Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain.

Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer

Structure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.

Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD

A new naturalized alien plant in Sicily: Cotula australis (Sieber ex Spreng.) Hook. f. (Asteraceae) on the Acropolis of Lipari Island (Aeolian Archipelago)

In February 2018 a copious population of Cotula australis Hook f. (Asteraceae, Anthemideae) was found on the cobblestones of the Acropolis of Lipari Island (Aeolian Archipelago, NE Sicily). This population represents the first record in southern Italy and is located at a distance of about 470 km as the crow flies from the nearest neighbour. From the phytosociological point of view, C. aus- tralis dominates a therophytic subnitrophilous dwarf vegetation of trampled sites which can be ascribed to the cosmopolitan class Polygono-Poetea annuae Rivas Mart. 1975. This plant communi- ty is proposed as a new association, Galio muralis-Cotuletum australis, which can be considered a Mediterranean vicariant of the Polycarpo tetraphylli-Cotuletum australis Wildpret, Perez de Paz, Del Arco & Garcia Gallo 1988, recorded from the Canary Islands and Portugal. Some hypotheses on the origin of the Aeolian population in the frame of a documented very fast recent propagation world- wide are discussed

Mycobacterium tuberculosis Drives Expansion of Low-Density Neutrophils Equipped With Regulatory Activities

In human tuberculosis (TB) neutrophils represent the most commonly infected phagocyte but their role in protection and pathology is highly contradictory. Moreover, a subset of low-density neutrophils (LDNs) has been identified in TB, but their functions remain unclear. Here, we have analyzed total neutrophils and their low-density and normal-density (NDNs) subsets in patients with active TB disease, in terms of frequency, phenotype, functional features, and gene expression signature. Full-blood counts from Healthy Donors (H.D.), Latent TB infected, active TB, and cured TB patients were performed. Frequency, phenotype, burst activity, and suppressor T cell activity of the two different subsets were assessed by flow cytometry while NETosis and phagocytosis were evaluated by confocal microscopy. Expression analysis was performed by using the semi-quantitative RT-PCR array technology. Elevated numbers of total neutrophils and a high neutrophil/lymphocyte ratio distinguished patients with active TB from all the other groups. PBMCs of patients with active TB disease contained elevated percentages of LDNs compared with those of H.D., with an increased expression of CD66b, CD33, CD15, and CD16 compared to NDNs. Transcriptomic analysis of LDNs and NDNs purified from the peripheral blood of TB patients identified 12 genes differentially expressed: CCL5, CCR5, CD4, IL10, LYZ, and STAT4 were upregulated, while CXCL8, IFNAR1, NFKB1A, STAT1, TICAM1, and TNF were downregulated in LDNs, as compared to NDNs. Differently than NDNs, LDNs failed to phagocyte live Mycobacterium tuberculosis (M. tuberculosis) bacilli, to make oxidative burst and NETosis, but caused significant suppression of antigen-specific and polyclonal T cell proliferation which was partially mediated by IL-10. These insights add a little dowel of knowledge in understanding the pathogenesis of human TB

Humoral immunological parameters in Italian patients with oral lichen planus

Serum humoral immunological parameters were determined in 25 patients with atrophic-erosive forms of oral lichen planus (OLP) (Group 1), in 28 patients with reticular-plaque-like lesions of OLP (Group 2) and in 21 healthy patients without oral lesions (Group 3). Comparing patients affected by atrophic-erosive forms of OLP (Group 1) with normal Controls (Group 3), increased levels of serum IgG approaching the statistical significance were found (Kruskal-Wallis test p = 0.0572). It was also found a significantly higher value of kappa (Kruskal-Wallis test p = 0.0017; Mann-Whitney test with Bonferroni’s correction p < 0.001) and lambda (Kruskal-Wallis test p = 0.0346; Mann-Whitney test with Bonferroni’s correction p = 0.013) light chains in patients with atrophic-erosive OLP (Group 1) as compared with normal controls (Group 3). However these higher levels were probably caused by strong prevalence of chronic liver diseases (40%), in patients with atrophic-erosive variety of OLP. No one of these patients was affected by autoimmune liver disease. No differences were noted between atrophic-erosive OLP (Group 1) and hyperkeratosic OLP (Group 2). This study does not confirm the suggestion that patients with OLP may have a generalized immunologic disorder and it also add some evidences that the role of humoral immunity in the pathogenesis of OLP is probably secondary to the cell-mediated reaction against basal keratinocytes.Les principaux aspects de l’immunologie humorale ont été évalués dans deux groupes de malades porteur d’un lichen plan de la muqueuse buccale, 25 à formes atrophiques-érosives (Groupe 1), 28 à formes en réseaux ou en plaques blanches (Groupe 2), et chez 21 sujets sains. Au terme de cette étude les différences les plus remarquables sont les suivantes: le taux des IgG sériques est nettement plus élevé chez les sujets du Groupe 1 ce qui est presque significatif par rapport au Groupe 3 (p = 0.0577). L’analyse statistique a surtout révélé des différences significatives entre le Groupe 1 et le Groupe 3 (contrôle) en ce qui concerne les taux sériques des chaînes Kappa (Kruskal-Wallis test p = 0.0017; Mann-Whitney test corrigé par Bonferroni p < 0.001 ) et des chaînes Lambda (Kruskal-Wallis test p = 0.0346; Mann-Whitney test corrigé par Bonferroni p = 0.013). Aucune autre différence significative entre les trois groupes n’a été observee. Nous pensons que ces résultats sont probablement dus à la présence d’une hépatopathie chronique non auto-immune qui a été diagnostiquée dans 40% des cas du Groupe 1. Cette étude ne confirme donc pas la thèse selon laquelle les sujets atteints de lichen plan buccal pourraient avoir une défaillance de l’immunité humorale. Elle nous permet de penser que le rôle de cette dernière dans la pathogénèse de la maladie est probablement secondaire à la réaction cellulaire dirigée contre les kératinocytes

Curcumin as scaffold for drug discovery against neurodegenerative diseases

Neurodegenerative diseases (NDs) are one of major public health problems and their impact is continuously growing. Curcumin has been proposed for the treatment of several of these pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the ability of this molecule to reduce inflammation and aggregation of involved proteins. Nevertheless, the poor metabolic stability and bioavailability of curcumin reduce the possibilities of its practical use. For these reasons, many curcumin derivatives were synthetized in order to overcome some limitations. In this review will be highlighted recent results on modification of curcumin scaffold in the search of new effective therapeutic agents against NDs, with particular emphasis on AD

Uncovering the Mechanism of Aggregation of Human Transthyretin.

The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of transthyretin has been reported as the cause of the life-threatening transthyretin amyloidosis. The standard treatment of familial cases of TTR amyloidosis has been liver transplantation. Although aggregation-preventing strategies involving ligands are known, understanding the mechanism of TTR aggregation can lead to additional inhibition approaches. Several models of TTR amyloid fibrils have been proposed, but the segments that drive aggregation of the protein have remained unknown. Here we identify β-strands F and H as necessary for TTR aggregation. Based on the crystal structures of these segments, we designed two non-natural peptide inhibitors that block aggregation. This work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy

Phenotypic analysis of peripheral blood cell immunity in Italian patients with different varieties of oral lichen planus

Quantitative analysis of peripheral blood lymphocytes was carried out in 25 patients with atrophic-erosive type of oral lichen planus (OLP) (Group 1), in 28 patients with reticular-plaque like lesions of OLP (Group 2) and in 21 healthy patients (Group 3) by using flow cytometry. CD4 + subsets decreased significantly in patients with reticular-plaque like varieties when compared with healthy patients (Group 3) (One way analysis of variance p = 0.039; t-test with Bonferroni correction p< 0.05). Moreover, in patients with hyperkeratosic forms of OLP (Group 2) CD8 + cell populations were significantly higher than in controls (Group 3) (Kruskal-Wallis test p = 0.035; Mann-Whitney test with Bonferroni’s correction p< 0.0001) and consequently CD4/CD8 ratio was significantly lower in patients with reticular-plaque like lesions than in controls (Kruskal-Wallis test p = 0.01; Mann-Whitney test with Bonferroni’s correction p = 0.013). No statistical differences between patients of Group 1 (atrophic-erosive OLP) and the other two Groups (hyperkeratosic OLP and healthy controls) were detected. 40% of the patients of Group 1 were affected by chronic hepatopathies, most of which were related to hepatitis C virus (HCV), but the data were not substantially modified after adjustment for the patients with chronic liver disease HCV positive. There is no clear evidence that these results indicate the existence of a different pathogenetic mechanism between erosive-atrophic and hyperkeratosic types of OLP. On the other hand, these results and the previously reported immunohistochemical findings suggest that quantitative alterations of peripheral blood lymphocytes in hyperkeratosic varieties of OLP could represent a shift of CD4 + cells from the vascular to the oral mucosa compartment.Les lymphocytes du sang périphérique ont été évalués par cytométrie de flux dans deux groupes de malades porteurs d’un lichen plan de la muqueuse buccale: 25 à forme atrophique-érosive (Groupe 1), 28 à forme en réseaux ou en plaques blanches (Groupe 2), et chez 21 sujets sains (Groupe 3). Au terme de cette étude les différences les plus remarquables ont été les suivantes: diminution de la fraction CD4 + et une augmentation de la fraction CD8 + dans le Groupe 2 (réseaux et plaques blanches) comparés au Groupe 3 (contrôle), la différence est statistiquement significative (One ways analysis of variance p = 0.039, t test corrigé par Bonferroni p<0.05 pour CD4 + et Kruskal-Wallis test p = 0.035, Mann-Whitney test corrigé par Bonferroni p< 0.001 pour CD8 + ) par conséquent le rapport CD4/CD8 du Groupe 2 a été significativement plus bas par rapport au Groupe 3 (Kruskal-Wallis test p = 0.014; Mann-Whitney test corrigé par Bonferroni p = 0.013). Aucune autre différence significative entre les trois groupes n’a été observée, en particulier avec le Groupe 1 (formes atrophiques-érosives) dont il faut signaler que le 40% des sujets sont porteurs d’une hépatopathie chronique souvent due au virus de l’hépatite C. En conclusion la différence des résultats entre les groupes 1 et 2 ne permet pas d’affirmer l’existence d’une pathogénie différente entre les formes atrophiques-érosives et les formes en réseaux ou en plaques, elle est en accord avec les précédentes études en histo-immunochimie. Il est possible que la diminution des lymphocytes CD4 + soit secondaire au déplacement de cette population cellulaire du compartement vasculaire de la muqueuse affectée par le lichen plan.

Gli uccelli delle isole circumsiciliane

Gli autori sintetizzano tutte le informazioni bibliografiche e inedite sulle specie che sino al 30 agosto 2015 sono state contattate almeno una volta nelle 14 isole circumsiciliane (Eolie, Ustica, Egadi, Pantelleria e Pelagie), confrontando alla fine la lista complessiva con quella delle isole Maltesi. In totale sono ad oggi note 434 specie (isole Maltesi incluse); molte di esse hanno mostrato nel corso dei secoli una notevole capacità di colonizzazione, fluttuando nel tempo o addirittura estinguendosi e ricolonizzando alcune isole. Questi piccoli territori in mezzo al mare rappresentano ottimi siti di controllo dell’andamento delle migrazioni nel corso dei decenni; alcune specie hanno chiaramente cambiato il loro status rispetto al passato, aumentando o diminuendo. Nel corso di circa 15 anni in alcune di queste isole (Ustica, Marettimo, Lampedusa e Linosa) sono stati condotti dei campi di inanellamento sia primaverili sia autunnali che hanno permesso di inanellare 102.208 uccelli, in gran parte Passeriformes; ciò ha consentito di raccogliere una notevole mole di dati sulle strategie migratorie, che vengono qui brevemente presentati. Le piccole isole sono davvero importanti per gli uccelli migratori transahariani, che devono sostare durante i loro lunghi viaggi per recuperare energie; la disponibilità di risorse sotto forma di frutti selvatici o di insetti (a seconda delle specie) consente a queste masse di migratori di continuare il loro viaggio. La conservazione degli uccelli è dettata dalla Direttiva Uccelli e l’istituzione delle Zone di Protezione Speciale ha proprio lo scopo di salvaguardare alcune specie in determinati territori. Questo è un impegno preso da parte di tutti i Paesi dell’Unione Europea, proprio perché le popolazioni di uccelli non conoscono confini amministrativi e la loro tutela va al di là delle competenze e degli interessi di un singolo Paese. Per quanto riguarda le specie nidificanti, è risultata un’elevata correlazione negativa (r=-0,746), altamente significativa (P=0,002) tra la capacità dispersiva media delle specie e la superficie in km2 delle isole. Le specie con minore capacità dispersiva hanno colonizzato le isole di maggiori dimensioni, ma non quelle più piccole; questo con molta probabilità dipende dalla eterogeneità ambientale, a sua volta legata alla dimensione delle isole ed alla loro posizione geografica. Nel caso delle isole circumsiciliane, sembra che non sia tanto la distanza dalla costa a determinare il numero di specie, quanto le condizioni ambientali e la posizione geografica; indubbiamente la posizione tirrenica delle isole settentrionali rappresenta un vantaggio per la presenza di habitat differenziati e la conseguente colonizzazione di specie ad essi legate, mentre la posizione meridionale, influenzata dall’aridità africana, riduce alcune possibilità colonizzatrici da parte di alcune specie di uccelli e rende altresì problematica la stessa esistenza di habitat diversificati. Il numero delle specie nidificanti in un’isola è variabile nel tempo, essendovi specie che vi nidificano in modo irregolare. La correlazione area/N° specie nelle isole circumsiciliane è pari a 0,58, ma se si esclude l’isola di Pantelleria, sale a 0,86; essa è pari a 0,92 per le sole isole settentrionali (Eolie, Ustica ed Egadi), mentre risulta 0,99 per le sole tre isole meridionali del Canale di Sicilia.Authors summarize all bibliographic and unpublished information on bird species that have been detected at least one time up to 30th August 2015 in the 14 circum-sicilian islands (Eolian, Ustica, Egadi, Pantelleria and Pelagian Is.). The Appendix 1 compares overall lists with that of the Maltese Is., also lying in the Sicilian waters. On the whole, 434 species are known till now (Maltese Is. included); many of them showed a high colonizing capacity along the centuries, fluctuating or even becoming extinct and re-colonising some islands. These small territories in the middle of the Mediterranean sea are very good check-control sites of long-term migration trend; compared to the past, some species changed their status, increasing or declining. Additionally, during the last 15 years in some of these islands (Ustica, Marettimo, Lampedusa and Linosa) bird ringing activity has been carried out, both in spring and in autumn; it allowed to ring 102,208 birds, mainly Passeriformes; this opportunity allowed to collect a remarkable amount of data on migration strategy, here presented. The small islands are very important stop-over sites for transsaharan migratory birds, that must rest during their long journey to recover fuel in the form of fat; the availability of natural resources, such as wild fruits or insects, allows these masses of migrant birds to continue their trip. The conservation of birds has been established by the Bird Directive and the institution of Zones of Special Protection has the aim to safeguard some species in some territories. This agreement was signed by all countries of the EU, because bird populations do not know administrative borders and their conservation lies beyond the interests and authorities of a single country. Concerning breeding birds, a high negative correlation (r=-0.746, P=0.002) has been found between the average dispersal power of species and the area in km2 of islands. Species with minor dispersal power colonized the biggest but not the smallest islands; this, very probably depended on habitat heterogeneity of islands, in turn linked to the size of them and to the geographical position, more than to the distance from the continental land. Tyrrhenian position of northern islands is certainly an advantage for the presence of diversified habitats and birds inhabiting them, whereas southern position of Pantelleria and Pelagian Is., as well as Maltese Is., affected by African dryness, decreases colonizing probabilities of some bird species and the same existence of diversified habitats. The number of breeding species in each island varied along the time and some species bred irregularly. The correlation area/No. species in the islands surrounding Sicily resulted to be 0.58, but if we exclude Pantelleria Is., it grows to 0.86; besides, it grows to 0.92 if we consider only northern islands (Eolian, Ustica and Egadi Is.), and to 0.99 if we consider only southern islands