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The ecological impact of non-native species arises from their establishment in local assemblages. However, the rates of non-native spread in new regions and their determinants have not been comprehensively studied. Here, we combined global databases documenting the occurrence of non-native species and residence of non-native birds, mammals, and vascular plants at regional and local scales to describe how the likelihood of non-native occurrence and their proportion in local assemblages relate with their residence time and levels of human usage in different ecosystems. Our findings reveal that local non-native occurrence generally increases with residence time. Colonization is most rapid in croplands and urban areas, while it is slower and variable in natural or semi-natural ecosystems. Notably, non-native occurrence continues to rise even 200 years after introduction, especially for birds and vascular plants, and in other land-use types rather than croplands and urban areas. The impact of residence time on non-native proportions is significant only for mammals. We conclude that the continental exchange of biotas requires considerable time for effects to manifest at the local scale across taxa and land-use types. The unpredictability of future impacts, implied by the slow spread of non-native species, strengthens the call for stronger regulations on the exchange of non-native species to reduce the long-lasting invasion debt looming on ecosystems' future., (© 2024 The Author(s). Global Change Biology published by John Wiley & Sons Ltd.)

Ecological Niche Models (ENMs) are often used to project species distributions within alien ranges and in future climatic scenarios. However, ENMs depend on species-environment equilibrium, which may be absent for actively expanding species. We present a novel framework to estimate whether species have reached environmental equilibrium in their native and alien ranges. The method is based on the estimation of niche breadth with the accumulation of species occurrences. An asymptote will indicate exhaustive knowledge of the realised niches. We demonstrate the CNA framework for 26 species of mammals, amphibians, and birds. Possible outcomes of the framework include: (1) There is enough data to quantify the native and alien realised niches, allowing us to calculate niche expansion between the native and alien ranges, also indicating that ENMs can be reliably projected to new environmental conditions. (2) The data in the native range is not adequate but an asymptote is reached in the alien realised niche, indicating low confidence in our ability to evaluate niche expansion in the alien range but high confidence in model projections to new environmental conditions within the alien range. (3) There is enough data to quantify the native realised niche, but not enough knowledge about the alien realised niche, hindering the reliability of projections beyond sampled conditions. (4) Both the native and alien ranges do not reach an asymptote, and thus few robust conclusions about the species' niche or future projections can be made. Our framework can be used to detect species' environmental equilibrium in both the native and alien ranges, to quantify changes in the realised niche during the invasion processes, and to estimate the likely accuracy of model projections to new environmental conditions., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Objective: Colorectal tumours are often densely infiltrated by immune cells that have a role in surveillance and modulation of tumour progression but are burdened by immunosuppressive signals, which might vary from primary to metastatic stages. Here, we deployed a multidimensional approach to unravel the T-cell functional landscape in primary colorectal cancers (CRC) and liver metastases, and genome editing tools to develop CRC-specific engineered T cells., Design: We paired high-dimensional flow cytometry, RNA sequencing and immunohistochemistry to describe the functional phenotype of T cells from healthy and neoplastic tissue of patients with primary and metastatic CRC and we applied lentiviral vectors (LV) and CRISPR/Cas9 genome editing technologies to develop CRC-specific cellular products., Results: We found that T cells are mainly localised at the front edge and that tumor-infiltrating T cells co-express multiple inhibitory receptors, which largely differ from primary to metastatic sites. Our data highlighted CD39 as the major driver of exhaustion in both primary and metastatic colorectal tumours. We thus simultaneously redirected T-cell specificity employing a novel T-cell receptor targeting HER-2 and disrupted the endogenous TCR genes (TCR editing (TCR ED )) and the CD39 encoding gene ( ENTPD1 ), thus generating TCR ED ENTPD1 KO HER-2-redirected lymphocytes. We showed that the absence of CD39 confers to HER-2-specific T cells a functional advantage in eliminating HER-2 + patient-derived organoids in vitro and in vivo ., Conclusion: HER-2-specific CD39 disrupted engineered T cells are promising advanced medicinal products for primary and metastatic CRC., Competing Interests: Competing interests: CBo has been member of Advisory Board and Consultant for Intellia, TxCell, Novartis, GSK, Allogene, Kite/Gilead, Kiadis, Evir, Janssen, Genyo, Epsilen and received research support from Intellia Therapeutics. AP, PDB, GC, ER, BCC and CBo are inventors on different patents on cancer immunotherapy and genetic engineering., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Current treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is neoadjuvant chemotherapy (nCT), alone or combined with radiotherapy, before surgery. However, fewer than 30% of treated patients show a pathologic complete response to nCT, which correlates with increased 5-year survival compared with nonresponders. Understanding the mechanisms of response to nCT is pivotal to better stratify patients and inform more efficacious therapies. Here, we investigated the immune mechanisms involved in nCT response by multidimensional profiling of pretreatment tumor biopsies and blood from 68 patients with EAC (34 prospectively and 34 retrospectively collected), comparing complete responders versus nonresponders to nCT. At the tumor level, complete response to nCT was associated with molecular signatures of immune response and proliferation, increased putative antitumor tissue-resident memory CD39+ CD103+ CD8+ T cells, and reduced immunosuppressive T regulatory cells (Treg) and M2-like macrophages. Systemically, complete responders showed higher frequencies of immunostimulatory CD14+ CD11c+ HLA-DRhigh cells, and reduced programmed cell death ligand 1-positive (PD-L1+) monocytic myeloid-derived suppressor cells, along with high plasma GM-CSF (proinflammatory) and low IL4, CXCL10, C3a, and C5a (suppressive). Plasma proinflammatory and suppressive cytokines correlated directly and inversely, respectively, with the frequency of tumor-infiltrating CD39+ CD103+ CD8+ T cells. These results suggest that preexisting immunity in baseline tumor drives the clinical activity of nCT in locally advanced EAC. Furthermore, it may be possible to stratify patients based on predictive immune signatures, enabling tailored neoadjuvant and/or adjuvant regimens., Significance: Multidimensional profiling of pretreatment esophageal adenocarcinoma shows patient response to nCT is correlated with active preexisting immunity and indicates molecular pathways of resistance that may be targeted to improve clinical outcomes., (©2023 The Authors; Published by the American Association for Cancer Research.)

The Common Agricultural Policy (CAP) is the European Union's main instrument for agricultural planning, with a new reform approved for 2023-2027. The CAP intends to align with the European Green Deal (EGD), a set of policy initiatives underpinning sustainable development and climate neutrality in the European Union (EU), but several flaws cast doubts about the compatibility of the objectives of these 2 policies. We reviewed recent literature on the potential of CAP environmental objectives for integration with the EGD: protection of biodiversity, climate change mitigation and adaptation, and sustainable management of natural resources. The CAP lacks appropriate planning measures, furthering instead risks to biodiversity and ecosystem services driven by landscape and biotic homogenization. Funding allocation mechanisms are not tailored to mitigate agricultural emissions, decreasing the efficiency of climate mitigation actions. The legislation subsidies farmers making extensive use of synthetic inputs without adequately supporting organic production, hindering the transition toward sustainable practices. We recommend proper control mechanisms be introduced in CAP Strategic Plans from each member state to ensure the EU is set on a sustainable production and consumption path. These include proportional assignment of funds to each CAP objective, quantitative targets to set goals and evidence-based interventions, and relevant indicators to facilitate effective monitoring of environmental performance. Both the CAP and the EGD should maintain ambitious environmental commitments in the face of crisis to avoid further degradation of the natural resources on which production systems stand., (© 2022 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

While the regional distribution of non-native species is increasingly well documented for some taxa, global analyses of non-native species in local assemblages are still missing. Here, we use a worldwide collection of assemblages from five taxa - ants, birds, mammals, spiders and vascular plants - to assess whether the incidence, frequency and proportions of naturalised non-native species depend on type and intensity of land use. In plants, assemblages of primary vegetation are least invaded. In the other taxa, primary vegetation is among the least invaded land-use types, but one or several other types have equally low levels of occurrence, frequency and proportions of non-native species. High land use intensity is associated with higher non-native incidence and frequency in primary vegetation, while intensity effects are inconsistent for other land-use types. These findings highlight the potential dual role of unused primary vegetation in preserving native biodiversity and in conferring resistance against biological invasions., (© 2023. The Author(s).)

Biological invasions have emerged as one of the main drivers of biodiversity change and decline, and numbers of species classed as alien in parts of their ranges are rapidly rising. The European Union established a dedicated regulation to limit the impacts of invasive alien species (IAS), which is focused on the species on a Union List of IAS of particular concern. However, no previous study has specifically addressed the ecology of invasive alien mammals included on the Union List.We performed a systematic review of published literature on these species. We retrieved 262 publications dealing with 16 species, and we complemented these with the most up-to-date information extracted from global databases on IAS.We show that most of the study species reached Europe as pets and then escaped from captivity or were intentionally released. On average each year in the period 1981-2020, 1.2 species were recorded for the first time as aliens in European countries, and most species are still expanding their alien ranges by colonising neighbouring territories. France is the most invaded nation, followed by Germany, Italy, and the Russian Federation, and the muskrat Ondatra zibethicus , the American mink Neovison vison , and the raccoon dog Nyctereutes procyonoides are the most widespread species, having invaded at least 27 countries each. Invasive mammals of European Union concern are threatening native biodiversity and human well-being: worryingly, 81% of the 16 study species are implicated in the epidemiological cycle of zoonotic pathogens.Containing secondary spread to further countries is of paramount importance to avoid the establishment of new populations of invasive mammals and the related impacts on native communities, ecosystem services, and human health.We present a compendium on the ecology and impacts of invasive mammals of European Union concern. It can be used to assist environmental policies, identify and subsequently fill knowledge gaps, and inform stakeholders., (© 2021 The Authors. Mammal Review published by Mammal Society and John Wiley & Sons Ltd.)

We developed the DAMA (Distribution of Alien Mammals) database, a comprehensive source reporting the global distribution of the 230 species of mammals that have established self-sustaining and free-ranging populations outside their native range due to direct or indirect human action. Every alien range is accompanied by information on its invasion stage, pathway, method of introduction, and date of introduction. We collected information from 827 different sources (scientific literature, books, risk assessments, reports, online biodiversity databases and websites), and used it to draw alien range maps for these species following the IUCN mapping framework. DAMA comprises 2,726 range polygons, covering 199 countries, 2,190 level 1 administrative areas, and 11 zoogeographic realms for the period 21500 BC-AD 2017. The most represented orders among introduced mammal species are Rodentia (n = 58, 25.22%), Cetartiodactyla (n = 49 species, 21.30%), Carnivora (n = 30 species, 13.04%), Diprotodontia (n = 28, 12.17%), and Primates (n = 26, 11.30%). Mammal species have been frequently introduced for hunting (n = 100), pet trade (n = 57), conservation (n = 51), and fauna improvement (n = 42). The majority of range polygons are placed on islands (n = 2,196, 80.56%), encompass populations that have moved beyond establishment and into the invasion stage (n = 1,655, 60.71%), and originated from 1500 AD to the present (n = 1,496, 54.88%). Despite inheriting literature biases towards more studied regions (e.g., developed countries), DAMA is the most up-to-date picture of alien mammal global distribution and can be used to investigate their invasion ecology across different biogeographical regions. There are no copyright or proprietary restrictions; IUCN range maps were modified into a derivative work according to the IUCN's terms of service., (© 2021 by the Ecological Society of America.)

Background: GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl., Methods: In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2., Results: Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling., Conclusions: Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis., Competing Interests: The authors have declared that no competing interests exist.

Mitochondrial dysfunction has been implicated in the pathogenesis of a number of neurodegenerative disorders including Parkinson, Alzheimer, and Amyotrophic Lateral Sclerosis (ALS). In addition, aberrant mRNA splicing has been documented in neurodegeneration. To characterize the cellular response to mitochondrial perturbations at the level of gene expression and alternative pre-mRNA splicing we used splicing-sensitive microarrays to profile human neuroblastoma SH-SY5Y cells treated with paraquat, a neurotoxic herbicide that induces the formation of reactive oxygen species and causes mitochondrial damage in animal models, and SH-SY5Y cells stably expressing the mutant G93A-SOD1 protein, one of the genetic causes of ALS. In both models we identified a common set of genes whose expression and alternative splicing are deregulated. Pathway analysis of the deregulated genes revealed enrichment in genes involved in neuritogenesis, axon growth and guidance, and synaptogenesis. Alterations in transcription and pre-mRNA splicing of candidate genes were confirmed experimentally in the cell line models as well as in brain and spinal cord of transgenic mice carrying the G93A-SOD1 mutation. Our findings expand the realm of the pathways implicated in neurodegeneration and suggest that alterations of axonal function may descend directly from mitochondrial damage., (© 2011 Wiley-Liss, Inc.)

Background and Aim of the Study: Thyroglobulin (Tg) evaluation is currently used in the follow-up of patients with differentiated thyroid carcinoma (DTC), but the measurement methods are flawed by analytical inaccuracy. In this paper we describe the results of a comparison between seven different immunoradiometric assays (IRMAs) for Tg determination., Material and Methods: Tg was measured in 50 patients with DTC by means of the following commercially available IRMA kits: HTGK-2 (DiaSorin), Tg IRMA (Schering-CIS bio international), ELSA-hTG (Schering-CIS bio international), Tg IRMA C.T. (ICN Pharmaceuticals), SELco Tg (Medipan Diagnostica), Tg Bridge IRMA (Adaltis) and IRMA-mat Tg (BYK-Sangtec Diagnostica). The distribution of the Tg values measured by the different IRMAs was compared and a correlation analysis was performed., Results: The Tg values were widely dispersed and the classification of patients according to Tg concentrations of clinical relevance varied depending on the IRMA used., Conclusion: Despite efforts to develop standardized Tg assays, the measurement of this biomarker is still affected by a considerable degree of analytical inaccuracy. Tg values vary widely between assays and the classification of patients according to Tg values with clinical relevance is still dependent on the assay used.

Postsurgical hypoparathyroidism is the most common cause of chronic hypocalcemia. This condition may occur after removal of all parathyroid glands or after interruption of the blood supply to the parathyroid glands during thyroidectomy and radical neck dissection. The severity of the clinical presentation of hypocalcemia may vary from an asymptomatic laboratory finding to a severe life-threatening condition. Persistent hypoparathyroidism requires treatment that must be maintained throughout the patient's lifetime, and for this reason care is required to avoid complications. In this review the most relevant aspects of calcium homeostasis and its alteration in hypoparathyroidism are briefly discussed. In addition, the main approaches to treatment of the hypocalcemic state are presented.

Background and Purpose: Cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant hereditary disease whose clinical expression is a stepwise subcortical vascular dementia. Initial presentation of the disease involves transient or stabilized focal neurological deficits, migraine and mood changes. Recently, a high prevalence of right-to-left shunt (RLS) due to patent foramen ovale has been reported in subjects with migraine. The aim of our study was to determine the prevalence of RLS in CADASIL with and without migraine., Methods: We performed transcranial Doppler with gaseous contrast in 5 members of an Italian family with CADASIL, diagnosed by means of genetic and skin biopsy criteria. We then compared the prevalence of RLS in 40 consecutive subjects with juvenile stroke, 80 asymptomatic subjects affected by migraine with aura and 50 normal controls., Results: A very high prevalence of RLS was found in CADASIL patients (4/5, 80%), as opposed to young subjects with ischemic stroke (15/40, 37%), asymptomatic subjects with migraine (32/80, 40%) and normal controls (8/50, 16%). All the subjects with CADASIL and migraine (4/4) showed RLS. The difference between CADASIL patients and controls was highly significant (p = 0.006)., Conclusions: We suggest an association between CADASIL and RLS, possibly due to the abnormal development of the endocardial cushion influenced by Notch 3 mutation. Our hypothesis needs to be tested in larger samples., (Copyright 2001 S. Karger AG, Basel)