Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory

Metastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescent and proliferative state in response to systemic and microenvironmental signals including immune-mediated surveillance. Despite its relevance, how intrinsic mechanisms sustain DTCs plasticity has not been addressed. By interrogating the epigenetic state of metastatic cells, we find that tumour progression is coupled with the activation of oncogenic enhancers that are organized in variable interconnected chromatin domains. This spatial chromatin context leads to the activation of a robust transcriptional response upon repeated exposure to retinoic acid (RA). We show that this adaptive mechanism sustains the quiescence of DTCs through the activation of the master regulator SOX9. Finally, we determine that RA-stimulated transcriptional memory increases the fitness of metastatic cells by supporting the escape of quiescent DTCs from NK-mediated immune surveillance. Overall, these findings highlight the contribution of oncogenic enhancers in establishing transcriptional memories as an adaptive mechanism to reinforce cancer dormancy and immune escape, thus amenable for therapeutic intervention

RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS

Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels

Early life of Neanderthals

The early onset of weaning in modern humans has been linked to the high nutritional demand of brain development that is intimately connected with infant physiology and growth rate. In Neanderthals, ontogenetic patterns in early life are still debated, with some studies suggesting an accelerated development and others indicating only subtle differences to modern humans. Here we report the onset of weaning and rates of enamel growth using an unprecedented sample set of three late (~70-50 ka) Neanderthals and one Upper Paleolithic modern human from Northeastern-Italy via spatially-resolved chemical/isotopic analyses and histomorphometry of deciduous teeth. Our results reveal that the modern human nursing strategy, with onset of weaning at 5-6 months, was present among these Neanderthals. This evidence, combined with dental development akin to modern humans, highlights their similar metabolic constraints during early life and excludes late weaning as a factor contributing to Neanderthals' demise

Unpublished Mediterranean and Black Sea records of marine alien, cryptogenic, and neonative species

To enrich spatio-temporal information on the distribution of alien, cryptogenic, and neonative species in the Mediterranean and the Black Sea, a collective effort by 173 marine scientists was made to provide unpublished records and make them open access to the scientific community. Through this effort, we collected and harmonized a dataset of 12,649 records. It includes 247 taxa, of which 217 are Animalia, 25 Plantae and 5 Chromista, from 23 countries surrounding the Mediterranean and the Black Sea. Chordata was the most abundant taxonomic group, followed by Arthropoda, Mollusca, and Annelida. In terms of species records, Siganus luridus, Siganus rivulatus, Saurida lessepsianus, Pterois miles, Upeneus moluccensis, Charybdis (Archias) longicollis, and Caulerpa cylindracea were the most numerous. The temporal distribution of the records ranges from 1973 to 2022, with 44% of the records in 2020–2021. Lethrinus borbonicus is reported for the first time in the Mediterranean Sea, while Pomatoschistus quagga, Caulerpa cylindracea, Grateloupia turuturu, and Misophria pallida are first records for the Black Sea; Kapraunia schneideri is recorded for the second time in the Mediterranean and for the first time in Israel; Prionospio depauperata and Pseudonereis anomala are reported for the first time from the Sea of Marmara. Many first country records are also included, namely: Amathia verticillata (Montenegro), Ampithoe valida (Italy), Antithamnion amphigeneum (Greece), Clavelina oblonga (Tunisia and Slovenia), Dendostrea cf. folium (Syria), Epinephelus fasciatus (Tunisia), Ganonema farinosum (Montenegro), Macrorhynchia philippina (Tunisia), Marenzelleria neglecta (Romania), Paratapes textilis (Tunisia), and Botrylloides diegensis (Tunisia).Stelios Katsanevakis, Michail Ragkousis, Maria Sini, Markos Digenis and Vasilis Gerovasileiou were supported by the Hellenic Foundation for Research and Innovation (HFRI) under the “First Call for HFRI Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project ALAS – “ALiens in the Aegean – a Sea under siege” (Katsanevakis et al. 2020b); Project Number: HFRI-FM17-1597). Konstantinos Tsirintanis was co-financed by Greece and the European Union (European Social Fund-ESF) through the Operational Programme “Human Resources Development, Education and Lifelong Learning”, 2014-2020, in the context of the Act “Enhancing Human Resources Research Potential by undertaking a Doctoral Research” Sub-action 2: IKY Scholarship Programme for PhD candidates in the Greek Universities. Maria Zotou was supported by the project “Coastal Environment Observatory and Risk Management in Island Regions AEGIS+” (MIS 5047038), implemented within the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020), co financed by the Hellenic Government (Ministry of Development and Investments) and the European Union (European Regional Development Fund, Cohesion Fund). Razy Hoffman was supported by Yad-Hanadiv Foundation, through the Israel Society of Ecology and Environmental Sciences and Israel Nature and Parks Authority, an integrated program for establishing biological baselines and monitoring protocols for marine reserves in the Israeli Mediterranean Sea (Grant #10669). Tatiana Begun, Adrian Teaca and Mihaela Muresan were supported by the European Union’s Horizon 2020 BRIDGE-BS project under grant agreement no. 101000240. Fiona Tomas was supported by the project “Invasion of the tropical alga Halimeda incrassata in the Balearic Islands: ecology and invasion dynamics (AAEE119/2017)”, funded by the Vicepresidencia y Consejería de Innovación, Investigación y Turismo del Govern de les Illes Balears, with support from the European Union and FEDER funds, and the project “Una nueva alga invasora en el Mediterráneo: invasibilidad, detección y erradicación del alga tropical Halimeda incrassata (INVHALI)”, funded by the Fundación Biodiversidad, del Ministerio para la Transición Ecológica y el Reto Demográfico. Simonetta Fraschetti, Laura Tamburello, Antonia Chiarore were supported by the project PO FEAMP 2014-2020 - DRD n. 35/2019, “Innovazione, sviluppo e sostenibilità nel settore della pesca e dell'acquacoltura per la Regione Campania” (ISSPA 2.51) and the EU EASME - EMFF (Sustainable Blue Econ-omy) Project AFRIMED (http://afrimed-project.eu/, grant agreement N. 789059). Carlos Jimenez, Louis Hadjioannou, Vasilis Resaikos, Valentina Fossati, Magdalene Papatheodoulou, and Antonis Petrou were supported by MedPan Small Projects, Mava, and LIFE-IP. Louis Hadjioannou, Manos L. Moraitis and Neophytos Agrotis received funding from the European Union’s Horizon 2020 research and innovation program within the framework of the CMMI/MaRITeC-X project under grant agreement No. 857586. Ernesto Azzurro was supported by the project USEIt - Utilizzo di Sinergie operative per la gestione integrata specie aliene Invasive in Italia, funded by the research programme @CNR. Antonietta Rosso and Francesco Sciuto were supported by the University of Catania through “PiaCeRi-Piano Incentivi per la Ricerca di Ateneo 2020–22 linea di intervento 2.” This is the Catania Paleoecological Research Group contribution n. 484. Diego K. Kersting was supported by the Beatriu de Pinós programme funded by the Secretary of Universities and Research (Government of Catalonia) and the Horizon 2020 programme of research and innovation of the European Union under the Marie Sklodowska-Curie grant agreement No 801370. Francesco Tiralongo was supported by the AlienFish project of Ente Fauna Marina Mediterranea (Scientific Organization for Research and Conservation of Marine Biodiversity, 96012 Avola, Italy), a citizen science project for monitoring and studying rare and non-indigenous fish in Italian waters. Adriana Vella, was supported by funds through the BioCon_Innovate Research Excellence Grant from the University of Malta awarded to her. Noel Vella was supported by REACH HIGH Scholars Programme-Post Doctoral Grant for the FINS project. Some of the records provided by Victor Surugiu were obtained during surveys carried out within the framework of the project “Adequate management of invasive species in Romania, in accordance with EU Regulation 1143/2014 on the prevention and management of the introduction and spread of invasive alien species”, SMIS 2014+ 120008, coordinated by the Romanian Ministry of Environment, Water and Forests in partnership with the University of Bucharest (2018–2022). Alan Deidun and Alessio Marrone were supported by the “Spot The Alien” citizen science campaign for the monitoring of the Alien species in the Maltese archipelago and by the Interreg Italia-Malta Harmony project. The authors from the National Institute of Biology (Slovenia) acknowledge the financial support of the Slovenian Research Agency (Research Core Funding No. P1-0237) and of the Ministry of Agriculture, Forestry and Food (project “Survey of the species richness and abundance of alien species in the Slovenian Sea”). Emanuele Mancini and Fabio Collepardo Coccia were supported by the project PO-FEAMP 2014-2020 “BIOBLITZ: research, knowledge and participation for the sustainable management of marine resources (BioBlitz Blu 2020)” coordinated by CURSA for MIPAAF, the Italian Ministry of Agricultural, Food and Forestry Policies, Measure 1.40 - Protection and restoration of biodiversity and marine ecosystems and compensation schemes in the context of sustainable fishing activities. Daniele Grech was supported by the PO-FEAMP 2014-2020 project ECOGESTOCK “Approccio ECOsistemico per la tutela e la GEStione delle risorse biologiche e STOCK ittici nelle acque interne”, the citizen science project Progetto Fucales: chi le ha viste? and the Paralenz Every dive counts sponsor. Jamila Rizgalla was supported by the project Snowball for the monitoring of alien species in Libyan waters له اهتفش له اهتدطصا ؟) have you seen it have you fished it?). Gerasimos Kondylatos and Dimitrios Mavrouleas were supported by the project “EXPLIAS” (MIS (ΟΠΣ): 5049912), design and piloting methods of commercial exploitation of invasive alien species with a view to contributing to their population control, coordinated by the National Technical University of Athens with the collaboration of the Hellenic Centre for Marine Research and the University of the Aegean and co-founded by Greece and the European Union. G. Kondylatos and Savvas Nikolidakis were supported by the project “SAMOS” (ID CODE: 32.2072004/001), a study for a submarine productive park in Marathokampos of Samos. Paraskevi K. Karachle, Aikaterini Dogrammatzi, Giorgos A. Apostolopoulos, Kassiani Konida and Melina Nalmpanti were supported by the project “4ALIEN: Biology and the potential economic exploitation of four alien species in the Hellenic Seas”, funded by NRSF 2017-2020 (MIS (ΟΠΣ): 5049511). Fabio Crocetta and Riccardo Virgili were partially funded by the project PO FEAMP Campania 2014–2020, DRD n. 35 of 15th March 2018, Innovazione, sviluppo e sostenibilità nel settore della pesca e dell’acquacoltura per la regione Campania, Misura 2.51, WP5, Task 5.5 Presenza e distribuzione di specie non indigene del macrozoobenthos e del necton in Campania. Michel Bariche was partially funded by the University Research Board of the American University of Beirut (DDF 103951/2592). Constantinos G. Georgiadis, Dimitra Lida Rammou, Paschalis Papadamakis and Sotiris Orfanidis were supported by the MSFD monitoring program. Sonia Smeraldo was supported by the MPA-Engage project, led by the Institute of Marine Sciences of the Spanish National Research Council and funded by the Interreg MED program. Evgeniia Karpova acknowledge that the publication of this article was in part carried out within the framework of the state assignment of the FRC IBSS “Patterns of Formation and Anthropogenic Transformation of Biodiversity and Bioresources of the Azov– Black Sea Basin and Other Regions of the World Ocean” (No. 121030100028-0). Elena Slynko’s work was carried out within the framework of a State Assignment no. 121051100109-1 of IBIW RAS. Manuela Falautano and Luca Castriota were supported by ISPRA citizen science campaigns for the monitoring of alien species through the dedicated institutional project ([email protected]). María Altamirano was supported by the project RUGULOPTERYX funded by Fundación Biodiversidad-Ministerio para la Transición Ecológica y el reto Demográfico (Spain) and the project UMA20-FEDERJA-006 with support from the European Union and FEDER funds and Junta de Andalucía. Records provided by L. Mangialajo were collected in the framework of projects funded by the Pew Charitable Trust, by the European Commission (AFRIMED, http://afrimed-project.eu/, grant agreement N. 789059) and by the Académie 3 de l’Université Côte d’Azur (projet CONVOST).Peer reviewe

Unpublished Mediterranean and Black Sea records of marine alien, cryptogenic, and neonative species

To enrich spatio-temporal information on the distribution of alien, cryptogenic, and neonative species in the Mediterranean and the Black Sea, a collective effort by 173 marine scientists was made to provide unpublished records and make them open access to the scientific community. Through this effort, we collected and harmonized a dataset of 12,649 records. It includes 247 taxa, of which 217 are Animalia, 25 Plantae and 5 Chromista, from 23 countries surrounding the Mediterranean and the Black Sea. Chordata was the most abundant taxonomic group, followed by Arthropoda, Mollusca, and Annelida. In terms of species records, Siganus luridus, Siganus rivulatus, Saurida lessepsianus, Pterois miles, Upeneus moluccensis, Charybdis (Archias) longicollis, and Caulerpa cylindracea were the most numerous. The temporal distribution of the records ranges from 1973 to 2022, with 44% of the records in 2020–2021. Lethrinus borbonicus is reported for the first time in the Mediterranean Sea, while Pomatoschistus quagga, Caulerpa cylindracea, Grateloupia turuturu, and Misophria pallida are first records for the Black Sea; Kapraunia schneideri is recorded for the second time in the Mediterranean and for the first time in Israel; Prionospio depauperata and Pseudonereis anomala are reported for the first time from the Sea of Marmara. Many first country records are also included, namely: Amathia verticillata (Montenegro), Ampithoe valida (Italy), Antithamnion amphigeneum (Greece), Clavelina oblonga (Tunisia and Slovenia), Dendostrea cf. folium (Syria), Epinephelus fasciatus (Tunisia), Ganonema farinosum (Montenegro), Macrorhynchia philippina (Tunisia), Marenzelleria neglecta (Romania), Paratapes textilis (Tunisia), and Botrylloides diegensis (Tunisia).peer-reviewe

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Source layer identification of liquefied sands ejected during the blast-induced liquefaction test at Mirabello (Ferrara, Italy) through a quantitative compositional study.

It is well known that the occurrence of sand liquefaction phenomena may cause significant modifications of soil geotechnical properties and reduction of load-bearing capacity. Recent experiences (New Zealand, United States) have shown that liquefaction can be induced and monitored with field scale blast tests in order to study the related effects on soil chacacteristics. In this context the composition of sand blows represents an important tool to identify the liquefied layers. This study reports the composition of sands ejected during the blast-induced liquefaction test carried out in May 2016 at Mirabello (Ferrara, Italy). In 2012, the same area was largely affected by liquefaction phenomena during the Mw 6.1 Emilia earthquake. Sand samples analyzed in thin section (34 samples, 300 points for each sample, fraction 0125-0.250 mm) include blast-induced sand blows, sands from 2 cores at different depths in the subsurface (from 2 to 20 m) and sands from 2 trenches in the blast site representative of 2012 liquefied sands. The sands from the cores show a clear trend from lithoarenitic to quartz-feldspar-rich compositions. The sands at shallow depth (up to 7 m) are the most lithoarenitic, with sedimentary fine-grained rock fragments (shales and siltstones) as the dominant lithic type. Lithic fragments derive mostly from the erosion of sedimentary terrigenous and carbonate successions of Apenninic affinity. These shallow sands are well distinguishable from the deeper sands (at depth > 7 m) that show compositions slightly enriched in quartz and feldspars and impoverished in lithic fragments that suggest affinity with the Po river sands. The composition of ejected sands largely overlap that of the shallow Apenninic sands at depth from 6 to 7 m. Similarly the sands from the 2012 dikes show a composition of Apenninic affinity compatible with that of the shallow sands. Results from the blast test fit well with data obtained from the study of the sands ejected in the nearby area of San Carlo during the Mw 6.1 earthquake (Fontana et al., 2015). Also in this case, sand composition and fabric indicate that liquefaction processes affected mainly sand layers at relatively shallow depth ( 6.8-7.5 m). The study shows that composition of sands is crucial for a better understanding of earthquake-induced liquefaction mechanisms, in particular to identify the source layer of the sand blows and, more generally, for the recognition of critical levels prone to hazardous sand liquefaction phenomena

The petrography of sands ejected during the blast-induced liquefaction test (Mirabello, Ferrara, Italy) as a tool to identify the provenance of the source level

It is well known that the occurrence of sand liquefaction phenomena may cause significant modifications of soil geotechnical properties and reduction of load-bearing capacity. Recent experiences (New Zealand, United States) have shown that liquefaction can be induced and monitored with field scale blast tests to study the related effects on soil chacacteristics. In this context the composition of sand blows represents an important tool to identify the liquefied layers. This study reports the composition of sands ejected during the blast-induced liquefaction test carried out in May 2016 at Mirabello (Ferrara, Italy). In 2012 the same area was largely affected by liquefaction phenomena during the Mw 6.1 Emilia earthquake. Sand samples analyzed in thin section (34 samples, 300 points for each sample, fraction 0125-0.250 mm) include blast-induced sand blows, sands from 2 cores at different depths in the subsurface (from 2 to 20 m) and sands from 2 trenches in the blast site representative of 2012 liquefied sands. The sands from the cores show a clear trend from lithoarenitic to quartz-feldspar-rich compositions. The sands at shallow depth (up to 7 m) are the most lithoarenitic, with sedimentary fine-grained rock fragments (shales and siltstones) as the dominant lithic type. Lithic fragments derive mostly from the erosion of sedimentary terrigenous and carbonate successions of Apenninic affinity. These shallow sands are well distinguishable from the deeper sands (at depth > 7 m) that show composition slightly enriched in quartz and feldspars and impoverished in lithic fragments. A similar composition suggests affinity with the Po river sands. The composition of ejected sands largely overlap that of the shallow Apenninic sands at depth from 6 to 7 m. Similarly the sands from the 2012 dikes show a composition of Apenninic affinity compatible with that of the shallow sands. Results from the blast test fit well with data obtained from the study of the sands ejected in the nearby area of San Carlo during the Mw 6.1 earthquake (Fontana et al., 2015). Also in this case, sand composition and fabric indicate that liquefaction processes affected mainly sand layers at relatively shallow depth (at depth of 6.8-7.5 m). The study shows that composition of sands is crucial for a better understanding of earthquake-induced liquefaction mechanisms, in particular to identify the source layer of the sand blows and, more generally, for the recognition of critical levels prone to hazardous sand liquefaction phenomena

Hospital health care offer. A monitoring multidisciplinar approach

The experience we are going to show here represents the synergic work of researchers coming from different cultural extractions: bioengineers, architects and physicians. The Monitoring System ( MonLAB) wanted by Careggi Hospital (Florence, Italy) together with University of Florence is supervising the process of deep rethinking of the hospital itself. To do this, we developed many procedures and ICT tools to achieve these main goals: time and cost monitoring, critical moments prevision and alerts generation, real-time control of hospital evolving estate in terms of beds, ambulatories, deposits, clinicians rooms, technologies and more

Human herpesvirus 8 and human herpesvirus 2 infections in prison population

Incarcerated persons have high rates of infectious diseases. Few data on the prevalence of sexually transmitted diseases in prisoners are available. This multi-center cross-sectional study enrolled 973 inmates from eight Italian prisons. Demographic and behavioral data were collected using an anonymous standardized questionnaire and antibodies to HIV, HCV, HBV, HSV-2, and HHV-8 were detected in a blood sample obtained from each person at the time of the enrollment in the study. Two hundred and two out of the 973 subjects (20.7%) had antibodies against HHV-8. HHV-8-seropositive subjects were more likely to be older than 30 years with a higher educational level. HHV-8 infection was associated significantly with HBV (P < 0.001) and HSV-2 (P = 0.004) seropositivity and with previous imprisonments. Multivariate analysis showed that HHV-8 infection in Italian inmates was associated with HBV (P < 0.001) and HSV-2 (P = 0.002) seropositivity otherwise among foreigners inmates HHV-8 was significantly associated with HBV infection (P = 0.05). One hundred and eighty-six (21.2%) prisoners had anti-HSV-2 antibodies. At multivariate analysis HSV-2-positivity was significantly associated with HIV (P < 0.001) and HHV-8 infections (P = 0.003), whereas it was inversely associated with HCV infection (0.004). A relatively high seroprevalence of HHV-8 and HSV-2 among Italian prison inmates was found. The association of HHV-8 and HSV-2 infections suggest sexual transmission of these viruses among Italian prison inmates