Phylogenetic networks: A tool to display character conflict and demographic history

Evolutionary trees have the assumption that evolution and phylogeny can be represented in a strictly bifurcating manner. Firmly speaking, from one ancestral taxon, two descendant taxa emerge. Nevertheless, hybridization, recombination and horizontal gene transfer is in conflict with this straightforward concept. In such cases, evolutionary lines do not only separate from each other, but have the possibility of melting again and are called reticulations. Consequently, networks can represent evolutionary events more realistically than phylogenetic trees. Networks can display alternative topologies and co-existence of ancestors and descendants, which are otherwise not obvious when a comparison is done on several single trees or a consensus tree. Therefore, networks have the ability to visualize the conflicting information in a given data set. Moreover, the distribution, frequencies and arrangement of haplotypes in populations can reveal the phylogenetic histories of the taxa, regarding predictions from the coalescent theory. This review aims to: (1) give a brief comparison between phylogenetic trees and networks, (2) provide the overall concept of the coalescent theory, (3) clarify how phylogenetic networks can be used to display conflict data and evaluate phylogenetic histories, and (4) offer a useful starting point and guide for sequence analysis, with the aim to discover population dynamics.Key words: Phylogenetic networks, reticulation, coalescent theory, population history, character conflict

Images of the Saturn Hexagon before Voyager 1

In 1981 the Voyager 1 probe photographed – and later the Cassini probe confirmed – a hexagonal vortex on Saturn's North pole. This cloud features extends for almost 30,000 km keeping its shape unchanged as it rotates with the planet. But, since we see it very foreshortened, it appears to us with the greater extension of 4" and the smaller one of 1.3": this makes it virtually visible from Earth with telescopes. And in fact, after the first images of Voyager 1, many amateur astronomers managed to photograph it even with modest instruments of a few tens of centimeters in diameter, but using digital photography techniques. We therefore wondered if the hexagon had been seen by astronomers of the past mainly using their professional telescopes. Our research gave positive results: E.E. Barnard (with the Yerkes' refractor) and E.M. Antoniadi (earlier with Juvisy's and later with Meudon's refractors) pictured it since the end of the 19th century, but they never mentioned it in their writings, probably because it was at the limit of visibility and it was impossible to explain the hexagon with the knowledge of that time. These pictures prove that the hexagon has been present and active for at least 124 years on the North pole of Saturn, similar to the (longer-lived) red spot of Jupiter

Salt stress in the renal tubules is Linked to TAL specific expression of uromodulin and an upregulation of heat shock genes

Previously, our comprehensive cardiovascular characterisation study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesised at the thick ascending limb of the loop of Henle and is encoded by the Umod gene. Umod(-/-) mice have significantly lower blood pressure than Umod(+/+) mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed to delineate salt stress pathways in tubules isolated from Umod(+/+) mice (a model of sodium retention) and Umod(-/-) mice (a model of sodium depletion) +/-300mOsmol sodium chloride (n=3 per group) performing RNA-Seq. In response to salt stress, the tubules of Umod(+/+) mice displayed an up regulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, p=2.48e-12) and Hspa1b (Log2 fold change 4.05, p=2.48e-12). This response was absent in tubules of Umod(-/-) mice. Interestingly, 7 of the genes discordantly expressed in the Umod(-/-) tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod(+/+) tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress

Temozolomide as salvage treatment in primary brain lymphomas

Methotrexate (MTX)-based chemotherapy extends survival in patients with primary brain lymphomas, but it is not clear whether multiagent chemotherapy is superior to MTX alone. Treatment options for patients with recurrent primary brain lymphoma are limited; there is no standard second-line chemotherapy. New chemotherapeutic agents with clear activity in brain lymphoma are needed for treatment of recurrent disease. We report the results of a phase II trial assessing activity of the alkylating agent temozolomide in immunocompetent patients with recurrent primary brain lymphomas, previously treated with high-dose MTX-containing chemotherapy and/or radiotherapy. A median of two courses (range 1–12) of temozolomide 150 mg m−2 day−1, for 5 days every 4 weeks was administered to 36 patients yielding nine complete and two partial responses (response rate: 31%; 95% confidence interval 16–46%). One-year survival was 31% (95% confidence interval 16–46%). Toxicity was negligible. We conclude that temozolomide is active in recurrent primary brain lymphomas and should further be evaluated in this disease, perhaps in combination with MTX as initial treatment

Utility of baseline 18FDG-PET/CT functional parameters in defining prognosis of primary mediastinal (thymic) large B-cell lymphoma

The International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of (18)F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P = .001) and PFS (P < .001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P < .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. The IELSG 26 study was registered at www.clinicaltrials.gov as #NCT00944567

Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee

These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments

The Social Life of Time and Methods: Studying London’s Temporal Architectures

This paper contributes to work on the social life of time. It focuses on how time is doubled; produced by and productive of the relations and processes it operates through. In particular, it explores the methodological implications of this conception of time for how social scientists may study the doubledness of time. It draws on an allied move within the social sciences to see methods as themselves doubled; as both emerging from and constitutive of the social worlds that they seek to understand. We detail our own very different methodological experiments with studying the social life of time in London, engaging interactive documentary to elucidate nonlinear imaginaries of space-time in London’s pop-up culture (Ella Harris) and encountering time on a series of walks along a particular stretch of road in south east London (Beckie Coleman). While clearly different projects in terms of their content, ambition and scope, in bringing these projects together we show the ability of our methods to grasp and perform from multiple angles and scales what Sharma calls ‘temporal architectures’. Temporal architectures, composed of elements including the built environment, commodities, services, technologies and labour, are infrastructures that enable social rhythms and temporal logics and that can entail a politicized valuing of the time of certain groups over others. We aim to contribute to an expanded and enriched conceptualisation of methods for exploring time, considering what our studies might offer to work on the doubled social life of time and methods, and highlighting in particular their implications for an engagement with a politics of time and temporality

Clinical and molecular characterization of diffuse large B-cell lymphomas with 13q14.3 deletion

Background: Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). Patients and methods: Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. Results: Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. Conclusions: Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulatio

Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma

PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients

Cyclin D1, cyclin E, and p21 have no apparent prognostic value in anal carcinomas treated by radiotherapy with or without chemotherapy

The purpose of this study was to assess the potential prognostic and/or predictive value of the expression of cyclin D1, cyclin E, and p21 protein in a series of 98 anal carcinomas (T1-4, N0-3) treated by radiotherapy with (51) or without (47) chemotherapy in one institution. Correlation with Mib1 index and p53 expression was also investigated. Median follow-up for surviving patients was 124 months (range: 30-266). Immunohistochemical staining was performed on pretreatment biopsies, applying a standard ABC technique for cyclin D1 (clone DSC6, DAKO, 1 : 300), cyclin E (clone 13A3, Novocastra, 1 : 100), p21(WAF/CIP1) (clone SX118, DAKO, 1 : 50), p53 (clone DO7, DAKO, 1 : 200), and Mib1 (Ki-67, Dianova, 1 : 20). Tumours were classified into low- or high-expression groups according to the expression level of the protein considered. High expression was found in 51% of tumours for cyclin E, in 33.7% for cyclin D1, and in 65% for p21. None of those factors were significantly associated with clinical variables such as advanced T or N categories. In a monovariate analysis, advanced T and N categories and longer overall treatment time were the only variables that correlated significantly with low rate of local control (LC) and disease-free survival. However, in a subgroup analysis, high p21 expression correlated with a trend for significantly higher 5-year LC (87 vs 68%, P=0.07) in the N0 patients. The results of this study suggest that the cell-cycle proteins investigated are unlikely to be clinically useful in predicting treatment response or prognosis in patients with anal carcinomas