Measurement of small forces in the physics of gravitation and geophysics

The measurement of weak forces or accelerations is of fundamental importance in a variety of problems in science and technology. This topic is addressed in this paper with particular attention to gravity measurements. A general review of the current gravity measurement techniques in geophysics, general relativity and gravitation is first presented. Then, a general description of the instruments used for gravitational measurements and a brief analysis of the noise sources are discussed

Experimental gravitation and geophysics

Seismic noise is the major obstacle to performing sensitive measurements of the gravitational field on the ground. The INFN (Istituto Nazionale di Fisica Nucleare) underground laboratory in Gran Sasso, L’Aquila(Italy), seems to be a favourable place from the environmental noise point of view. This paper describes briefly two, relatively low cost, gravity experiments that can be performed in the underground laboratory: a) A measurement of preferred-frame and preferred-location effects. b) A test of the equivalence principle. Preliminary experimental data of the seismic noise are also presented

Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth.

Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of \u3b1 catalytic and \u3b2 regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2\u3b1 immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-\u3baB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL

Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective B therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5’-azacytidine and decitabine in controlling disease progression in vivo

Enly: improving draft genomes through reads recycling

The reconstruction of the complete genome sequence of an organism is an important point for comparative, functional and evolutionary genomics. Nevertheless, overcoming the problems encountered while completing the sequence of an entire genome can still be demanding in terms of time and resources. We have developed Enly, a simple tool based on the iterative mapping of sequence reads at contig edges, capable to extend the genomic contigs deriving from high-throughput sequencing, especially those deriving by Newbler-like assemblies. Testing it on a set of de novo draft genomes led to the closure of up to 20% of the gaps originally present. Enly is cross-platform and most of the steps of its pipeline are parallelizable, making easy and fast to improve a draft genome resulting from a de novo assembly

Burkitt lymphoma beyond MYC translocation: N-MYC and DNA methyltransferases dysregulation

Background: The oncogenic transcription factor MYC is pathologically activated in many human malignancies. A paradigm for MYC dysregulation is offered by Burkitt lymphoma, where chromosomal translocations leading to Immunoglobulin gene-MYC fusion are the crucial initiating oncogenic events. However, Burkitt lymphoma cases with no detectable MYC rearrangement but maintaining MYC expression have been identified and alternative mechanisms can be involved in MYC dysregulation in these cases. Methods: We studied the microRNA profile of MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases in order to uncover possible differences at the molecular level. Data was validated at the mRNA and protein level by quantitative Real-Time polymerase chain reaction and immunohistochemistry, respectively. Results: We identified four microRNAs differentially expressed between the two groups. The impact of these microRNAs on the expression of selected genes was then investigated. Interestingly, in MYC translocation-negative cases we found over-expression of DNA-methyl transferase family members, consistent to hypo-expression of the hsa-miR-29 family. This finding suggests an alternative way for the activation of lymphomagenesis in these cases, based on global changes in methylation landscape, aberrant DNA hypermethylation, lack of epigenetic control on transcription of targeted genes, and increase of genomic instability. In addition, we observed an over-expression of another MYC family gene member, MYCN that may therefore represent a cooperating mechanism of MYC in driving the malignant transformation in those cases lacking an identifiable MYC translocation but expressing the gene at the mRNA and protein levels. Conclusions: Collectively, our results showed that MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases are slightly different in terms of microRNA and gene expression. MYC translocation-negative Burkitt lymphoma, similarly to other aggressive B-cell non Hodgkin's lymphomas, may represent a model to understand the intricate molecular pathway responsible for MYC dysregulation in cancer

SOCS2 controls proliferation and stemness of hematopoietic cells under stress conditions and its deregulation marks unfavorable acute leukemias

Hematopoietic stem cells (HSC) promptly adapt hematopoiesis to stress conditions, such as infection and cancer, replenishing bone marrow-derived circulating populations, while preserving the stem cell reservoir. SOCS2, a feedback inhibitor of JAK-STAT pathways, is expressed in most primitive HSC and is upregulated in response to STAT5-inducing cytokines. We demonstrate that Socs2 deficiency unleashes HSC proliferation in vitro, sustaining STAT5 phosphorylation in response to IL3, thrombopoietin, and GM-CSF. In vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-fluorouracil (5-FU) and, in turn, induces exhaustion of long-term HSC function along serial bone marrow transplantations. The emerging role of SOCS2 in HSC under stress conditions prompted the investigation of malignant hematopoiesis. High levels of SOCS2 characterize unfavorable subsets of acute myeloid and lymphoblastic leukemias, such as those with MLL and BCR/ABL abnormalities, and correlate with the enrichment of genes belonging to hematopoietic and leukemic stemness signatures. In this setting, SOCS2 and its correlated genes are part of regulatory networks fronted by IKZF1/Ikaros and MEF2C, two transcriptional regulators involved in normal and leukemic hematopoiesis that have never been linked to SOCS2. Accordingly, a comparison of murine wt and Socs2-/- HSC gene expression in response to 5-FU revealed a significant overlap with the molecular programs that correlate with SOCS2 expression in leukemias, particularly with the oncogenic pathways and with the IKZF1/Ikaros and MEF2C-predicted targets. Lentiviral gene transduction of murine hematopoietic precursors with Mef2c, but not with Ikzf1, induces Socs2 upregulation, unveiling a direct control exerted by Mef2c over Socs2 expression

A comparative study on the health and well-being of adolescent immigrants in Spain and Portugal

The terms on which the integration of new generations of immigrants into Portuguese and Spanish societies happens will have a decisive influence in the future of both countries. Therefore, promoting their health, well-being, and psychosocial adaptation is a matter of strategic interest. This paper analyses psychosocial factors associated with well-being and psychological adjustment on a sample of 108 adolescents (55 males and 53 females), children of immigrants from Huelva (Spain) and Algarve (Portugal), aged between 10 and 17 years. Adolescents were assessed for demographic characteristics and perceived well-being. We used the "KIDSCREEN-5", a self-report questionnaire that yields detailed profile information for children aged 8 to 18 years for the following ten dimensions: Physical well-being, Psychological well-being, Moods and emotions, Self-perception, Autonomy, Parental relationships and home life, Financial resources, Social support and peers, School environment, and Social acceptance (Bullying). Overall, significant differences were found between the Spanish and Portuguese samples on physical well-being, psychological well-being, mood, financial resources and social acceptance (bullying). Boys perceived themselves as having a better physical well-being than girls. Mothers' educational level was associated with psychological well-being and mood. Also, results suggested that residence location and other socio-demographical variables were not associated with the adolescents' well-being and psychological adjustment

Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma

The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (?H2AX), marker of DNA damage and genomic instability. Constitutive ?H2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL