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Spring of 2017, Rowan University School of Osteopathic Medicine’s student-run free clinic, the Rowan Community Health Center, launched an outreach initiative named the Unity Project. This is an ongoing initiative aimed at fostering relationships with Camden, New Jersey organizations to both educate community members about our clinic services and collaborate on improving Camden’s health. The objective of the Unity Project is to work towards affecting long-term change by forming authentic and impactful relationships with organizations that are already participating in meaningful community work. In order to achieve such a goal, we needed to overcome the traditional model of medical school outreach, which we feel is often short-term and limited. When reaching out to potential community partners, we realized an absence in the crucial first steps of establishing a relationship. We filled this void by simply asking what the organization’s need is. Thus, moving forward, when the Unity Project contacted organizations, we asked how we could help rather than offer suggestions. We termed this method the ‘Ask First’ approach and to this date, we have been observing a successful outcome. We are currently partnered with 38 organizations and are continually growing. The Unity Project has provided a variety of services that ultimately benefit the target populations these organizations are serving. Collaborating with our membered organizations in this way enables us to establish a trusting relationship and work towards bridging the gap between a community in need and a medical organization willing to help by asking a simple, albeit, powerful question.

Understanding the environmental processes shaping connectivity can greatly improve management and conservation actions which are essential in the trailing edge of species’ distributions. In this study, we used a dataset built from 32 populations situated in the southern limit of the kelp speciesLaminaria digitata. By extracting data from 11 microsatellite markers, our aim was to (1) refine the analyses of population structure, (2) compare connectivity patterns and genetic diversity between island and mainland populations and (3) evaluate the influence of sampling year, hydrodynamic processes, habitat discontinuity, spatial distance and sea surface temperature on the genetic structure using a distance-based redundancy analysis (db-RDA). Analyses of population structure enabled to identify well connected populations associated to high genetic diversity, and others which appeared genetically isolated from neighboring populations and showing signs of genetic erosion verifying contrasting ecological (and demographic) status in Brittany and the English Channel. By performing db-RDA analyses on various sampling sizes, geographic distance appeared as the dominant factor influencing connectivity between populations separated by great distances, while hydrodynamic processes were the main factor at smaller scale. Finally, Lagrangian simulations enabled to study the directionality of gene flow which has implications on source-sink dynamics. Overall, our results have important significance in regard to the management of kelp populations facing pressures both from global warming and their exploitation for commercial use.

Nidogen 1 (NID1) is an important basement membrane protein secreted by many cell types. We previously found that human cytomegalovirus (HCMV) infection rapidly induced chromosome 1 breaks and that the basement membrane protein NID1, encoded near the 1q42 break site, was downregulated. We have now determined that the specific breaks in and of themselves did not regulate NID1, rather interactions between several viral proteins and the cellular machinery and DNA regulated NID1. We screened a battery of viral proteins present by 24 hours postinfection (hpi) when regulation was induced, including components of the incoming virion and immediate early (IE) proteins. Adenovirus (Ad) delivery of the tegument proteins pp71 and UL35 and the IE protein IE1 influenced steady-state (ss) NID1 levels. IE1’s mechanism of regulation was unclear, while UL35 influenced proteasomal regulation of ss NID1. Real-time quantitative PCR (RT-qPCR) experiments determined that pp71 downregulated NID1 transcription. Surprisingly, WF28-71, a fibroblast clone that expresses minute quantities of pp71, suppressed NID1 transcription as efficiently as HCMV infection, resulting in the near absence of ss NID1. Sequence analysis of the region surrounding the 1q42 break sites and NID1 promoter revealed CCCTC-binding factor (CTCF) binding sites. Chromatin immunoprecipitation experiments determined that pp71 and CTCF were both bound at these two sites during HCMV infection. Expression of pp71 alone replicated this binding. Binding was observed as early as 1 hpi, and colocalization of pp71 and CTCF occurred as quickly as 15 min postinfection (pi) in infected cell nuclei. In fibroblasts where CTCF was knocked down, Adpp71 infection did not decrease NID1 transcription nor ss NID1 protein levels. Our results emphasize another aspect of pp71 activity during infection and identify this viral protein as a key contributor to HCMV’s efforts to eliminate NID1. Further, we show, for the first time, direct interaction between pp71 and the cellular genome. IMPORTANCE We have found that human cytomegalovirus (HCMV) utilizes multiple viral proteins in multiple pathways to regulate a ubiquitous cellular basement membrane protein, nidogen-1 (NID1). The extent of the resources and the redundant methods that the virus has evolved to affect this control strongly suggest that its removal provides a life cycle advantage to HCMV. Our discoveries that one of the proteins that HCMV uses to control NID1, pp71, binds directly to the cellular DNA and can exert control when present in vanishingly small quantities may have broad implications in a wide range of infection scenarios. Dysregulation of NID1 in an immunocompetent host is not known to manifest complications during infection; however, in the naive immune system of a developing fetus, disruption of this developmentally critical protein could initiate catastrophic HCMV-induced birth defects.

Supplementary Figure S1. BL #1 cells display low HR activity. Supplementary Figure S2. BL #1 induced BL-like leukemia in NSG mice Supplementary Figure S3. IGH/MYC-positive cells are hypersensitive to RAD52 inhibitor. Supplementary Figure S4. IGH/MYC does not downregulate mRNA encoding BRCA2. Supplementary Figure S5. c-MYC regulates the expression of BRCA2 protein. Supplementary Figure S6. miR-1245 is upregulated in IGH/MYC-positive cells.

Burkitt lymphoma/leukemia cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC–positive Burkitt lymphoma cells accumulate a high number of potentially lethal DNA double-strand breaks (DSB) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC–positive cells was associated with diminished HR activity and hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro. Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary Burkitt lymphoma xenografts. In conclusion, IGH/MYC–positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies.Implications: This study postulates that IGH/MYC–induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpg.Mol Cancer Res; 15(8); 967–72. ©2017 AACR.

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms' tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.Significance:TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase–positive malignant hematopoietic cells to PARP inhibitors.

CTLA4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti–CTLA4 immunotherapy is highly effective at reactivating T-cell responses against melanoma, which is postulated to be due to targeting CTLA4 on T cells. Here, we report that CTLA4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-γ (IFNG) signaling activated the expression of the human CTLA4 gene in a melanocyte and melanoma cell–specific manner. Mechanistically, IFNG activated CTLA4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a specific gamma-activated sequence site on the CTLA4 promoter, thereby licensing CBP/p300-mediated histone acetylation and local chromatin opening. In melanoma cell lines, elevated baseline expression relied upon constitutive activation of the MAPK pathway. Notably, RNA-seq analyses of melanoma specimens obtained from patients who had received anti–CTLA4 immunotherapy (ipilimumab) showed upregulation of an IFNG-response gene expression signature, including CTLA4 itself, which correlated significantly with durable response. Taken together, our results raise the possibility that CTLA4 targeting on melanoma cells may contribute to the clinical immunobiology of anti–CTLA4 responses.Significance: These findings show that human melanoma cells express high levels of the immune checkpoint molecule CTLA4, with important possible implications for understanding how anti-CTLA4 immunotherapy mediates its therapeutic effects. Cancer Res; 78(2); 436–50. ©2017 AACR.

Supplementary Methods and Results

Supplementary Figure S1: CTLA4 mRNA expression in human tumor cell lines. Supplementary Figure S2: CTLA4 promoter analysis. Supplementary Figure S3: UCSC genome browser view of human CTLA4 locus. Supplementary Figure S4: Recruitment of STAT1 and POL II to CTLA4 promoter by IFNG treatment. Supplementary Figure S5: The effects of CBP inhibitors on CTLA4 expression. Supplementary Figure S6: Quantification of western blotting in Fig. 5H. Supplementary Figure S7: The effects of Ruxolitinib on expression of genes of IFNG signaling pathway.

The Rowan Community Health Clinic (RCHC), located in a small community in southern New Jersey, strives to promote positive healthcare experiences as part of its service in a largely underserved area. A significant number of RCHC’s patients are immigrants, lack primary care physicians, or have difficulty communicating with doctors. Many of them demonstrate limited health literacy, which has been associated with mismanagement of health conditions, increased costs, and distrust of physicians. Lack of opportunities for health education may contribute to decreased health literacy. To address this concern affecting its patient population, the RCHC implemented a monthly Preventative Health Series (PHS) with the goal of engaging the community in order to improve health literacy. A specific health topic was emphasized each month, such as Diabetes Awareness in November and Mental Health Awareness in December. Infographics providing information about the selected topic were shared throughout the month via social media. Furthermore, during the third week of the month, a doctor or medical student gave an interactive presentation intended to facilitate discussion about the topic among healthcare workers and community members. Due to the coronavirus disease of 2019 (COVID-19) pandemic, these discussions had to be conducted online. However, using an online platform also allowed us to reach a wider audience.

Habitat-forming cold-water corals (CWCs) represent a key component of deep-sea benthic communities and a priority target for conservation. Although research efforts have been mounting to try and identify the drivers of CWC distributions, progress has been limited by the scarcity of ecological data. The present work employs habitat suitability models (HSMs) to estimate spatial distributions, environmental drivers and co-existence patterns of 14 habitat-forming CWCs in the Azores, an area considered a hotspot of coral diversity in the Atlantic. The modelled CWCs showed a strong bathymetric zonation, which seems to be determined by the vertical stratification of water masses in the region. In particular, the modelled CWCs can be clustered in four groups named after the isopycnal (vertical) layers in which Atlantic water masses are organized: species restricted to upper water masses, species extending down from upper water masses, species restricted to intermediate water masses and species extending up from deep water masses. Horizontal patterns further indicate that the Azores Current and different production regimes north and south of the archipelago likely influence the distribution of CWCs in sub-surface waters. Such results have important implications for the regional management of deep-sea benthic communities and, in particular, for the design of representative networks of protected areas. The combined habitat of all modelled species covered only 11%. Given that they all possess the characteristics of benthic foundation organisms and represent indicator taxa of vulnerable marine ecosystems all the modelled species should be viewed as important targets for conservation. The lace coral Errina dabneyi deserves particular attention since this species appears to be endemic to the Azores and has a very limited estimated distribution.

BACKGROUND AND AIMS. Epstein-Barr Virus (EBV)-associated Gastric Carcinoma (EBVaGC) is the most common EBV-associated cancer and accounts for ~10% of all gastric cancers (GC). Epstein-Barr virus Nuclear Antigen 1 (EBNA1), which is critical for the replication and maintenance of the EBV latent genome, is consistently expressed in all EBVaGC tumors. We previously developed small molecule inhibitors of EBNA1. In this study, we investigated the efficacy and selectivity of an EBNA1 inhibitor in cell-based and animal xenograft models of EBV-positive and EBV-negative gastric carcinoma. METHODS. We tested the potency of an EBNA1 inhibitor, VK-1727, in vitro and in xenograft studies, using EBV-positive (SNU-719 and YCCEL1) and EBV-negative (AGS and MKN74) GC cell lines. After treatment, we analyzed cell viability, proliferation, and RNA expression of EBV genes by RT-qPCR. RESULTS. Treatment with VK-1727 selectively inhibits cell cycle progression and proliferation in vitro. In animal studies, treatment with an EBNA1 inhibitor resulted in a significant dose-dependent decrease in tumor growth in EBVaGC xenograft models, but not in EBV-negative GC xenograft studies. Gene expression analysis revealed that short term treatment in cell culture tended towards viral gene activation, while long-term treatment in animal xenografts showed a significant decrease in viral gene expression. CONCLUSIONS. EBNA1 inhibitors are potent and selective inhibitors of cell growth in tissue culture and animal models of EBV-positive GC. Long-term treatment with EBNA1 inhibitors may lead to loss of EBV in mouse xenografts. These results suggest that pharmacological targeting of EBNA1 may be an effective strategy to treat patients with EBVaGC.

O início de carreira de um professor é um período desafiante para o desenvolvimento das suas práticas educativas. Apesar de valorizarem métodos ativos de ensino, tais como a Metodologia de Trabalho de Projeto, a pressão sentida nesta fase leva a que os professores em início de carreira experienciem dificuldades de natureza diversa na sua implementação. Este estudo visa conhecer a forma como os professores do 1.º Ciclo do Ensino Básico, em início de carreira, integram a Metodologia de Trabalho de Projeto nas suas práticas educativas. Os dados foram recolhidos através de entrevistas semiestruturadas e da análise documental ao espólio de oito professores. Os resultados demonstram que os professores valorizam e procuram contemplar o Trabalho de Projeto nas suas práticas educativas. As dificuldades sentidas poderiam ser atenuadas através de uma abordagem metodológica mais consistente na formação inicial de professores e de uma análise das prioridades educativas nas escolas onde lecionam, que sobrecarrega os professores iniciantes com demasiadas tarefas paralelas ao serviço docente.

The increased incidence of antimicrobial resistance during coronavirus disease 2019 (COVID-19) is a very important collateral damage of global concern. The cause is multifactorial and is particularly related to the high rates of antibiotic use in COVID-19 patients with a relatively low rate of secondary co-infection. To this end, we conducted a retrospective observational study of 1269 COVID-19 patients admitted during the years 2020, 2021 and 2022 in two Italian hospitals, with a focus on bacterial co-infections and antimicrobial therapy. Multivariate logistic regression was used to analyze the association between bacterial co-infection, antibiotic use and hospital death after adjustment for age and comorbidity. Bacterial co-infection was detected in 185 patients. The overall mortality rate was 25% (n = 317). Concomitant bacterial infections were associated with increased hospital mortality (β = 1.002, p < 0.001). A total of 83.7% (n = 1062) of patients received antibiotic therapy, but only 14.6% of these patients had an obvious source of bacterial infection. There was a significantly higher rate of hospital mortality in patients who received antibiotics than in those who did not (χ2 = 6.22, p = 0.012). Appropriate prescribing and the rational use of antimicrobials according to the principles of antimicrobial stewardship can help prevent the emergence of antibiotic resistance.

Epstein–Barr Virus (EBV) is a human gamma-herpesvirus that is widespread worldwide. To this day, about 200,000 cancer cases per year are attributed to EBV infection. EBV is capable of infecting both B cells and epithelial cells. Upon entry, viral DNA reaches the nucleus and undergoes a process of circularization and chromatinization and establishes a latent lifelong infection in host cells. There are different types of latency all characterized by different expressions of latent viral genes correlated with a different three-dimensional architecture of the viral genome. There are multiple factors involved in the regulation and maintenance of this three-dimensional organization, such as CTCF, PARP1, MYC and Nuclear Lamina, emphasizing its central role in latency maintenance.

Viral infection is an indisputable causal factor for nearly 17% of all human cancers. However, the diversity and complexity of oncogenic mechanisms raises new questions as to the mechanistic role of viruses in cancer. Classical viral oncogenes have been identified for all tumor-associated viruses. These oncogenes can have multiple oncogenic activities that may or may not be utilized in a particular tumor cell. In addition, stochastic events, like viral mutation and integration, as well as heritable host susceptibilities and immune deficiencies are also implicated in tumorigenesis. A more contemporary view of tumor biology highlights the importance of evolutionary forces that select for phenotypes better adapted to a complex and changing environment. Given the challenges of prioritizing singular mechanistic causes, it may be necessary to integrate concepts from evolutionary theory and systems biology to better understand viral cancer-driving forces. Here, we propose that viral infection provides a biological “entropy” that increases genetic variation and phenotypic plasticity, accelerating the main driving forces of cancer cell evolution. Viruses can also influence the evolutionary selection criteria by altering the tumor microenvironment and immune signaling. Utilizing concepts from cancer cell evolution, population genetics, thermodynamics, and systems biology may provide new perspectives on viral oncogenesis and identify novel therapeutic strategies for treating viruses and cancer.

Epstein-Barr virus (EBV) persists in human B-cells by maintaining its chromatinized episomes within the nucleus. We have previously shown that cellular factor Poly [ADP-ribose] polymerase 1 (PARP1) binds the EBV genome, stabilizes CTCF binding at specific loci, and that PARP1 enzymatic activity correlates with maintaining a transcriptionally active latency program. To better understand PARP1’s role in regulating EBV latency, here we functionally characterize the effect of PARP enzymatic inhibition on episomal structure through in situ HiC mapping, generating a complete 3D structure of the EBV genome. We also map intragenomic contact changes after PARP inhibition to global binding of chromatin looping factors CTCF and cohesin across the EBV genome. We find that PARP inhibition leads to fewer total unique intragenomic interactions within the EBV episome, yet new chromatin loops distinct from the untreated episome are also formed. This study also illustrates that PARP inhibition alters gene expression at the regions where chromatin looping is most effected. We observe that PARP1 inhibition does not alter cohesin binding sites but does increase its frequency of binding at those sites. Taken together, these findings demonstrate that PARP has an essential role in regulating global EBV chromatin structure and latent gene expression., Genome folding in the nucleus plays an important role in regulating gene expression. Here the authors show that 3D genome architecture also plays an important role for gene expression adaptability for the Epstein-Barr Virus (EBV), a virus that is associated with cancer. They also observe major changes in the fold of the EBV chromosome between silent and transcriptional active viral genomes.

Marine ecosystem-based management requires good spatial information on the distribution of marine species and habitats. Often, such information is limited to a few sampled locations, but modelling techniques can be applied to produce predictive distribution maps. A harmonized broad-scale seabed habitat map was recently produced for the archipelagos of Macaronesia under the EMODnet Seabed Habitats Programme. We use this new information to produce an extent-based evaluation of the representativeness and level of protection conferred by the current set of marine protected areas (MPAs) in the Azores to the variety of benthic marine habitats found in this oceanic region. A more objective assessment of the protection effectively provided to the habitats is obtained by applying a scoring system to the MPAs based on the number of allowed extractive and non-extractive human activities and their potential impact on marine biodiversity and habitats. Results show that Azorean habitats within the MPAs are nearly entirely classified as highly protected. In total, 26 habitats (7 of which are endangered and 2 are rare) have at least 10% of their extent in the Azores EEZ protected by MPAs, but another 29 fail to meet this target (4 on-shelf habitats and 25 deep-sea habitats), highlighting the need to extend current protection of bathyal and abyssal habitats and applying adequate ecological coherence criteria. This approach sets a standard that can be used wherever similar information is available, be it in other European regions or beyond. info:eu-repo/semantics/publishedVersion

The Epstein Barr virus (EBV) establishes a persistent latent infection in almost 90% of the population worldwide. EBV latent infection is associated with several malignancies of epithelial and lymphoid origin. In latently infected cells, the EBV genome persists as a chromatinized episome that expresses a limited set of viral genes. Latent genes are expressed in different patterns that are referred to as latency types. Latency types coincide with varying stages of EBV infection and various malignancies. Our previous work demonstrated that latency types correlate with differences in the composition and structure of the EBV episome. Several cellular factors, including nuclear lamina, regulate chromatin composition and chromatin architecture. The interaction with nuclear lamina has already been studied in the context of EBV lytic reactivation. Still, the role of nuclear lamina in controlling EBV latency has not been investigated. Here, we reported that nuclear lamina is also another essential epigenetic regulator of the EBV episome. First, we observed that in B cells, EBV infection affects the composition of nuclear lamina by inducing the expression of Lamin A/C, and Lamin A/C is present only in EBV+ B cells expressing the Type III latency program. By ChIP-seq, we determined that lamins, Lamin B1 and Lamin A/C, bind the EBV genome, and their binding correlates with deposition of the histone repressive mark H3K9me2. By RNA-seq, we observed that the knock-out of Lamin A/C alters EBV gene expression in B cells and decreases H3K9me2 levels across the viral genome. Our data indicate that the interaction between lamins and the EBV episome contributes to the epigenetic control of viral genes expression during latency, suggesting a restrictive function of the nuclear lamina in the host response against the intrusion of viral DNA into the nucleus. AUTHOR SUMMARY Epstein-Barr virus (EBV) is a common herpesvirus that establishes lifelong latent infection in a small fraction of the B cells of infected individuals. In most cases, EBV infection is asymptomatic; however, especially in the context of immune suppression, EBV latent infection is associated with several malignancies. In EBV+ cancer cells, latent viral gene expression plays an essential role in sustaining the cancer phenotype. In previous works, we and others established that epigenetic modifications of the viral genomes are critical to regulating EBV gene expression during latency. Understanding how the EBV genome is epigenetically regulated during latent infection can help us develop new specific therapeutic targets for treating EBV+ malignancies. Nuclear Lamina plays an essential role in regulating the composition and the structure of cellular chromatin. In the present study, we determined that Nuclear Lamina binds the EBV genome during latency, influencing viral gene expression in the present study. Depleting one component of the nuclear lamina, Lamin A/C, increases the expression of latent EBV genes that are usually associated with cellular proliferation, indicating that the binding of the nuclear lamina with the viral genome is essential to control viral gene expression in infected cells. Our data show for the first time that the nuclear lamina may be involved in the cellular response against EBV infection by restricting viral gene expression.

Helicobacter pylori is an established cause of many gastrointestinal pathologies including peptic ulcer disease, gastritis, and gastric cancer. It is an entity that affects the global population, and its true nature has only been known since the 1980s. Although there is much known about H. pylori including its pathophysiology, detection, and eradication, resistance to current therapy models is common. This is problematic because untreated or inadequately treated H. pylori increases morbidity and mortality related to gastric cancer and peptic ulcer disease among others. In order to improve the treatment and reduce resistance, there is significant ongoing research identifying new detection and eradication methods for H. pylori. This review aims to highlight what has already been established regarding H. pylori’s epidemiology, pathophysiology, detection, and treatment as well as the most current and novel research involving detection and treatment of H. pylori.

Sediment waves are common on the submarine flanks of volcanic islands, but the processes that form them are difficult to decipher from geophysical data alone. Here, we identify downslope-trending trains of sediment waves in multibeam sonar data from five islands of the Azores. Train abundances are derived by counting the train intersections with depth contours around each island, revealing that they are typically twice as common on the north slopes of the islands compared with their south slopes. To provide context, we also characterise the Holocene mobility of sediments on the shelves, ocean density structure (for evaluating internal wave critical gradients) and sediment lithologies in four cores from beneath the slopes, which contain shelf carbonates in some volcaniclastic turbidites. Holocene mobility is assessed using sidescan sonar data, which reveal shelf-crossing sand streams. Using results of a high-resolution wave model, wave-imposed shear stresses are found to have exceeded the stresses at threshold of motion for most of the modern shelf sediments during recent extreme wave conditions.Sediment waves could potentially arise from sedimentary flows, gravity mass movements (shallow slumping) or ocean internal waves. Sedimentary flow origins are favoured by streamwise changes of wavelengths and upslope bedform migrations suggested by seismic reflections. The asymmetry of abundances north and south of each island is also an important clue. For example, it is unlikely that systematically different sediment geotechnical properties occur on the two sides of the islands, hence no reason to expect greater mass movements on northern slopes. Internal waves originate mainly from the south and hence also do not explain the asymmetry. Primary volcaniclastic flows are likely to be equally important on both sides. Sedimentary flows originating from shelf sediment agitated during storms or from failed slope sediment appear to explain best the asymmetry. In that case, prevailing wind and waves approaching the islands from the northwest lead to more frequent sediment gravity flows because they lead to greater flux of sediment from coastal erosion towards northerly outer shelves and upper slopes, where it is prone to slope failure. Offshore-directed near-bed currents originating from northwesterly wind-driven surface currents also transport shelf sediment efficiently to the north, further aided by greater wave agitation on that side. The high abundances of wave trains on the north sides of the islands therefore favours origins involving sedimentary gravity flows associated with wind and wave effects.

This study aims to understand how Project-based learning, addressed in initial teacher education programs, is reflected in the practices and professional development of elementary school teachers, as it is a method that contrasts with students' conceptions about teaching and promotes the development of pupils’ skills and knowledge. The study uses a multiple case study design, in which the main data collection techniques are interviews and document analysis. The results show that initial teacher education institutions are concerned with the integration of this teaching method in its programs, although its approach is insufficient for future teachers and beginning teachers to implement it with confidence. Data also reveal the need for greater monitoring by higher education institutions during teachers' induction phase, in order to support them during the constraints of this stage, encouraging the use of active teaching methods and contributing to an early stage of their professional development. Este estudio tiene como objetivo comprender cómo la Metodología de trabajo por proyectos, abordada en los programas de formación inicial del profesorado, se refleja en las prácticas y en el desarrollo profesional de los profesores de educación básica, ya que es un método que contrasta con las concepciones de los estudiantes sobre la enseñanza y promueve el desarrollo de competencias y conocimientos de los niños. El estudio utiliza un diseño de estudio de caso múltiple, cuyos principales métodos de recolección de datos son las entrevistas y el análisis documental. Los resultados muestran que las instituciones de educación superior están preocupadas por la integración de este método de enseñanza en los programas, aunque su enfoque es insuficiente para que los futuros profesores y los profesores principiantes lo implementen con confianza. Los datos también revelan la necesidad de un mayor seguimiento por parte de las instituciones durante la fase de inducción de los profesores, con el fin de apoyarlos durante los desafíos de esta etapa, fomentando el uso de métodos activos de enseñanza y contribuyendo a una etapa temprana de su desarrollo profesional. This study aims to understand how Project-based learning, addressed in initial teacher education programs, is reflected in the practices and professional development of elementary school teachers, as it is a method that contrasts with students' conceptions about teaching and promotes the development of pupils’ skills and knowledge. The study uses a multiple case study design, in which the main data collection techniques are interviews and document analysis. The results show that initial teacher education institutions are concerned with the integration of this teaching method in its programs, although its approach is insufficient for future teachers and beginning teachers to implement it with confidence. Data also reveal the need for greater monitoring by higher education institutions during teachers' induction phase, in order to support them during the constraints of this stage, encouraging the use of active teaching methods and contributing to an early stage of their professional development.

Kelp was first recorded for the remote warm‐temperate Azores archipelago (central North Atlantic) as late as 1971, when a few Laminaria specimens were collected on the Formigas Bank at depths beyond conventional SCUBA diving reach. A shortage of technical means and projects targeting mesophotic environments has since kept this offshore marine protected area as the single known kelp occurrence site. Here, we present new kelp records collected on previously unexplored mesophotic reefs using remote imaging systems, open and closed‐circuit SCUBA diving and fisheries by‐catch information. The new data extends the known distribution range of kelp in the Azores 350 km to the west and 25 km to the southwest, henceforth including several island shelves in eastern and central Azores. In addition to the previously recorded Laminaria ochroleuca, kelp specimens with a morphology akin to Phyllariopsis brevipes subsp. brevipes are also reported. For the first time, seabed imagery is used to document the depth‐wise diversity of the Azores kelp beds and their associated biota. Our findings emphasize the poor knowledge that persists in regard to Macaronesia’s mesophotic environments located beyond conventional SCUBA diving limits. The new on‐shelf kelp occurrences add conservation value to coastal areas and should facilitate island‐based research. However, their greater proximity to land‐based impacts and exposure to climate change also raise management needs.

Pre-gradual teacher education involves students’ practice teaching as carried out in so-called university schools or faculty schools. The objective of this digital handbook is to provide various options of implementation of university school concepts in teacher education programmes. General ideas and specific steps comprising organization of collaboration-supporting practices, internship activities and requirements for school-based teacher educators’ competences are presented within this structure. This digital handbook is one of the outputs of Enhancing European Teacher Education through University Schools, an Erasmus+ EdUSchool project aimed to develop a common European understanding of university schools and their concepts among all stakeholders.

Despite many attempts to develop novel therapies, EBV-specific therapies currently remain largely investigational, and EBV-associated malignancies are often associated with a worse prognosis. Therefore, there is a clear demand for EBV-specific therapies for both prevention and treatment of virus-associated malignancies., Latent membrane protein 1 (LMP1) is the major transforming protein of Epstein-Barr virus (EBV) and is critical for EBV-induced B-cell transformation in vitro. Several B-cell malignancies are associated with latent LMP1-positive EBV infection, including Hodgkin’s and diffuse large B-cell lymphomas. We have previously reported that promotion of B cell proliferation by LMP1 coincided with an induction of aerobic glycolysis. To further examine LMP1-induced metabolic reprogramming in B cells, we ectopically expressed LMP1 in an EBV-negative Burkitt’s lymphoma (BL) cell line preceding a targeted metabolic analysis. This analysis revealed that the most significant LMP1-induced metabolic changes were to fatty acids. Significant changes to fatty acid levels were also found in primary B cells following EBV-mediated B-cell growth transformation. Ectopic expression of LMP1- and EBV-mediated B-cell growth transformation induced fatty acid synthase (FASN) and increased lipid droplet formation. FASN is a crucial lipogenic enzyme responsible for de novo biogenesis of fatty acids in transformed cells. Furthermore, inhibition of lipogenesis caused preferential killing of LMP1-expressing B cells and significantly hindered EBV immortalization of primary B cells. Finally, our investigation also found that USP2a, a ubiquitin-specific protease, is significantly increased in LMP1-positive BL cells and mediates FASN stability. Our findings demonstrate that ectopic expression of LMP1- and EBV-mediated B-cell growth transformation leads to induction of FASN, fatty acids, and lipid droplet formation, possibly pointing to a reliance on lipogenesis. Therefore, the use of lipogenesis inhibitors could be used in the treatment of LMP1+ EBV-associated malignancies by targeting an LMP1-specific dependency on lipogenesis. IMPORTANCE Despite many attempts to develop novel therapies, EBV-specific therapies currently remain largely investigational, and EBV-associated malignancies are often associated with a worse prognosis. Therefore, there is a clear demand for EBV-specific therapies for both prevention and treatment of virus-associated malignancies. Noncancerous cells preferentially obtain fatty acids from dietary sources, whereas cancer cells will often produce fatty acids themselves by de novo lipogenesis, often becoming dependent on the pathway for cell survival and proliferation. LMP1- and EBV-mediated B-cell growth transformation leads to induction of FASN, a key enzyme responsible for the catalysis of endogenous fatty acids. Preferential killing of LMP1-expressing B cells following inhibition of FASN suggests that targeting LMP-induced lipogenesis is an effective strategy in treating LMP1-positive EBV-associated malignancies. Importantly, targeting unique metabolic perturbations induced by EBV could be a way to explicitly target EBV-positive malignancies and distinguish their treatment from EBV-negative counterparts.

PURPOSE: Oral cancer causes over 120,000 deaths annually and affects the quality of life for survivors. Over 90% of oral cancers are derived from oral squamous cell carcinoma cells (OSCCs) which are generally resistant to standard cytotoxic chemotherapy agents. OSCC cells often exhibit increased TGFβ and PDPN receptor activity compared to nontransformed oral epithelial cells. Maackia amurensis seed lectin (MASL) can target the PDPN receptor and has been identified as a novel agent that can be used to treat oral cancer. However, mechanisms by which MASL inhibits OSCC progression are not yet clearly defined. METHODS: Here, we performed cell migration and cytotoxicity assays to assess the effects of MASL on OSCC motility and viability at physiologically relevant concentrations. We then performed comprehensive transcriptome analysis combined with transcription factor reporter assays to investigate the how MASL affects OSCC gene expression at these concentration. Key data were then confirmed by western blotting to evaluate the effects of MASL on gene expression and kinase signaling activity at the protein level. RESULTS: MASL significantly affected the expression of about 27% of approximately 15 thousand genes found to be expressed by HSC-2 cells used to model OSCC cells in this study. These genes affected by MASL include members of the TGFβ-SMAD, JAK-STAT, and Wnt-βCTN signaling pathways. In particular, MASL decreased expression of PDPN, SOX2, and SMAD5 at the RNA and protein levels. MASL also inhibited SMAD and MAPK activity and exhibited potential for combination therapy with doxorubicin and 5-fluorouracil. CONCLUSIONS: Taken together, results from this study indicate that MASL decreases activity of JAK-STAT, TGFβ-SMAD, and Wnt-βCTN signaling pathways to inhibit OSCC growth and motility. These data suggest that further studies should be undertaken to determine how MASL may also be used alone and in combination with other agents to treat oral cancer.

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Streptococcus agalactiae (also known Group B Streptococcus or GBS) represents the main pathogen responsible for early- and late-onset infections in newborns. The present study aimed to determine the antimicrobial susceptibility pattern and the capsular serotypes of GBS isolated in Eastern Sicily over 5 years, from January 2015 to December 2019. A total of 3494 GBS were isolated from vaginal swabs of pregnant women (37–39 weeks), as recommended by the Centers for Disease Control and Prevention. Capsular polysaccharide’s typing of GBS was determined by a commercial latex agglutination test containing reagents to serotypes I–IX. The antimicrobial resistance pattern of GBS was determined through the disk diffusion method (Kirby-Bauer) and the double-disk diffusion test on Mueller-Hinton agar plates supplemented with 5% defibrinated sheep blood, according to the guidelines of the Clinical and Laboratory Standards Institute. Serotypes III (1218, 34.9%) and V (1069, 30.6%) were the prevalent colonizers, followed by not typable (570, 16.3%) and serotypes Ia (548, 15.7%), Ib (47, 1.3%), II (40, 1.1%), and IV (2, 0.1%). All 3494 clinical isolates were susceptible to cefditoren and vancomycin. Resistance to penicillin, ampicillin, levofloxacin, clindamycin, and erythromycin was observed in 6 (0.2%), 5 (0.1%), 161 (4.6%), 1090 (31.2%), and 1402 (40.1%) of the strains, respectively. Most of erythromycin-resistant GBS (1090/1402) showed the cMLSB phenotype, 276 the M phenotype, and 36 the iMLSB phenotype. Our findings revealed a higher prevalence of serotype III and a relevant resistance rate, among GBS strains, to the most frequently used antibiotics in antenatal screening. Electronic supplementary material The online version of this article (10.1007/s10096-020-03992-8) contains supplementary material, which is available to authorized users.

Orobanche crenata Forssk. (Orobanchaceae) is a holoparasitic plant noxious to legumes. Orobanchaceae are well known in traditional medicine for their hypotensive, antihyperglycemic, antispasmodic, analgesic and antimicrobial effects. In this work, the biological activities of the acetonic leaves extract were evaluated. Qualitative chemical analysis was determined through thin layer chromatography. Total phenols and flavonoids content was obtained by the Folin-Ciocalteu and the Aluminium chloride colorimetric methods, respectively. The antimicrobial activity was performed by the broth microdilution method. The extract showed antibacterial activity, particularly against Gram-positive strains, with MIC ranging from 376.00 to 3011.00 µg/ml. Besides, it exhibited antifungal effects on Candida spp. with MIC ranging from 94.10 to 3011.00 µg/ml. In addition, O. crenata inhibited superoxide anion formation and showed a DPPH quenching capacity, particularly at 80 µg/ml. Interestingly, our results are promising thus indicating the importance of O. crenata as a significant source of biologically active natural compounds.

Summary: Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGFβR) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-β1). Genetic and/or pharmacological targeting of the TGF-β1-TGFβR kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGFβR inhibitor in patients receiving PARPis.

The Epstein Barr virus (EBV) infects almost 95% of the population worldwide. While typically asymptomatic, EBV latent infection is associated with several malignancies of epithelial and lymphoid origin in immunocompromised individuals. In latently infected cells, the EBV genome persists as a chromatinized episome that expresses a limited set of viral genes in different patterns, referred to as latency types, which coincide with varying stages of infection and various malignancies. We have previously demonstrated that latency types correlate with differences in the composition and structure of the EBV episome. Several cellular factors, including the nuclear lamina, regulate chromatin composition and architecture. While the interaction of the viral genome with the nuclear lamina has been studied in the context of EBV lytic reactivation, the role of the nuclear lamina in controlling EBV latency has not been investigated. Here, we report that the nuclear lamina is an essential epigenetic regulator of the EBV episome. We observed that in B cells, EBV infection affects the composition of the nuclear lamina by inducing the expression of lamin A/C, but only in EBV+ cells expressing the Type III latency program. Using ChIP-Seq, we determined that lamin B1 and lamin A/C bind the EBV genome, and their binding correlates with deposition of the histone repressive mark H3K9me2. By RNA-Seq, we observed that knock-out of lamin A/C in B cells alters EBV gene expression. Our data indicate that the interaction between lamins and the EBV episome contributes to the epigenetic control of viral gene expression during latency, suggesting a restrictive function of the nuclear lamina as part of the host response against viral DNA entry into the nucleus.

We aimed to evaluate risk factors for local recurrence following lateral neck dissection (LND) for papillary thyroid carcinoma (PTC). Two hundred and nine patients who underwent therapeutic primary or reoperative LND for PTC were included. One hundred eighty-one patients underwent primary LND at our Institution, the remaining 28 were referred for recurrence following LND outside the Institution. Comparing patients who required reoperation for recurrent lateral neck disease with those who did not recur, no significant difference was found concerning sex, tumor size, multifocal disease, extracapsular invasion, histological variant, pT stage (P = NS). At univariate analysis, age, mean number of removed lateral neck nodes at first operation, the extent of initial LND and surgery performed outside the Institution were risk factors for recurrence (P

A seabed sediment-sampling survey conducted on the Pico insular shelf found abundant rhodoliths between −64 and −73 m off the south coast of the island. These were small and mainly ellipsoidal in shape with a maximum diameter of 3.75 cm. Granules and small pebbles of eroded basalt were also a typical component of these samples. Thin algal crusts were secreted on basalt pebbles by the coralline red algae Phymatolithon calcareum which, in turn, were covered by Lithophyllum incrustans. Additional samples were collected by snorkelling at Mare (Lajes do Pico), a shallow lagoon (2–4 m in depth) on the south coast. Here, rhodoliths are mostly spheroidal and bigger (maximum diameter of 4.75 cm), formed by thin thalli of P. calcareum. Based on these results (distribution of shapes and species) and previous work on the characteristics of fossil specimens from Neogene deposits on Santa Maria Island (Azores) and other North Atlantic Archipelagos, an empirical depositional model is proposed for the development of rhodoliths on the Pico Island shelf: (1) Nearshore rhodoliths, formed solely by P. calcareum, are subjected to a wide range of currents and waves resulting in their spheroidal shapes. However, those of Mare lagoon are protected from offshore transport and tend to grow larger than deep-water rhodoliths; (2) Although not sampled, there must be middle shelf rhodoliths formed solely by P. calcareum that tend to form more ellipsoidal shapes due to seafloor oscillatory movements caused by waves crossing the shelf; (3) During storms, these middle shelf rhodoliths are then transported to the outer shelf, where L. incrustans overgrows the initial cover of P. calcareum. Shallow associations are normally larger, reflecting therefore, a longer life span than the deeper associations. Transport by storms appears to be an important factor in the formation of some deep-water rhodoliths around volcanic oceanic islands subjected to high-wave energy. However, their exposure to an energetic environment and likely frequent offshore transport does not allow them to grow as large as those from shallow-water.

Aim Drivers of intraspecific biodiversity include past climate-driven range shifts and contemporary ecological conditions mediating connectivity, but these are rarely integrated in a common comprehensive approach. This is particularly relevant for marine organisms, as ocean currents strongly influence population isolation or connectivity, keeping or diluting the signatures left by past climates. Here we ask whether the coupling between past range shifts and contemporary connectivity explain the extant gene pools of Laminaria ochroleuca, a large brown alga structuring important marine forests from shallow to deep infralittoral grounds. Location Northeastern Atlantic Ocean. Taxon Laminaria ochroleuca. Methods We estimated population genetic diversity and structure of L. ochroleuca across its entire distribution range using 15 polymorphic microsatellite markers. This was compared with the outcomes of a palaeoclimatic model predicting latitudinal and depth range shifts from the Last Glacial Maximum (LGM) to the present. Genetic differentiation was further compared with potential connectivity inferred with a biophysical model developed with high-resolution data from HYCOM (Hybrid Coordinate Ocean Model). Results The biogeographical distribution of genetic variability showed overall agreement with the predictions from independently inferred past range shifts. Multiple regions of persistence were identified in deep and upwelling settings at the lowest latitudes of the current species distribution, where higher and unique genetic diversity was retained. The biophysical model revealed that despite the possibility of long-distance migration, contemporary oceanographic barriers strongly restrict connectivity of isolated genetic lineages. Main conclusions Integrating different processes at biogeographical scales explained the extant gene pools of marine forests of L. ochroleuca. Low-latitude genetic relics harbour a disproportional evolutionary significance, persisting as ancient populations in isolated deep and upwelling climate refugia. Their inferred rates of dispersal may be insufficient to accommodate anticipated climate warming.

Marine reserves across different eco-regions and habitats have proven to benefit exploited fish populations within their borders. There is also mounting evidence, mostly from continental shelf regions, that such positive effects will depend on the species ecological traits (e.g. mobility) and on the characteristics of the reserves (e.g. design, age and enforcement). This study examines the effects of protection on commercial coastal fishes with different ecological traits from three marine reserves with distinct habitats (coastal vs. offshore reefs), protection regime (legal vs. voluntary, partial vs. total protection) and age (8, 15 and 26 years old) across the oceanic archipelago of the Azores, mid North Atlantic. Overall, positive effects of protection on fish abundance or individual size were limited to species of larger maximum size and lower mobility in reserves with higher compliance levels. This result agrees with many studies elsewhere showing that reserves of small size and/or insufficient compliance do not provide adequate protection to the entire fish community, limiting their contribution to manage fisheries and conserve biodiversity. That might very well be the case of Azorean marine reserves but a more conclusive result will require testing the effects of protection on larger, well enforced reserves, which still do not exist in the region. There was also a clear influence of depth in commercial fish distribution and a common preference for substrates of higher complexity across ecological traits. Combined, these results highlight the need to include complex reef structures, diverse coastal habitats and larger areas when designing multispecies marine reserves and stress that an appropriate management regime is crucial for the success of the reserve, in particular to promote compliance.

El inicio de la carrera docente es un período desafiante para el desarrollo de las prácticas educativas del profesor, siendo fundamental para su desarrollo profesional. Este estudio tiene como objetivo comprender el papel de la metodología de trabajo por proyectos en el desarrollo profesional de los profesores de educación básica al inicio de sus carreras. El análisis cualitativo realizado se basa en datos recopilados a través de entrevistas semiestructuradas con ocho profesores principiantes. Los resultados muestran que los profesores principiantes tienen algunas dificultades para integrar este método en sus prácticas docentes, lo que podría mitigarse mediante una colaboración más consistente entre las instituciones de formación inicial del profesorado y las escuelas, con el fin de facilitar su integración en la carrera docente y su desarrollo profesional. The beginning of a teacher's career is a challenging period for the development of their educational practices, being essential for their professional development. This study aims to understand the role of Project-based learning in the professional development of elementary school teachers at the beginning of their careers. The qualitative analysis carried out is based on the data collected through semi-structured interviews to eight beginning teachers. Results show that beginning teachers show some difficulties in integrating these methods in their teaching practices, which could be lightened through a more consistent collaboration between initial teacher education institutions and schools, in order to facilitate their career integration and professional development. The beginning of a teacher's career is a challenging period for the development of their educational practices, being essential for their professional development. This study aims to understand the role of Project-based learning in the professional development of elementary school teachers at the beginning of their careers. The qualitative analysis carried out is based on the data collected through semi-structured interviews to eight beginning teachers. Results show that beginning teachers show some difficulties in integrating these methods in their teaching practices, which could be lightened through a more consistent collaboration between initial teacher education institutions and schools, in order to facilitate their career integration and professional development.

The enzyme Poly(ADP-ribose) polymerase 1 (PARP1) plays a very important role in the DNA damage response, but its role in numerous aspects is not fully understood. We recently showed that in the absence of DNA damage, PARP1 regulates the expression of the chromatin-modifying enzyme EZH2. Work from other groups has shown that EZH2 participates in the DNA damage response. These combined data suggest that EZH2 could be a target of PARP1 in both untreated and genotoxic agent-treated conditions. In this work we tested the hypothesis that, in response to DNA damage, PARP1 regulates EZH2 activity. Here we report that PARP1 regulates EZH2 activity after DNA damage. In particular, we find that EZH2 is a direct target of PARP1 upon induction of alkylating and UV-induced DNA damage in cells and in vitro. PARylation of EZH2 inhibits EZH2 histone methyltransferase (H3K27me) enzymatic activity. We observed in cells that the induction of PARP1 activity by DNA alkylating agents decreases the association of EZH2 with chromatin, and PARylation of histone H3 reduces EZH2 affinity for its target histone H3. Our findings establish that PARP1 and PARylation are important regulators of EZH2 function and link EZH2-mediated heterochromatin formation, DNA damage and PARylation. These findings may also have clinical implications, as they suggest that inhibitors of EZH2 can improve anti-tumor effects of PARP1 inhibitors in BRCA1/2-deficient cancers.

CTLA4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti–CTLA4 immunotherapy is highly effective at reactivating T-cell responses against melanoma, which is postulated to be due to targeting CTLA4 on T cells. Here, we report that CTLA4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-γ (IFNG) signaling activated the expression of the human CTLA4 gene in a melanocyte and melanoma cell–specific manner. Mechanistically, IFNG activated CTLA4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a specific gamma-activated sequence site on the CTLA4 promoter, thereby licensing CBP/p300-mediated histone acetylation and local chromatin opening. In melanoma cell lines, elevated baseline expression relied upon constitutive activation of the MAPK pathway. Notably, RNA-seq analyses of melanoma specimens obtained from patients who had received anti–CTLA4 immunotherapy (ipilimumab) showed upregulation of an IFNG-response gene expression signature, including CTLA4 itself, which correlated significantly with durable response. Taken together, our results raise the possibility that CTLA4 targeting on melanoma cells may contribute to the clinical immunobiology of anti–CTLA4 responses. Significance: These findings show that human melanoma cells express high levels of the immune checkpoint molecule CTLA4, with important possible implications for understanding how anti-CTLA4 immunotherapy mediates its therapeutic effects. Cancer Res; 78(2); 436–50. ©2017 AACR.

Bryozoan records from the shores and upper shelf (≤50 m depth) of the remote Azores Archipelago (central North Atlantic) have been analyzed, along with unpublished data and data from recent surveys. A checklist of 67 shallow-water species is hereby compiled for the region, of which more than one third represent records from campaigns conducted during the last 20 years. A classification on the origin of the species indicates that the majority (62%) are cryptogenic while 27% (n = 18) are considered native. Given the natural limitations for genetic exchange between the archipelago’s bryozoan populations and those from neighboring shores, the taxa presently considered as cryptogenic may yield a considerable amount of endemic species after taxonomic revision. The remaining 11% are confirmed as non-indigenous species, highlighting the importance of human-mediated transport in considerably enhancing the diversity of bryozoans in remote oceanic archipelagos, which would otherwise be off-limits to their natural dispersal capacity. In view of the need to quantitatively evaluate the certainty of species-level identification when assembling such biodiversity inventories, we have developed a method to attribute a degree of certainty to species records. The application of this method to the current checklist highlights the importance of further studies to ascertain the identification of many species recorded for the Azores, and to be able to categorize them confidently as either native, cryptogenic or non-indigenous.

Many fish species are well-known obligatory inhabitants of shallow-water tropical coral reefs but such associations are difficult to study in deep-water environments. We address the association between two deep-sea fish with low mobility and large sessile invertebrates using a compilation of 20 years of unpublished in situ observations. Data were collected on Northeast Atlantic (NEA) island slopes and seamounts, from the Azores to the Canary Islands, comprising 127 new records of the circalittoral Labridae Lappanella fasciata and 15 of the upper bathyal Ophiididae Benthocometes robustus. Observations by divers, remote operated vehicles (ROV SP, Luso, Victor, Falcon Seaeye), towed vehicles (Greenpeace) and manned submersibles (LULA, Nautile) validated the species association to cold water corals (CWC) and large hydrozoans. L. fasciata occurred from lower infralittoral (41 m) throughout the circalittoral, down to the upper bathyal at 398 m depth. Smaller fishes ( 10 cm) occurring at

Burkitt lymphoma/leukemia cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC–positive Burkitt lymphoma cells accumulate a high number of potentially lethal DNA double-strand breaks (DSB) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC–positive cells was associated with diminished HR activity and hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro. Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary Burkitt lymphoma xenografts. In conclusion, IGH/MYC–positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies. Implications: This study postulates that IGH/MYC–induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpg. Mol Cancer Res; 15(8); 967–72. ©2017 AACR.

The genus Teucrium (Lamiaceae) includes 300 species widespread all around the world, which are perennial herbs or shrubs commonly, named germanders. In Italy, Teucrium flavum L., Teucrium fruticans L., and Teucrium siculum Rafin are mostly present in Liguria, Sicily, and Sardegna. Teucrium species are characterized by mono and sesquiterpene hydrocarbons, flavonoids, fatty acid esters, and essential oils. Many species of this genus show antioxidant, antimicrobial, and antifungal activities, rendering them useful as natural preservative ingredients. In view of the interesting biological properties reported for Teucrium spp., in this study we determined the total phenol and flavonoid content of inflorescence extracts of T. flavum L., T. fruticans L., and T. siculum Rafin. In addition, we investigated the in vitro antioxidant and antibacterial activities of inflorescence extracts against pathogenic bacteria. Obtained results demonstrated that extracts had in vitro antioxidant activity and showed antim...