Hexagonal Voronoi pattern detected in the microstructural design of the echinoid skeleton.

Repeated polygonal patterns are pervasive in natural forms and structures. These patterns provide inherent structural stability while optimizing strength-per-weight and minimizing construction costs. In echinoids (sea urchins), a visible regularity can be found in the endoskeleton, consisting of a lightweight and resistant micro-trabecular meshwork (stereom). This foam-like structure follows an intrinsic geometrical pattern that has never been investigated. This study aims to analyse and describe it by focusing on the boss of tubercles-spine attachment sites subject to strong mechanical stresses-in the common sea urchin Paracentrotus lividus. The boss microstructure was identified as a Voronoi construction characterized by 82% concordance to the computed Voronoi models, a prevalence of hexagonal polygons, and a regularly organized seed distribution. This pattern is interpreted as an evolutionary solution for the construction of the echinoid skeleton using a lightweight microstructural design that optimizes the trabecular arrangement, maximizes the structural strength and minimizes the metabolic costs of secreting calcitic stereom. Hence, this identification is particularly valuable to improve the understanding of the mechanical function of the stereom as well as to effectively model and reconstruct similar structures in view of future applications in biomimetic technologies and designs.

Modeling Provincial Covid-19 Epidemic Data Using an Adjusted Time-Dependent SIRD Model.

In this paper, we develop a forecasting model for the spread of COVID-19 infection at a provincial (i.e., EU NUTS-3) level in Italy by using official data from the Italian Ministry of Health integrated with data extracted from daily official press conferences of regional authorities and local newspaper websites. This data integration is needed as COVID-19 death data are not available at the NUTS-3 level from official open data channels. An adjusted time-dependent SIRD model is used to predict the behavior of the epidemic; specifically, the number of susceptible, infected, deceased, recovered people and epidemiological parameters. Predictive model performance is evaluated using comparison with real data.

Are Epidemiological Estimates Able to Describe the Ability of Health Systems to Cope with COVID-19 Epidemic?

INTRODUCTION: The coronavirus disease 2019 (COVID-19) epidemic is an infectious disease which was declared a pandemic and hit countries worldwide from the beginning of the year 2020. Despite the emergency vigilance plans, health systems in all countries experienced a different ratio of lethality, amount of admissions to intensive care units and quarantine management of positive patients. The aim of this study is to investigate whether some epidemiological estimates could have been useful in understanding the capacity of the Italian Regional Health Services to manage the COVID-19 epidemic. METHODS: We have compared data between two different Italian regions in the Northern part of Italy (Lombardy and Veneto) and the national data to determine whether different health strategies might be significant in explaining dissimilar patterns of the COVID-19 epidemic in Italy. Data have been extracted from a public database and were available only in an aggregated form. RESULTS: The regions in question displayed two different health policies to face the COVID-19 epidemic: while Veneto's health service was largely territorially oriented, Lombardy's strategy was more hospital-centered. DISCUSSION: The key to facing epidemics like this one consists in identifying solutions outside of hospitals. This however requires there be well-trained general practitioners and enough healthcare personnel working outside hospitals.

CoViD-19, learning from the past: A wavelet and cross-correlation analysis of the epidemic dynamics looking to emergency calls and Twitter trends in Italian Lombardy region.

The first case of Coronavirus Disease 2019 in Italy was detected on February the 20th in Lombardy region. Since that date, Lombardy has been the most affected Italian region by the epidemic, and its healthcare system underwent a severe overload during the outbreak. From a public health point of view, therefore, it is fundamental to provide healthcare services with tools that can reveal possible new health system stress periods with a certain time anticipation, which is the main aim of the present study. Moreover, the sequence of law decrees to face the epidemic and the large amount of news generated in the population feelings of anxiety and suspicion. Considering this whole complex context, it is easily understandable how people "overcrowded" social media with messages dealing with the pandemic, and emergency numbers were overwhelmed by the calls. Thus, in order to find potential predictors of possible new health system overloads, we analysed data both from Twitter and emergency services comparing them to the daily infected time series at a regional level. Particularly, we performed a wavelet analysis in the time-frequency plane, to finely discriminate over time the anticipation capability of the considered potential predictors. In addition, a cross-correlation analysis has been performed to find a synthetic indicator of the time delay between the predictor and the infected time series. Our results show that Twitter data are more related to social and political dynamics, while the emergency calls trends can be further evaluated as a powerful tool to potentially forecast new stress periods. Since we analysed aggregated regional data, and taking into account also the huge geographical heterogeneity of the epidemic spread, a future perspective would be to conduct the same analysis on a more local basis.

Monitoring emergency calls and social networks for COVID-19 surveillance. To learn for the future: The outbreak experience of the Lombardia region in Italy.

On 18th February the first Italian case of Coronavirus Induced Disease 2019 (COVID19) due to secondary transmission outside China was identified in Codogno, Lombardia region. In the following days the number of cases started to rise not only in Lombardia but also in other Italian regions, although Lombardia remained and it is still the most affected region in Italy. At the moment, 234801 cases have been identified in Italy, out of which 90070 in Lombardia region. The (Severe Acute Respiratory Syndrome Coronavirus 2) SARS CoV 2 outbreak in Italy has been characterized by a massive spread of news coming from both official and unofficial sources leading what has been defined as infodemia, an over-abundance of information - some accurate and some not - that has made hard for people to find trustworthy sources and reliable guidance needed. Infodemia on SARS CoV 2 created the perfect field to build uncertainty in the population, which was scared and not prepared to face this outbreak. It is understandable how the rapid increase of the cases' number , the massive spread of news and the adoption of laws to face this outbreak led to a feeling of anxiety in the population whose everyday life changed very quickly. A way to assess the dynamic burden of social anxiety is a context analysis of major social networks activities over the Internet. To this aim Twitter represents a possible ideal tool since the focused role of the tweets according to the more urgent needs of information and communication rather than general aspects of social projection and debate as in the case of Facebook, which could provide slower responses for the fast individual and social context evolution dynamics.  Aim of the paper is to analyse the most common reasons for calling and outcomes. Furthermore, the joint analysis with Twitter trends related to emergency services might be useful to understand possible correlations with epidemic trends and predict new outbreaks.

slan+ Monocytes and Macrophages Mediate CD20-Dependent B-cell Lymphoma Elimination via ADCC and ADCP.

Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extranodal, forms. Nodal slan+ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in patients with DLBCL that peripheral blood slan+ monocytes, but not CD14+ monocytes, increased in number and displayed highly efficient rituximab-mediated antibody-dependent cellular cytotoxicity, almost equivalent to that exerted by NK cells. Notably, slan+ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression, and became very efficient in rituximab-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14+ monocytes performed very efficient rituximab-mediated ADCP, however, using different FcγRs from those used by slan+ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan+ monocytes homing to cancer tissues. Altogether, data identify slan+ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in patients with DLBCL.Significance: slan+ monocytes differentiate into macrophages that function as prominent effectors of antibody-mediated tumor cell targeting in lymphoma.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3544/F1.large.jpg Cancer Res; 78(13); 3544-59. ©2018 AACR.

Potential contribution of tumor-associated slan+ cells as anti-CSF-1R targets in human carcinoma.

The precise identification of the types and respective roles of the tumor-associated myeloid cells, which include tumor-associated Mϕs (TAMs), neutrophils, dendritic cells, and myeloid-derived suppressor cells, is under intensive investigation. Although tumor-associated myeloid cells may contribute to tumor cell eradication by virtue of their effector functions, they are retained to fulfill predominantly protumorigenic roles. It follows that depletion of tumor-associated myeloid cells represents one of the currently pursued therapeutic options in advanced malignancies. In that regard, RG7155/emactuzumab, a specific anti-CSF-1R humanized Ab, has been reported recently to deplete CSF-1R+ TAMs, in association with objective clinical responses in patients with advanced cancer. Because RG7155/emactuzumab has also been shown to deplete blood non-classic CD14dim/- CD16++ monocytes, which in large part include the CD16++ slan+ monocytes, we asked whether RG7155/emactuzumab could target tumor-associated slan+ cells. In this study, we confirmed that slan+ cells localize only to metastatic tumor-draining lymph nodes, not to primary tumors or distant metastases in patients with different types of carcinoma. Notably, by cell scoring on serial sections, we found that slan+ cells represent a minor fraction of the total CSF-1R+ cell pool, suggesting that slan+ cells potentially represent minor targets of anti-CSF-1R therapy. Therefore, a protumorigenic role for slan+ cells, such as that of CSF-1R+ TAMs, based on our current data, remains questionable.

slanDCs/M-DC8+ cells constitute a distinct subset of dendritic cells in human tonsils [corrected].

Human blood dendritic cells (DCs) include three main distinct subsets, namely the CD1c+ and CD141+ myeloid DCs (mDCs) and the CD303+ plasmacytoid DCs (pDCs). More recently, a population of slan/M-DC8+ cells, also known as "slanDCs", has been described in blood and detected even in inflamed secondary lymphoid organs and non-lymphoid tissues. Nevertheless, hallmarks of slan/M-DC8+ cells in tissues are poorly defined. Herein, we report a detailed characterization of the phenotype and function of slan/M-DC8+ cells present in human tonsils. We found that tonsil slan/M-DC8+ cells represent a unique DC cell population, distinct from their circulating counterpart and also from all other tonsil DC and monocyte/macrophage subsets. Phenotypically, slan/M-DC8+ cells in tonsils display a CD11c+HLA-DR+CD14+CD11bdim/negCD16dim/negCX3CR1dim/neg marker repertoire, while functionally they exhibit an efficient antigen presentation capacity and a constitutive secretion of TNFα. Notably, such DC phenotype and functions are substantially reproduced by culturing blood slan/M-DC8+ cells in tonsil-derived conditioned medium (TDCM), further supporting the hypothesis of a full DC-like differentiation program occurring within the tonsil microenvironment. Taken together, our data suggest that blood slan/M-DC8+ cells are immediate precursors of a previously unrecognizedcompetent DC subset in tonsils, and pave the way for further characterization of slan/M-DC8+ cells in other tissues.

Neutrophil-derived cytokines: facts beyond expression.

Polymorphonuclear neutrophils, besides their involvement in primary defense against infections - mainly through phagocytosis, generation of toxic molecules, release of enzymes, and formation of extracellular traps - are also becoming increasingly important for their contribution to the fine regulation in development of inflammatory and immune responses. These latter functions of neutrophils occur, in part, via their de novo production and release of a large variety of cytokines, including chemotactic cytokines (chemokines). Accordingly, the improvement in technologies for molecular and functional cell analysis, along with concomitant advances in cell purification techniques, have allowed the identification of a continuously growing list of neutrophil-derived cytokines, as well as the characterization of their biological implications in vitro and/or in vivo. This short review summarizes crucial concepts regarding the modalities of expression, release, and regulation of neutrophil-derived cytokines. It also highlights examples illustrating the potential implications of neutrophil-derived cytokines according to recent observations made in humans and/or in experimental animal models.

The representativeness of a European multi-center network for influenza-like-illness participatory surveillance.

BACKGROUND: The Internet is becoming more commonly used as a tool for disease surveillance. Similarly to other surveillance systems and to studies using online data collection, Internet-based surveillance will have biases in participation, affecting the generalizability of the results. Here we quantify the participation biases of Influenzanet, an ongoing European-wide network of Internet-based participatory surveillance systems for influenza-like-illness. METHODS: In 2011/2012 Influenzanet launched a standardized common framework for data collection applied to seven European countries. Influenzanet participants were compared to the general population of the participating countries to assess the representativeness of the sample in terms of a set of demographic, geographic, socio-economic and health indicators. RESULTS: More than 30,000 European residents registered to the system in the 2011/2012 season, and a subset of 25,481 participants were selected for this study. All age classes (10 years brackets) were represented in the cohort, including under 10 and over 70 years old. The Influenzanet population was not representative of the general population in terms of age distribution, underrepresenting the youngest and oldest age classes. The gender imbalance differed between countries. A counterbalance between gender-specific information-seeking behavior (more prominent in women) and Internet usage (with higher rates in male populations) may be at the origin of this difference. Once adjusted by demographic indicators, a similar propensity to commute was observed for each country, and the same top three transportation modes were used for six countries out of seven. Smokers were underrepresented in the majority of countries, as were individuals with diabetes; the representativeness of asthma prevalence and vaccination coverage for 65+ individuals in two successive seasons (2010/2011 and 2011/2012) varied between countries. CONCLUSIONS: Existing demographic and national datasets allowed the quantification of the participation biases of a large cohort for influenza-like-illness surveillance in the general population. Significant differences were found between Influenzanet participants and the general population. The quantified biases need to be taken into account in the analysis of Influenzanet epidemiological studies and provide indications on populations groups that should be targeted in recruitment efforts.

slanDCs in carcinoma-draining lymph nodes.

Dendritic cells (DCs) are known to initiate adaptive immune responses against malignant cells. However, the role in anticancer immunosurveillance of 6-sulfo LacNAc-expressing DCs (slanDCs), a distinct population of circulating and tissue-resident pro-inflammatory DCs, is unclear. We have recently demonstrated the involvement of slanDCs in nodal immune responses against carcinoma cells.

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells.

Dendritic cells (DCs) initiate adaptive immune responses to cancer cells by activating naive T lymphocytes. 6-sulfo LacNAc(+) DCs (slanDCs) represent a distinct population of circulating and tissue proinflammatory DCs, whose role in cancer immune surveillance is unknown. Herein, by screening a large set of clinical samples, we demonstrate accumulation of slanDCs in metastatic tumour-draining lymph nodes (M-TDLN) from carcinoma patients. Remarkably, slanDCs are absent at the primary carcinoma site, while their selective nodal recruitment follows the arrival of cancer cells to M-TDLN. slanDCs surround metastatic carcinoma deposits in close proximity to dead cells and efficiently phagocytose tumour cells. In colon carcinoma patients, the contingent of circulating slanDCs remains intact and competent in terms of IL-12p70 and tumour necrosis factor alpha production, induction of T-cell proliferation and migratory capacity to a set of chemokines produced in M-TDLN. We conclude that activated slanDCs represent previously unrecognized players of nodal immune responses to cancer cells.

Neutrophils promote 6-sulfo LacNAc+ dendritic cell (slanDC) survival.

There is increasing evidence supporting the notion that neutrophils and other leukocytes establish cooperative actions in regulating innate and adaptive immune responses. In such a context, we have shown recently that human neutrophils amplify NK cell/slanDC-mediated cytokine production by directly costimulating IFN-γ production by NK cells, as well as by potentiating IL-12p70 release by slanDCs via CD18/ICAM-1 interactions. To gain more insights into the molecular bases of the neutrophil-mediated cytokine potentiation by NK cells and slanDCs under coculture conditions, we now report that neutrophils efficaciously maintain slanDC survival by contact-dependent mechanisms. Such a phenomenon occurs in the absence or presence of NK cells, which, in the presence of LPS and IL-2 or the IL-15/IL-18 combination, accelerates slanDC apoptosis significantly. Noteworthy, αICAM-1- and αCD18-neutralizing antibodies, previously shown to suppress IL-12p70 production by slanDCs and consequently, IFN-γ by NK cells under similar experimental conditions, did not minimally alter the neutrophil-mediated prosurvival effect on slanDCs. Altogether, data not only expand our knowledge on the interactions between human neutrophils and slanDCs but also prove that neutrophil-mediated promotion of slanDC survival and potentiation of slanDC-derived IL-12p70 occur via different mechanisms.

Orchestration of inflammation and adaptive immunity in Borrelia burgdorferi-induced arthritis by neutrophil-activating protein A.

OBJECTIVE: Lyme arthritis (LA) is characterized by infiltration of inflammatory cells, mainly neutrophils (polymorphonuclear cells [PMNs]) and T cells, into the joints. This study was undertaken to evaluate the role of the neutrophil-activating protein A (NapA) of Borrelia burgdorferi in eliciting inflammation and in driving the adaptive immune response. METHODS: Levels of NapA, interferon-γ (IFNγ), interleukin-17 (IL-17), and T cell-attracting chemokines were assessed by enzyme-linked immunosorbent assay in synovial fluid from patients with LA. The profile of T cells recruited into the synovia of patients with LA was defined by fluorescence-activated cell sorting analysis. NapA was intraarticularly injected into rat knees, and the cells recruited in synovia were characterized. The role of NapA in recruiting immune cells was confirmed by chemotaxis assays using a Transwell system. RESULTS: NapA, IFNγ, IL-17, CCL2, CCL20, and CXCL10 accumulated in synovial fluid from patients with LA. Accordingly, T cells obtained from these patients produced IFNγ or IL-17, but notably, some produced both cytokines. NapA promoted neutrophil and T lymphocyte recruitment both in vitro and in vivo. Interestingly, the infiltration of T cells not only resulted from the chemotactic activity of NapA but also relied on the chemokines produced by PMNs exposed to NapA. CONCLUSION: We provide evidence that NapA functions as one of the main bacterial products involved in the pathogenesis of LA. Accordingly, we show that, at very early stages of LA, NapA accumulates and, in turn, orchestrates the recruitment of inflammatory cells into the joint cavity. Thereafter, with the contribution of recruited cells, NapA promotes the infiltration of T cells producing IL-17 and/or IFNγ.

On the potential involvement of CD11d in co-stimulating the production of interferon-γ by natural killer cells upon interaction with neutrophils via intercellular adhesion molecule-3.

Interaction between neutrophils and other leukocytes plays a variety of important roles in regulating innate and adaptive immune responses. Recently, we have shown that neu-trophils amplify NK cell/6-sulfo LacNAc(+) dendritic cells (slanDC)-mediated cytokine production, by potentiating IL-12p70 release by slanDC via CD18/ICAM-1 and directly co-stimulating IFNγ production by NK cells via ICAM-3. Herein, we have identified additional molecules involved in the interactions among neutrophils, NK cells and slanDC. More specifically, we provide evidence that: i) the cross-talk between neutrophils and NK cells is mediated by ICAM-3 and CD11d/CD18, respectively; ii) slanDC potentiate the production of IFNγ by NK cells via CD11a/CD18. Altogether, our studies shed more light on the role that adhesion molecules play within the neutrophil/NK cell/slanDC network. Our data also have potential implications in the pathogenesis of diseases driven by hyperactivated leukocytes, such as Sweet's syndrome, in which a neutrophil/NK cell co-localization is frequently observed.

Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils.

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are stromal precursors endowed with extensive immunomodulative properties. In this study, we aimed to assess whether Toll-like receptor-3 (TLR3)- and TLR4-activated BM-MSC influence human neutrophil (PMN) responses under coculture conditions. We show that TLR3 triggering by polyinosinic:polycytidylic acid dramatically amplifies, in a more significant manner than TLR4 triggering by lipopolysaccharide, the antiapoptotic effects that resting BM-MSC constitutively exert on PMN under coculture conditions, preserving a significant fraction of viable and functional PMN up to 72 hours. In addition, TLR3- and TLR4-activated BM-MSC enhance respiratory burst ability and CD11b expression by PMN. The coculture in the absence of cell contact and the incubation of PMN in supernatants harvested from TLR3- and TLR4-activated BM-MSC yield comparable results in terms of increased survival and immunophenotypic changes, thus suggesting the involvement of endogenous soluble factors. Neutralizing experiments reveal that the biological effects exerted on PMN by TLR3-activated BM-MSC are mediated by the combined action of interleukin 6, interferon-ß (IFN-ß), and granulocyte macrophage colony-stimulating factor (GM-CSF), while those exerted by TLR4-activated BM-MSC mostly depend on GM-CSF. MSC isolated from thymus, spleen, and subcutaneous adipose tissue behaves similarly. Finally, the effects exerted by TLR3- or TLR4-stimulated BM-MSC on PMN are conserved even after the previous priming of BM-MSC with IFN-γ and tumor necrosis factor-α. Our data highlight a novel mechanism by which MSC sustain and amplify the functions of PMN in response to TLR3- and TLR4-triggering and may consequently contribute to inflammatory disorders.

Human neutrophils interact with both 6-sulfo LacNAc+ DC and NK cells to amplify NK-derived IFN{gamma}: role of CD18, ICAM-1, and ICAM-3.

The role of neutrophils as key players in the regulation of innate and adaptive immune responses is increasingly being recognized. We report that human neutrophils establish a network with both natural killer (NK) cells and 6-sulfo LacNAc(+) dendritic cells (slanDCs), which ultimately serves to up-regulate NK-derived interferonγ (IFNγ). This network involves direct reciprocal interactions and positive amplification loops mediated by cell-derived cytokines. Accordingly, we show that after lipopolysaccharide + interleukin-2 (IL-2) or IL-15/IL-18 stimulation, neutrophils directly interact with and potentiate the activity of both slanDCs and NK cells. On the one hand, neutrophils augment the release of IL-12p70 by slanDCs via a CD18/ intercellular adhesion molecule-1 (ICAM-1) interaction that stimulates activated NK cells to produce IFNγ. IFNγ further potentiates the interaction between neutrophils and slanDCs and the release of slanDC-derived IL-12p70, thus creating a positive feedback loop. On the other hand, neutrophils directly co-stimulate NK cells via CD18/ICAM-3, leading to the production of IFNγ. Colocalization of neutrophils, NK cells, and slanDCs, as well as of IL-12p70 and IFNγ, in inflamed tissues of Crohn disease and psoriasis provides strong evidence for a novel cellular and cytokine cooperation within the innate immune system in which neutrophils act as amplifiers of NK cell/slanDC-mediated responses.