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International human rights law on minorities sets forth a complex system of provisions affecting religious groups; still, the question of defining religious minorities remains largely unsettled. While assessing the legal framework of protection established under the UN system, this article explores the current debate drawing on the two key concepts of intersectionality and synergy. The intersectionality approach suggests that belonging to a religious minority cannot be dissociated from other features defining personal and groups’ identities (e.g., culture, ethnic origin, gender, language) and that this distinctive quality marks the multiple forms of violations and cross-cutting discriminations of which religious minorities are often victims. On the other hand, the synergy approach implies a comprehensive understanding of the legal sources protecting individual freedom of conscience and religion as well as religious minorities. Moreover, it entails fruitful cooperation among the relevant institutional and civil actors and the need for inclusive participation of persons belonging to religious minorities in democratic decision-making processes to the aim of the accomplishment of equal and full enjoyment of their human rights.

Background SARS-CoV-2 is a RNA coronavirus responsible for the pandemic of the Severe Acute Respiratory Syndrome (COVID-19). RNA viruses are characterized by a high mutation rate, up to a million times higher than that of their hosts. Virus mutagenic capability depends upon several factors, including the fidelity of viral enzymes that replicate nucleic acids, as SARS-CoV-2 RNA dependent RNA polymerase (RdRp). Mutation rate drives viral evolution and genome variability, thereby enabling viruses to escape host immunity and to develop drug resistance. Methods We analyzed 220 genomic sequences from the GISAID database derived from patients infected by SARS-CoV-2 worldwide from December 2019 to mid-March 2020. SARS-CoV-2 reference genome was obtained from the GenBank database. Genomes alignment was performed using Clustal Omega. Mann–Whitney and Fisher-Exact tests were used to assess statistical significance. Results We characterized 8 novel recurrent mutations of SARS-CoV-2, located at positions 1397, 2891, 14408, 17746, 17857, 18060, 23403 and 28881. Mutations in 2891, 3036, 14408, 23403 and 28881 positions are predominantly observed in Europe, whereas those located at positions 17746, 17857 and 18060 are exclusively present in North America. We noticed for the first time a silent mutation in RdRp gene in England (UK) on February 9th, 2020 while a different mutation in RdRp changing its amino acid composition emerged on February 20th, 2020 in Italy (Lombardy). Viruses with RdRp mutation have a median of 3 point mutations [range: 2–5], otherwise they have a median of 1 mutation [range: 0–3] (p value < 0.001). Conclusions These findings suggest that the virus is evolving and European, North American and Asian strains might coexist, each of them characterized by a different mutation pattern. The contribution of the mutated RdRp to this phenomenon needs to be investigated. To date, several drugs targeting RdRp enzymes are being employed for SARS-CoV-2 infection treatment. Some of them have a predicted binding moiety in a SARS-CoV-2 RdRp hydrophobic cleft, which is adjacent to the 14408 mutation we identified. Consequently, it is important to study and characterize SARS-CoV-2 RdRp mutation in order to assess possible drug-resistance viral phenotypes. It is also important to recognize whether the presence of some mutations might correlate with different SARS-CoV-2 mortality rates.

The Coronavirus Disease 2019 (COVID-19) is a new viral infection caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2). Genomic analyses have revealed that SARS-CoV-2 is related to Pangolin and Bat coronaviruses. In this report, a structural comparison between the Sars-CoV-2 Envelope and Membrane proteins from different human isolates with homologous proteins from closely related viruses is described. The analyses here reported show the high structural similarity of Envelope and Membrane proteins to the counterparts from Pangolin and Bat coronavirus isolates. However, the comparisons have also highlighted structural differences specific of Sars-CoV-2 proteins which may be correlated to the cross-species transmission and/or to the properties of the virus. Structural modelling has been applied to map the variant sites onto the predicted three-dimensional structure of the Envelope and Membrane proteins.

Brucella spp. are Gram-negative, non-motile, non-spore-forming, slow-growing, facultative intracellular bacteria causing brucellosis. Brucellosis is an endemic of specific geographic areas and, although underreported, represents the most common zoonotic infection, with an annual global incidence of 500,000 cases among humans. Humans represent an occasional host where the infection is mainly caused by B. melitensis, which is the most virulent; B. abortus; B. suis; and B. canis. A microbiological analysis is crucial to identifying human cases because clinical symptoms of human brucellosis are variable and aspecific. The laboratory diagnosis is based on three different microbiological approaches: (i) direct diagnosis by culture, (ii) indirect diagnosis by serological tests, and (iii) direct rapid diagnosis by molecular PCR-based methods. Despite the established experience with serological tests and highly sensitive nucleic acid amplification tests (NAATs), a culture is still considered the “gold standard” in the laboratory diagnosis of brucellosis due to its clinical and epidemiological relevance. Moreover, the automated BC systems now available have increased the sensitivity of BCs and shortened the time to detection of Brucella species. The main limitations of serological tests are the lack of common interpretative criteria, the suboptimal specificity due to interspecies cross-reactivity, and the low sensitivity during the early stage of disease. Despite that, serological tests remain the main diagnostic tool, especially in endemic areas because they are inexpensive, user friendly, and have high negative predictive value. Promising serological tests based on new synthetic antigens have been recently developed together with novel point-of-care tests without the need for dedicated equipment and expertise. NAATs are rapid tests that can help diagnose brucellosis in a few hours with high sensitivity and specificity. Nevertheless, the interpretation of NAAT-positive results requires attention because it may not necessarily indicate an active infection but rather a low bacterial inoculum, DNA from dead bacteria, or a patient that has recovered. Refined NAATs should be developed, and their performances should be compared with those of commercial and home-made molecular tests before being commercialized for the diagnosis of brucellosis. Here, we review and report the most common and updated microbiological diagnostic methods currently available for the laboratory diagnosis of brucellosis.

Background Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the first coronavirus disease 2019 (COVID-19) outbreak in China and has become a public health emergency of international concern. SARS-CoV-2 outbreak has been declared a pandemic by WHO on March 11th, 2020 and the same month several Countries put in place different lockdown restrictions and testing strategies in order to contain the spread of the virus. Methods The calculation of the Case Fatality Rate of SARS-CoV-2 in the Countries selected was made by using the data available at https://github.com/owid/covi-19-data/tree/master/public/data . Case fatality rate was calculated as the ratio between the death cases due to COVID-19, over the total number of SARS-CoV-2 reported cases 14 days before. Standard Case Fatality Rate values were normalized by the Country-specific ρ factor, i.e. the number of PCR tests/1 million inhabitants over the number of reported cases/1 million inhabitants. Case-fatality rates between Countries were compared using proportion test. Post-hoc analysis in the case of more than two groups was performed using pairwise comparison of proportions and p value was adjusted using Holm method. We also analyzed 487 genomic sequences from the GISAID database derived from patients infected by SARS-CoV-2 from January 2020 to April 2020 in Italy, Spain, Germany, France, Sweden, UK and USA. SARS-CoV-2 reference genome was obtained from the GenBank database (NC_045512.2). Genomes alignment was performed using Muscle and Jalview software. We, then, calculated the Case Fatality Rate of SARS-CoV-2 in the Countries selected. Results In this study we analyse how different lockdown strategies and PCR testing capability adopted by Italy, France, Germany, Spain, Sweden, UK and USA have influenced the Case Fatality Rate and the viral mutations spread. We calculated case fatality rates by dividing the death number of a specific day by the number of patients with confirmed COVID-19 infection observed 14 days before and normalized by a ρ factor which takes into account the diagnostic PCR testing capability of each Country and the number of positive cases detected. We notice the stabilization of a clear pattern of mutations at sites nt241, nt3037, nt14408 and nt23403. A novel nonsynonymous SARS-CoV-2 mutation in the spike protein (nt24368) has been found in genomes sequenced in Sweden, which enacted a soft lockdown strategy. Conclusions Strict lockdown strategies together with a wide diagnostic PCR testing of the population were correlated with a relevant decline of the case fatality rate in different Countries. The emergence of specific patterns of mutations concomitant with the decline in case fatality rate needs further confirmation and their biological significance remains unclear.

Background The new Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which was first detected in Wuhan (China) in December of 2019 is responsible for the current global pandemic. Phylogenetic analysis revealed that it is similar to other betacoronaviruses, such as SARS-CoV and Middle-Eastern Respiratory Syndrome, MERS-CoV. Its genome is ∼ 30 kb in length and contains two large overlapping polyproteins, ORF1a and ORF1ab that encode for several structural and non-structural proteins. The non-structural protein 1 (nsp1) is arguably the most important pathogenic determinant, and previous studies on SARS-CoV indicate that it is both involved in viral replication and hampering the innate immune system response. Detailed experiments of site-specific mutagenesis and in vitro reconstitution studies determined that the mechanisms of action are mediated by (a) the presence of specific amino acid residues of nsp1 and (b) the interaction between the protein and the host’s small ribosomal unit. In fact, substitution of certain amino acids resulted in reduction of its negative effects. Methods A total of 17,928 genome sequences were obtained from the GISAID database (December 2019 to July 2020) from patients infected by SARS-CoV-2 from different areas around the world. Genomes alignment was performed using MAFFT (REFF) and the nsp1 genomic regions were identified using BioEdit and verified using BLAST. Nsp1 protein of SARS-CoV-2 with and without deletion have been subsequently modelled using I-TASSER. Results We identified SARS-CoV-2 genome sequences, from several Countries, carrying a previously unknown deletion of 9 nucleotides in position 686-694, corresponding to the AA position 241-243 (KSF). This deletion was found in different geographical areas. Structural prediction modelling suggests an effect on the C-terminal tail structure. Conclusions Modelling analysis of a newly identified deletion of 3 amino acids (KSF) of SARS-CoV-2 nsp1 suggests that this deletion could affect the structure of the C-terminal region of the protein, important for regulation of viral replication and negative effect on host’s gene expression. In addition, substitution of the two amino acids (KS) from nsp1 of SARS-CoV was previously reported to revert loss of interferon-alpha expression. The deletion that we describe indicates that SARS-CoV-2 is undergoing profound genomic changes. It is important to: (i) confirm the spreading of this particular viral strain, and potentially of strains with other deletions in the nsp1 protein, both in the population of asymptomatic and pauci-symptomatic subjects, and (ii) correlate these changes in nsp1 with potential decreased viral pathogenicity.

α -1 antitrypsin (A1AT) is a 52 kDa acute-phase glycoprotein belonging to the serine protease inhibitor superfamily (SERPIN). It is primarily synthesized by hepatocytes and to a lesser extent by monocytes, macrophages, intestinal epithelial cells, and bronchial epithelial cells. A1AT is encoded by SERPINA1 locus, also known as PI locus, highly polymorphic with at least 100 allelic variants described and responsible for different A1AT serum levels and function. A1AT inhibits a variety of serine proteinases, but its main target is represented by Neutrophil Elastase (NE). However, recent attention has been directed towards its immune-regulatory and homeostatic activities. A1AT exerts immune-regulatory effects on different cell types involved in innate and adaptive immunity. Additionally, it plays a role in metal and lipid metabolism, contributing to homeostasis. An adequate comprehension of these mechanisms could support the use of A1AT augmentation therapy in many disorders characterized by a chronic immune response. The aim of this review is to provide an up-to-date understanding of the molecular mechanisms and regulatory pathways responsible for immune-regulatory and homeostatic activities of A1AT. This knowledge aims to support the use of A1AT in therapeutic applications. Furthermore, the review summarizes the current state of knowledge regarding the application of A1AT in clinical and laboratory settings human and animal models.

Endothelial barrier (EB) breaching is a frequent event during inflammation, and it is followed by the rapid recovery of microvascular integrity. The molecular mechanisms of EB recovery are poorly understood. Triggering of MHC molecules by migrating T-cells is a minimal signal capable of inducing endothelial contraction and transient microvascular leakage. Using this model, we show that EB recovery requires a CD31 receptor-induced, robust glycolytic response sustaining junction re-annealing. Mechanistically, this response involves src-homology phosphatase activation leading to Akt-mediated nuclear exclusion of FoxO1 and concomitant β-catenin translocation to the nucleus, collectively leading to cMyc transcription. CD31 signals also sustain mitochondrial respiration, however this pathway does not contribute to junction remodeling. We further show that pathologic microvascular leakage in CD31-deficient mice can be corrected by enhancing the glycolytic flux via pharmacological Akt or AMPK activation, thus providing a molecular platform for the therapeutic control of EB response. The mechanisms that restore endothelial barrier integrity following inflammation-induced breaching are incompletely understood. Here the authors show that the CD31 immune receptor contributes to reestablishing vascular integrity via its effects on endothelial cell metabolism.

In patients with psoriatic arthritis (PsA) an increased cardiovascular (CV) risk has been observed. Recently, a EULAR taskforce suggested to use a multiplication by the factor of 1.5 of CV risk algorithms in patients with inflammatory arthritis. This study aims to evaluate the performance of five original and adapted according to EULAR recommendations CV risk algorithms in PsA: SCORE, CUORE, Framingham Risk Score (FRS), QRISK2, and Reynold's Risk Score (RRS). Prospectively collected data from two Italian cohorts were used. Discriminatory ability for CV risk prediction was evaluated by the area under the ROC curves. Calibration between predicted and observed events was assessed by Hosmer-Lemeshow (HL) tests. Sensibility and specificity were calculated for low-to-intermediate and intermediate-to-high risk cut-offs. One hundred fifty-five patients were enrolled with an observation of 1550 patient/years. Area under the ROC were 0.7679 (95% CI 0.64768 to 0.88812), 0.864 (95% CI 0.79675 to 0.93278), 0.7575 (95% CI 0.65784 to 0.85708), 0.8660 (95% CI 0.79428 to 0.93772), and 0.7183 (95% CI 0.57795 to 0.85862) for SCORE, CUORE, FRS, QRSIK2, and RRS, respectively. HL tests demonstrated poor model fit (p<0.05) for SCORE, CUORE, and RRS. Discriminative ability and calibration were not improved by adaption of the algorithms according to EULAR recommendations. Up to 80% of CV events occurred in patients at \"low risk\" and up to 93% of CV events in patients at \"low-intermediate risk\". Adaption of the CV risk algorithms according to EULAR indications did not provide improvement in discriminative ability and calibration in patients with PsA.

Viridans Group Streptococci (VGS) species-level identification is fundamental for patients management. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has been used for VGS identification but discrimination within the Mitis group resulted difficult. In this study, VGS identifications with two MALDI-TOF instruments, the Biotyper (Bruker) and the VITEK MS (bioMérieux) have been compared to those derived from tuf, soda and rpoB genes sequencing. VGS isolates were clustered and a dendrogram constructed using the Biotyper 3.0 software (Bruker). RpoB gene sequencing resulted the most sensitive and specific molecular method for S. pneumonia identification and was used as reference method. The sensitivity and the specificity of the VITEK MS in S. pneumonia identification were 100%, while the Biotyper resulted less specific (92.4%). In non pneumococcal VGS strains, the group-level correlation between rpoB and the Biotyper was 100%, while the species-level correlation was 61% after database upgrading (than 37% before upgrading). The group-level correlation between rpoB and the VITEK MS was 100%, while the species-level correlation was 36% and increases at 69% if isolates identified as S. mitis/S. oralis are included. The less accurate performance of the VITEK MS in VGS identification within the Mitis group was due to the inability to discriminate between S. mitis and S. oralis. Conversely, the Biotyper, after the release of the upgraded database, was able to discriminate between the two species. In the dendrogram, VGS strains from the same group were grouped into the same cluster and had a good correspondence with the gene-based clustering reported by other authors, thus confirming the validity of the upgraded version of the database. Data from this study demonstrated that MALDI-TOF technique can represent a rapid and cost saving method for VGS identification even within the Mitis group but improvements of spectra database are still recommended.