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Abstract Tectonic plate motions drive the earthquake cycle, as they result in the slow accrual and sudden release of energy along plate boundaries. Steadiness of plate motions over the earthquake cycle is a central tenet of the plate tectonics theory and has long been a main pillar in models of earthquake genesis, or of plate-margins seismic potential inferred from slip-deficit estimates. The advent of geodesy in the geosciences and the availability of multi-year-long series of position measurements permit tracking the motions of tectonic plates from before to after the time of significant seismic events that occur along their margins. Here, we present evidence that large earthquakes are capable of modifying the motions of entire microplates. We use high precision Global Navigation Satellite System (GNSS) position time-series covering the periods 2001–2004 and 2014–2017 to demonstrate that, contrary to the tenet above, the South China microplate motion changed after the 2008 $$M_W$$ M W 7.9 Great Wenchuan earthquake. The GNSS data and associated uncertainties indicate a plate motion slowdown of up to 20% that is beyond the possible impact of data noise and is thus tectonically meaningful. We use quantitative models of torque balance to show that generating this kinematic change requires a force upon the South China microplate compatible with that imparted by the Great Wenchuan earthquake of 2008. The existence of a kinematic signal linked to the earthquake cycle that impacts an entire microplate might offer an additional, novel perspective to assessing the hazards of earthquake-prone tectonic regions.

Abstract Over million years, convergence between the Nazca and South America tectonic plates results in Andean orogeny. Over decades/centuries, it fuels the earthquake cycle of the Andean megathrust. It is well recognised that, over the geologically-long term of million years, Andean orogeny feeds back onto plate convergence rates, generating temporal changes documented throughout the Neogene. In contrast, no feedback mechanism operated over the geologically-short term by the earthquake cycle is currently contemplated. In fact, it is commonly assumed that the rates of contemporary convergence, which are accurately measured via geodesy, remain steady during the megathrust earthquake cycle. Here we investigate whether the contemporary Nazca/South America plate motion varies over year-/decade-long periods in response to megathrust stress variations associated with the earthquake cycle. We focus on the decade preceding the three largest and most recent $${\varvec{M_w > 8}}$$ M w > 8 earthquakes (2010 $${\varvec{M_w = 8.8}}$$ M w = 8.8 Maule, 2014 $${\varvec{M_w = 8.1}}$$ M w = 8.1 Iquique, 2015 $${\varvec{M_w = 8.3}}$$ M w = 8.3 Illapel), and find slowdowns of both Nazca and South America whole-plate motions that exceed the impact of data uncertainty or noise. We show that the torque variations required upon Nazca and South America to generate the slowdowns are consistent with that arising from the buildup of interseismic stress preceding the earthquakes.

Abstract Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, and the lack of pathophysiological experimental models limit the applicability and development of this form of therapy. Here we present a comprehensive humanized mouse model, by which we show that IFNγ neutralization by the clinically approved monoclonal antibody, emapalumab, mitigates severe toxicity related to CAR-T cell therapy. We demonstrate that emapalumab reduces the pro-inflammatory environment in the model, thus allowing control of severe CRS and preventing brain damage, characterized by multifocal hemorrhages. Importantly, our in vitro and in vivo experiments show that IFNγ inhibition does not affect the ability of CD19-targeting CAR-T (CAR.CD19-T) cells to eradicate CD19+ lymphoma cells. Thus, our study provides evidence that anti-IFNγ treatment might reduce immune related adverse effect without compromising therapeutic success and provides rationale for an emapalumab-CAR.CD19-T cell combination therapy in humans.

A high-resolution model of the motion between Nazca and South American plates is presented. The work shows rapid changes that help explaining tectono-magmatic events via a balance between kinematic energy and gravitational potential energy stored in the roots of the Andes.

The Mediterranean brown trout is one of the most endangered freshwater species. A complicated network of climate and human influences has severely harmed its biodiversity. The introduction of alien trout is one of the most serious threats to native populations’ intraspecific diversity. In Molise region (south-Italy) an important conservation program (LIFE Nat.Sal.Mo project) has recently been proposed to preserve the genetic integrity of native Mediterranean trout. This project, alongside safeguarding and re-establishing the habitats’ usefulness aims to restore the genetic integrity of the autochthonous population. This is one of the major goals, and it is accomplished by employing frozen wild breeder semen in conjunction with proper fertilization techniques to carry out artificial reproduction to enhance genetic diversity in the progeny and maintain fitness within self-sustaining populations. In this regard, the implementation of the first European semen cryobank has played a strategic role for conserving extant genomic diversity of native population. The goal of this review is to outline the procedures developed and guidelines established for the creation of a Mediterranean trout sperm cryobank. Here, we specifically provide an overview of some of the main challenges associated with the implementation of semen cryobank, the results achieved, the prospects for restoring genetic integrity in native populations, and lastly, future views for hatchery management to preserve the wild biodiversity of native salmonid species. During the project timeframe 1,683 semen doses, from 150 native breeders were stored inside the cryobank. Our results clearly showed the efficiency of the freezing procedure used, both in vitro and in vivo. In fact, we recorded satisfactory values of post-thaw sperm motility and viability that ranged from 40% to 80%, and excellent fertilization rate in vivo, which ranged from 64% to 81%.

BACKGROUND: The aim of this study is to analyze the prognostic factors in patients that underwent induction therapy and surgery for clinical stage III NSCLC. METHODS: Clinical and pathological characteristics of stage III NSCLC patients for N2 involvement that underwent neoadjuvant treatment (NAD) and surgery from 1/01/1998 to 31/12/2017 were collected and retrospectively analyzed. Tumor characteristics, yClinical, yPathological stage and lymph node characteristics were correlated to Overall Survival (OS). RESULTS: The analysis was conducted on 180 patients. Five-year OS (5YOS) was 50.9%. Univariable analysis results revealed old age (p = 0.003), clinical N2 post-NAD (p = 0.01), pneumonectomy (0.005), persistent pathological N2 (p = 0.039, HR 1.9, 95% CI 1.09–2.68) and adjuvant therapy absence (p = 0.049) as significant negative prognostic factors. Multivariable analysis confirmed pN0N1 (p = 0.02, HR 0.29, 95% CI 0.13–0.62) as a favorable independent prognostic factor and adjuvant therapy absence (p = 0.012, HR 2.61, 95% CI 1.23–5.50) as a negative prognostic factor. Patients with persistent N2 presented a 5YOS of 35.3% vs. 55.8% in pN0N1 patients. Regarding lymph node parameters, the lymph node ratio (NR) significantly correlated with OS: 5YOS of 67.6% in patients with NR < 50% vs. 29.5% in NR > 50% (p = 0.029). CONCLUSION: Clinical response aided the stratification of prognosis in patients that underwent multimodal treatment for stage III NSCLC. Adjuvant therapy seemed to be an important option in these patients, while node ratio was a strong prognosticator in patients with persistent nodal involvement.

Knowledge of the composition of the gut microbiota in freshwater fish living in their natural habitat has taxonomic and ecological importance. Few reports have been produced on the composition of the gut microbiota and on the presence of LAB in the intestines of freshwater fish that inhabit river environments. In this study, we investigated the LAB community that was present in the gastrointestinal tract (GIT) of Mediterranean trout (Salmo macrostigma) that colonized the Biferno and Volturno rivers of the Molise region (Italy). The partial 16S rRNA gene sequences of these strains were determined for the species-level taxonomic placement. The phylogenetic analysis revealed that the isolated LABs belonged to seven genera (Carnobacterium, Enterococcus, Lactobacillus, Lactiplantibacillus, Vagococcus, Lactococcus, and Weissella). The study of the enzymatic activities showed that these LABs could contribute to the breakdown of polysaccharides, proteins, and lipids. In future studies, a greater understanding of how the LABs act against pathogens and trigger the fish immune response may provide practical means to engineer the indigenous fish microbiome and enhance disease control and fish health.

Abstract The directed differentiation of patient-derived induced pluripotent stem cells into cell-type specific neurons has inspired the development of therapeutic discovery for neurodegenerative diseases. Many forms of ataxia result from degeneration of cerebellar Purkinje cells, but thus far it has not been possible to efficiently generate Purkinje neuron (PN) progenitors from human or mouse pluripotent stem cells, let alone to develop a methodology for in vivo transplantation in the adult cerebellum. Here, we present a protocol to obtain an expandable population of cerebellar neuron progenitors from mouse embryonic stem cells. Our protocol is characterized by applying factors that promote proliferation of cerebellar progenitors. Cerebellar progenitors isolated in culture from cell aggregates contained a stable subpopulation of PN progenitors that could be expanded for up to 6 passages. When transplanted into the adult cerebellum of either wild-type mice or a strain lacking Purkinje cells (L7cre-ERCC1 knockout), GFP-labeled progenitors differentiated in vivo to establish a population of calbindin-positive cells in the molecular layer with dendritic trees typical of mature PNs. We conclude that this protocol may be useful for the generation and maturation of PNs, highlighting the potential for development of a regenerative medicine approach to the treatment of cerebellar neurodegenerative diseases.

Metabolic profile of fresh turkey spermatozoa at three different reproductive period ages, namely 32, 44 and 56 weeks, was monitored by Nuclear Magnetic Resonance (NMR) spectroscopy and correlated to sperm quality parameters. The age-related decrease in sperm quality as indicated by reduction of sperm concentration, sperm mobility and osmotic tolerance was associated to variation in the level of specific water-soluble and liposoluble metabolites. In particular, the highest levels of isoleucine, phenylalanine, leucine, tyrosine and valine were found at 32 weeks of age, whereas aspartate, lactate, creatine, carnitine, acetylcarnitine levels increased during the ageing. Lipid composition also changed during the ageing: diunsaturated fatty acids level increased from 32 to 56 weeks of age, whereas a reduction of polyunsaturated fatty acids content was observed at 56 weeks. The untargeted approach attempts to give a wider picture of metabolic changes occurring in ageing suggesting that the reduction of sperm quality could be due to a progressive deficiency in mitochondrial energy producing systems, as also prompted by the negative correlation found between sperm mobility and the increase in certain mitochondrial metabolites.

Relapsing Remitting Multiple Sclerosis (RRMS) patients treated with interferon beta (IFN beta) can develop neutralizing antibodies (NAbs) that reduce treatment efficacy. Several clinical studies explored the association of NAb+ status with increased disease activity.The aim of this study was to estimate the cost of RRMS patients who develop NAbs while treated with IFN beta by the Italian National Healthcare Service (NHS) and the Italian Society perspectives.The clinical data derived from a published observational study on 567 RRMS Italian patients treated with IFN beta. The management cost data derived from the published literature. Cost data were inflated to Euro 2014.The annual direct cost to treat a patient was estimated in €15,428 in the NAb+ cohort and €14,317 in the NAb- cohort. The annual societal cost was estimated in €33,890 and €30,790 in NAb+ and NAb- patients, respectively. The cost increase related to the NAb+ status was €3,100 in the Italian societal perspective and €1,111 in the Italian NHS perspective.The results of this economic evaluation suggest the presence of an association between NAb+ status and increased costs for the management of RRMS in Italy. Further pharmacoeconomic research will be needed to confirm this first result.

Background and objectivesNatalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years.MethodsCognitive performances were examined by the Rao's Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient's self-reported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively.ResultsAfter 1 year of treatment the percentage of CI patients decreased from 29% (29/100) at baseline to 19% (19/100) (p = 0.031) and the mean baseline values of CII (13.52±6.85) and FSS (4.01±1.63) scores were significantly reduced (10.48±7.12, pConclusionsThese results demonstrate that a short-term NTZ treatment may significantly improve cognitive performances and fatigue in RRMS patients.

BACKGROUND: Urate is a natural antioxidant and may prevent CNS tissue damage and the clinical manifestations of experimental autoimmune encephalitis. Results from clinical studies are conflicting and the contribution of urate to the pathogenesis of Multiple Sclerosis (MS) remains uncertain. OBJECTIVE: To evaluate serum urate levels in MS patients and their relationships with clinical, demographic and MRI variables. METHODS: Levels of non-fasting serum uric acid and creatinine were determined by an automated enzymatic assay and glomerular filtration rate was assessed in 245 MS patients, in 252 age/sex-matched neurological controls (NC) and in 59 Healthy controls (HC). RESULTS: Median serum urate levels did not differ between MS patients (3.8 mg/dL), HC (4.0 mg/dl) and NC (4.0 mg/dL). Serum urate levels were lower in females than in males in all groups (p = 2 (3.3 mg/dL) than in those with an ARR ≤2: 3.9 mg/dL; p = 0.05). Significant lower serum urate levels were found in females than in males in all clinical MS subtypes (p

BACKGROUND: A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out. OBJECTIVE: In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas. METHODS: Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births. RESULTS: Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p

MiRNAs play a relevant role in regulating gene expression in a variety of physiological and pathological conditions including autoimmune disorders. MiRNAs are also important in the differentiation and function of the mouse intestinal epithelium. Our study was aimed to look for miRNA-based modulation of gene expression in celiac small intestine, and particularly for genes involved in cell intestinal differentiation/proliferation mechanisms. A cohort of 40 children (20 with active CD, 9 on a gluten-free diet (GFD), and 11 controls), were recruited at the Paediatrics Department (University of Naples Federico II). The expression of 365 human miRNAs was quantified by TaqMan low-density arrays. We used bioinformatics to predict putative target genes of miRNAs and to select biological pathways. The presence of NOTCH1, HES1, KLF4, MUC-2, Ki67 and beta-catenin proteins in the small intestine of CD and control children was tested by immunohistochemistry. The expression of about 20% of the miRNAs tested differed between CD and control children. We found that high miR-449a levels targeted and reduced both NOTCH1 and KLF4 in HEK-293 cells. NOTCH1, KLF4 signals and the number of goblet cells were lower in small intestine of children with active CD and in those on a GFD than in controls, whereas more nuclear beta-catenin staining, as a sign of the WNT pathway activation, and more Ki67 staining, as sign of proliferation, were present in crypts from CD patients than in controls. In conclusion we first demonstrate a miRNA mediated gene regulation in small intestine of CD patients. We also highlighted a reduced NOTCH1 pathway in our patients, irrespective of whether the disease was active or not. We suggest that NOTCH pathway could be constitutively altered in the celiac small intestine and could drive the increased proliferation and the decreased differentiation of intestinal cells towards the secretory goblet cell lineage.