant interviews) with quantitative methods (network analysis) and demonstrate the application and value of our approach in a case study comparing three research fields in chemistry. A mesoscopic level of analysis means that in addition to the basic analytic unit of the individual researcher as node in a co-author network, we base our analysis on the observed modular structure of co-author networks. We interpret the clustering of authors into groups as bibliometric footprints of the basic collective units of knowledge production in a research specialty. We find two types of coauthor-linking patterns between author clusters that we interpret as representing two different forms of cooperative behavior, transfer-type connections due to career migrations or one-off services rendered, and stronger, dedicated inter-group collaboration. Hence the generic coauthor network of a research specialty can be understood as the overlay of two distinct types of cooperative networks between groups of authors publishing in a research specialty. We show how our analytic approach exposes field specific differences in the social organization of research.Comment: An earlier version of the paper was presented at ISSI 2009, 14-17 July, Rio de Janeiro, Brazil. Revised version accepted on 2 April 2010 for publication in Scientometrics. Removed part on node-role connectivity profile analysis after finding error in calculation and deciding to postpone analysis

Contribution of Rare and Low-Frequency Variants to Multiple Sclerosis Susceptibility in the Italian Continental Population

Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and in silico functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in EFCAB13, a gene coding for a protein of an unknown function (p < 10–4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (p = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases

Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma

Background: Genomic instability is a feature of multiple myeloma (MM), and impairment in DNA damaging response (DDR) has an established role in disease pathobiology. Indeed, a deregulation of DNA repair pathways may contribute to genomic instability, to the establishment of drug resistance to genotoxic agents, and to the escape from immune surveillance. On these bases, we evaluated the role of different DDR pathways in MM and investigated, for the first time, the direct and immune-mediated anti-MM activity of the nucleotide excision repair (NER)-dependent agent trabectedin. Methods: Gene-expression profiling (GEP) was carried out with HTA2.0 Affymetrix array. Evaluation of apoptosis, cell cycle, and changes in cytokine production and release have been performed in 2D and 3D Matrigel-spheroid models through flow cytometry on MM cell lines and patients-derived primary MM cells exposed to increasing nanomolar concentrations of trabectedin. DNA-damage response has been evaluated through Western blot, immunofluorescence, and DNA fragmentation assay. Trabectedin-induced activation of NK has been assessed by CD107a degranulation. miRNAs quantification has been done through RT-PCR. Results: By comparing GEP meta-analysis of normal and MM plasma cells (PCs), we observed an enrichment in DNA NER genes in poor prognosis MM. Trabectedin triggered apoptosis in primary MM cells and MM cell lines in both 2D and 3D in vitro assays. Moreover, trabectedin induced DDR activation, cellular stress with ROS production, and cell cycle arrest. Additionally, a significant reduction of MCP1 cytokine and VEGF-A in U266-monocytes co-cultures was observed, confirming the impairment of MM-promoting milieu. Drug-induced cell stress in MM cells led to upregulation of NK activating receptors ligands (i.e., NKG2D), which translated into increased NK activation and degranulation. Mechanistically, this effect was linked to trabectedin-induced inhibition of NKG2D-ligands negative regulators IRF4 and IKZF1, as well as to miR-17 family downregulation in MM cells. Conclusions: Taken together, our findings indicate a pleiotropic activity of NER-targeting agent trabectedin, which appears a promising candidate for novel anti-MM therapeutic strategies

Quality of t-cell response to SARS-CoV-2 mrrna vaccine in art-treated plwh

We investigated specific humoral and T-cell responses in people living with HIV (PLWH) before (T0), after two (T1) and after six months (T2) from the third dose of the BNT162b2 vaccine. Healthy donors (HD) were enrolled. The specific humoral response was present in most PLWH already after the second dose, but the third dose increased both the rate of response and its magnitude. Collectively, no significant differences were found in the percentage of responding T-cells between PLWH and HD. At T0, stratifying PLWH according to CD4 cell count, a lower percentage of responding T-cells in 200 cells/mu L one was observed. At T1, this parameter was comparable between the two subgroups, and the same result was found at T2. However, the pattern of co-expression of IFN gamma, IL2 and TNF alpha in PLWH was characterized by a higher expression of TNF alpha, independently of CD4 cell count, indicating a persistent immunological signature despite successful ART. mRNA vaccination elicited a specific response in most PLWH, although the cellular one seems qualitatively inferior compared to HD. Therefore, an understanding of the T-cell quality dynamic is needed to determine the best vaccination strategy and, in general, the capability of immune response in ART-treated PLWH

Effects of aging and life-long moderate calorie restriction on IL-15 signaling in the rat white adipose tissue

OBJECTIVE: Phosphorylation of insulin receptor substrate (IRS) 1 by tumor necrosis factor alpha (TNF-\u3b1) has been implicated as a factor contributing to insulin resistance. Administration of IL-15 reduces adipose tissue deposition in young rats and stimulates secretion of adiponectin, an insulin sensitizing hormone that inhibits the production and activity of TNF-a. We aimed at investigating the effects of age life-long moderate calorie restriction (CR) on IL-15 and TNF-\u3b1 signaling in rat white adipose tissue (WAT). MATERIALS AND METHODS: Thirty-six 8-month-old, 18-month-old, and 29-month-old male Fischer344 Brown Norway F1 rats (6 per group) were either fed ad libitum (AL) or calorie restricted by 40%. The serum levels of IL-15 and IL-15 receptor a-chain (IL-15Ra) were increased by CR controls regardless of age. An opposite pattern was detected in WAT. In addition, CR reduced gene expression of TNF-a and cytosolic IRS1 serine phosphorylation in WAT, independently from age. RESULTS: IL-15 signaling in WAT is increased over the course of aging in AL rats compared with CR rodents. Protein levels of IL-15Ra are greater in WAT of AL than in CR rats independently from age. This adaptation was paralleled by increased IRS1 phosphorylation through TNF-a-mediated insulin resistance. Adiponectin decreased at old age in AL rats, while no changes were evident in CR rats across age groups. CONCLUSIONS: IL-15 signaling could therefore represent a potential target for interventions to counteract metabolic alterations and the deterioration of body composition during aging

Spatial Localisation of Actin Filaments across Developmental Stages of the Malaria Parasite

Actin dynamics have been implicated in a variety of developmental processes during the malaria parasite lifecycle. Parasite motility, in particular, is thought to critically depend on an actomyosin motor located in the outer pellicle of the parasite cell. Efforts to understand the diverse roles actin plays have, however, been hampered by an inability to detect microfilaments under native conditions. To visualise the spatial dynamics of actin we generated a parasite-specific actin antibody that shows preferential recognition of filamentous actin and applied this tool to different lifecycle stages (merozoites, sporozoites and ookinetes) of the human and mouse malaria parasite species Plasmodium falciparum and P. berghei along with tachyzoites from the related apicomplexan parasite Toxoplasma gondii. Actin filament distribution was found associated with three core compartments: the nuclear periphery, pellicular membranes of motile or invasive parasite forms and in a ring-like distribution at the tight junction during merozoite invasion of erythrocytes in both human and mouse malaria parasites. Localisation at the nuclear periphery is consistent with an emerging role of actin in facilitating parasite gene regulation. During invasion, we show that the actin ring at the parasite-host cell tight junction is dependent on dynamic filament turnover. Super-resolution imaging places this ring posterior to, and not concentric with, the junction marker rhoptry neck protein 4. This implies motor force relies on the engagement of dynamic microfilaments at zones of traction, though not necessarily directly through receptor-ligand interactions at sites of adhesion during invasion. Combined, these observations extend current understanding of the diverse roles actin plays in malaria parasite development and apicomplexan cell motility, in particular refining understanding on the linkage of the internal parasite gliding motor with the extra-cellular milieu

U.S. academic libraries: understanding their web presence and their relationship with economic indicators

The final publication is available at Springer via http://dx.doi.org/10.1007/s11192-013-1001-0The main goal of this research is to analyze the web structure and performance of units and services belonging to U.S. academic libraries in order to check their suitability for webometric studies. Our objectives include studying their possible correlation with economic data and assessing their use for complementary evaluation purposes. We conducted a survey of library homepages, institutional repositories, digital collections, and online catalogs (a total of 374 URLs) belonging to the 100 U.S. universities with the highest total expenditures in academic libraries according to data provided by the National Center for Education Statistics. Several data points were taken and analyzed, including web variables (page count, external links, and visits) and economic variables (total expenditures, expenditures on printed and electronic books, and physical visits). The results indicate that the variety of URL syntaxes is wide, diverse and complex, which produces a misrepresentation of academic libraries’ web resources and reduces the accuracy of web analysis. On the other hand, institutional and web data indicators are not highly correlated. Better results are obtained by correlating total library expenditures with URL mentions measured by Google (r = 0.546) and visits measured by Compete (r = 0.573), respectively. Because correlation values obtained are not highly significant, we estimate such correlations will increase if users can avoid linkage problems (due to the complexity of URLs) and gain direct access to log files (for more accurate data about visits).Orduña Malea, E.; Regazzi, JJ. (2014). U.S. academic libraries: understanding their web presence and their relationship with economic indicators. Scientometrics. 98(1):315-336. doi:10.1007/s11192-013-1001-0S315336981Adecannby, J. (2011). 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Cardiometabolic multimorbidity is associated with a worse Covid-19 prognosis than individual cardiometabolic risk factors. A multicentre retrospective study (CoViDiab II)

Background: Cardiometabolic disorders may worsen Covid-19 outcomes. We investigated features and Covid-19 outcomes for patients with or without diabetes, and with or without cardiometabolic multimorbidity. Methods: We collected and compared data retrospectively from patients hospitalized for Covid-19 with and without diabetes, and with and without cardiometabolic multimorbidity (defined as ≥ two of three risk factors of diabetes, hypertension or dyslipidaemia). Multivariate logistic regression was used to assess the risk of the primary composite outcome (any of mechanical ventilation, admission to an intensive care unit [ICU] or death) in patients with diabetes and in those with cardiometabolic multimorbidity, adjusting for confounders. Results: Of 354 patients enrolled, those with diabetes (n = 81), compared with those without diabetes (n = 273), had characteristics associated with the primary composite outcome that included older age, higher prevalence of hypertension and chronic obstructive pulmonary disease (COPD), higher levels of inflammatory markers and a lower PaO2/FIO2 ratio. The risk of the primary composite outcome in the 277 patients who completed the study as of May 15th, 2020, was higher in those with diabetes (Adjusted Odds Ratio (adjOR) 2.04, 95%CI 1.12-3.73, p = 0.020), hypertension (adjOR 2.31, 95%CI: 1.37-3.92, p = 0.002) and COPD (adjOR 2.67, 95%CI 1.23-5.80, p = 0.013). Patients with cardiometabolic multimorbidity were at higher risk compared to patients with no cardiometabolic conditions (adjOR 3.19 95%CI 1.61-6.34, p = 0.001). The risk for patients with a single cardiometabolic risk factor did not differ with that for patients with no cardiometabolic risk factors (adjOR 1.66, 0.90-3.06, adjp = 0.10). Conclusions: Patients with diabetes hospitalized for Covid-19 present with high-risk features. They are at increased risk of adverse outcomes, likely because diabetes clusters with other cardiometabolic conditions