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Fil: Mattoni, Camilo Ivan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; Argentina

A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b ) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-κB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling. This study identifies a deubiquitinase (DUB) that specifically recognises and cleaves linear ubiquitin chains, implicating linear (de)ubiquitination in Wnt signalling and angiogenesis; mutations in gumby cause defects in angiogenesis in mice, and structural and biochemical analysis shows that gumby encodes a linear-ubiquitin-specific DUB. Gumby protein is linear ubiquitin-specific deubiquitinase The gumby mutation in mice is associated with lethal angiogenic defects in the embryo. Here Sabine Cordes and colleagues show that the gumby gene encodes a deubiquitinase that specifically recognizes and cleaves linear ubiquitin chains and they implicate linear (de)ubiquitination in Wnt signalling and angiogenesis. In humans, gumby-containing deletions on chromosome 5p15.2 are associated with mental retardation and craniofacial anomalies observed in cri du chat syndrome (CdCS) patients. Although not the only gene deleted, gumby might contribute to some CdCS symptoms via its effects on linear deubiquitination. This work identifies gumby and the pathways regulating the deubiquitination–ubiquitination balance as of possible relevance to antiangiogenic therapies.

Tityus curupi n. sp., belonging to the bolivianus complex, is described from the biogeogra- phically distinct area of Paraje Tres Cerros in north-eastern Argentina. We also present a molecular species delimitation analysis between Tityus curupi n. sp. and its sister species Tityus uruguayensis Borelli 1901 to confirm species integrity. Furthermore, a cytogenetic analysis is presented for these two species which contain different multivalent associations in meiosis, as a consequence of chromosome rearrangements, and the highest chromosome numbers in the genus.

Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF-κB, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren’s syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 (P=0.02, OR=1.92). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE (P=0.03, OR=1.53), pSS (P=0.016, OR=1.69), and RA (P=0.0001, OR=2.35) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.

A new troglobitic harvestman, Relictopiolus galadriel gen. nov et sp. nov., is described from Olhos d'Água cave, Itacarambi, Minas Gerais State, Brazil. Morphological characters, including male genitalia and exomorphology, suggest that this species belongs to the family Kimulidae, and it appears to share the greatest similarities with Tegipiolus pachypus. Bayesian inference analyses of a molecular dataset strongly support the inclusion of this species in Kimulidae and confirm the hypothesized sister-group relationship between R. galadriel and T. pachypus. A time calibrated phylogeny indicates that these sister-taxa diverged from a common ancestor approximately 40 Mya, during the Paleogene. The current range of Kimulidae illustrates a remarkable disjunct distribution, and leads us to hypothesize that the ancestral distribution of Kimulidae was once much more widespread across eastern Brazil. This may be attributed to the Eocene radiation associated with the warming (and humidifying) events in the Cenozoic when the best conditions for evergreen tropical vegetation in South America were established and followed by the extinction of kimulid epigean populations together with the retraction of rain forests during the Oligocene to Miocene cooling. The discovery of this relictual troglobite indicates that the Olhos d'Água cave was a stable refugium for this ancient lineage of kimulids and acted as a \"museum\" of biodiversity. Our findings, considered collectively with the diverse troglofauna of the Olhos d'Água cave, highlight it as one of the most important hotspots of troglobite diversity and endemism in the Neotropics. Given the ecological stresses on this habitat, the cavernicolous fauna are at risk of extinction and we emphasize the urgent need for appropriate conservation actions. Finally, we propose the transfer of Acanthominua, Euminua, Euminuoides and Pseudominua from Kimulidae to Zalmoxidae, resulting in two new synonymies and 13 new combinations.

Closely related organisms with transoceanic distributions have long been the focus of historical biogeography, prompting the question of whether long-distance dispersal, or tectonic-driven vicariance shaped their current distribution. Regarding the Southern Hemisphere continents, this question deals with the break-up of the Gondwanan landmass, which has also affected global wind and oceanic current patterns since the Miocene. With the advent of phylogenetic node age estimation and parametric bioinformatic advances, researchers have been able to disentangle historical evolutionary processes of taxa with greater accuracy. In this study, we used the coastal spider genus Amaurobioides to investigate the historical biogeographical and evolutionary processes that shaped the modern-day distribution of species of this exceptional genus of spiders. As the only genus of the subfamily Amaurobioidinae found on three Southern Hemisphere continents, its distribution is well-suited to study in the context of Gondwanic vicariance versus long-distance, transoceanic dispersal. Ancestral species of the genus Amaurobioides appear to have undergone several long-distance dispersal events followed by successful establishments and speciation, starting from the mid-Miocene through to the Pleistocene. The most recent common ancestor of all present-day Amaurobioides species is estimated to have originated in Africa after arriving from South America during the Miocene. From Africa the subsequent dispersals are likely to have taken place predominantly in an eastward direction. The long-distance dispersal events by Amaurobioides mostly involved transoceanic crossings, which we propose occurred by rafting, aided by the Antarctic Circumpolar Current and the West Wind Drift.

Background Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. Methods Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. Results PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. Conclusions Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.

A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development. Antibody diversification relies on the intentional mutagenesis of immunoglobulin genes for adaptive immune responses. Here, the authors identified a CTLH E3 ubiquitin ligase complex that co-opts FAM72A to recruit and degrade the UNG2 base excision repair factor to permit mutagenesis.

While grasslands, one of Earth’s major biomes, are known for their close evolutionary ties with ungulate grazers, these habitats are also paramount to the origins and diversification of other animals. Within the primarily South American spider subfamily Amaurobioidinae (Anyphaenidae), several species are found living in the continent’s grasslands, with some displaying putative morphological adaptations to dwelling unnoticed in the grass blades. Herein, a dated molecular phylogeny provides the backbone for analyses revealing the ecological and morphological processes behind these spiders’ grassland adaptations. The multiple switches from Patagonian forests to open habitats coincide with the expansion of South America’s grasslands during the Miocene, while the specialized morphology of several grass-dwelling spiders originated at least three independent times and is best described as the result of different selective regimes operating on macroevolutionary timescales. Although grass-adapted lineages evolved towards different peaks in adaptive landscape, they all share one characteristic: an anterior narrowing of the prosoma allowing spiders to extend the first two pairs of legs, thus maintaining a slender resting posture in the grass blade. By combining phylogenetic, morphological, and biogeographic perspectives we disentangle multiple factors determining the evolution of a clade of terrestrial invertebrate predators alongside their biomes.

Background:It is reported that up to 90.4% of individuals diagnosed with Rheumatoid Arthritis (RA) seek medical assistance due to severe pain. The underlying causes of this pain are multifaceted, involving factors such as inflammation, secondary osteoarthritis, as well as central and peripheral sensitization. CGRP (calcitonin gene-related peptide) is a peptide exerting nociceptive and vasodilatory effects and a debated immunomodulatory effect; inflammatory arthropathies have been associated a local increase of CGRP release and CGRP seems to increase IL6 and IL8 secretion from fibroblast-like synoviocytes isolated from RA patients.Objectives:The aim of this prospective pilot study was to determine whether patients with RA have detectable levels of circulating CGRP, to investigate the correlation between CGRP and with pain levels reported by the patients and to assess the effect of baricitinib on pain and CGRP levels.Methods:We enrolled RA patients starting treatment with baricitinib for high-to-moderate active RA. At baseline and after 4 and 12 weeks of treatment we collected clinical data (number of tender and swollen joints), Erytrhosedimentation Rate (ESR), C Reactive Protein (CRP) levels, and patients reported outcomes [Patients Global Assessment (PGA) and pain on a 0-10 cm Visual Analogic Scale (VAS)]. CGRP serum levels were assessed in serum from RA patients at baseline and after 4 and 12 weeks of treatment with baricitinib using an ELISA kit. Data were expressed as mean ± standard deviation or median (IQR) according to distribution. Mann-Whitney and Spearman tests were performed for comparisons and p values < 0.05 were considered statistically significant.Results:We enrolled 43 patients (F:M =36:7, median age=58, IQR 11 years, median disease duration =144, IQR 150) starting baricitinib. We defined responders (R) patients those who achieved at least a EULAR moderate response (1.2 point reduction) of DAS28_CRP from baseline value and not-responders (NR) those who did not. At baseline pain VAS score did not differ significantly between R and NR. Already after 4 weeks of treatment all patients showed a significant reduction of pain (median pain score was 8(2) at baseline, 4(5) and 2(5) after 4 and 12 weeks, respectively; p=0.0014 and p<0.0001 vs baseline, respectively). R patients had lower pain VAS scores after 4 and 12 weeks of follow-up (p=0.0038 and p=0.0026) compared to NR. CGRP was significantly reduced in the whole cohort at 4 (p=0.0016) and 12 weeks (p=0.018) (Figure 1a). NR patients showed higher CGRP serum levels compared to R, after one month of baricitinib. Levels of CGRP significantly correlated with pain VAS (p=0.0152, r=0.22) (Figure 1b) and PGA (p=0.02, r=0.21), but not with ESR, CRP or disease activity (DAS28_CRP).Conclusion:With the same disease activity, we found higher levels of CGRP in active RA patients with higher levels of pain. Interestingly, CGRP was reduced to a greater extent in patients who responded to the JAK inhibitor. This preliminary result sheds light on a possible additional mechanism of baricitinib efficacy, linked to modulation of neurotransmission other than to control of inflammation. On the other hand, in NR patients, other mechanisms underlying pain may contribute to non-response to therapy.REFERENCES:[1] Walsh DA, et al. Nat Rev Rheumatol. Oct 2014;10(10):581-92.[2] Russell FA, et al. Physiol Rev. Oct 2014;94(4):1099-142.[3] Raap T, et al. J Rheumatol. Nov 2000;27(11):2558-65.Figure 1.a. Reduction of serum CGRP in patients treated with baricitinib, from baseline (T0) and after 1 and 3 months of treatment (T1, T3). b. correlation between levels of pain and serum CGRP.Acknowledgements:NIL.Disclosure of Interests:Cristina Garufi: None declared, Silvia Mancuso: None declared, Letizia Caruso: None declared, Fulvia Ceccarelli: None declared, Simona Truglia: None declared, Fabrizio Conti Eli Lilly, Abbvie, UCB, Pfizer, Galapagos, Francesca Romana Spinelli Eli Lilly, Abbvie, UCB, Galapagos