What links BRAF to the heart function? New insights from the cardiotoxicity of BRAF inhibitors in cancer treatment

none11noThe RAS-related signalling cascade has a fundamental role in cell. It activates differentiation and survival. It is particularly important one of its molecules, B-RAF. B-RAF has been a central point for research, especially in melanoma. Indeed, it lacked effective therapeutic weapons since the early years of its study. Molecules targeting B-RAF have been developed. Nowadays, two classes of molecules are approved by FDA. Multi-target molecules, such as Sorafenib and Regorafenib, and selective molecules, such as Vemurafenib and Dabrafenib. Many other molecules are still under investigation. Most of them are studied in phase 1 trials. Clinical studies correlate B-RAF inhibitors and QT prolongation. Though this cardiovascular side effect is not common using these drugs, it must be noticed early and recognize its signals. Indeed, Oncologists and Cardiologists should work in cooperation to prevent lethal events, such as fatal arrhythmias or sudden cardiac death. These events could originate from an uncontrolled QT prolongation.openBronte E.; Bronte G.; Novo G.; Bronte F.; Bavetta M.G.; Re G.L.; Brancatelli G.; Bazan V.; Natoli C.; Novo S.; Russo A.Bronte, E.; Bronte, G.; Novo, G.; Bronte, F.; Bavetta, M. G.; Re, G. L.; Brancatelli, G.; Bazan, V.; Natoli, C.; Novo, S.; Russo, A

Seismic properties of the crust and uppermost mantle of North America

Seismic refraction profiles for the North American continent were compiled. The crustal models compiled data on the upper mantle seismic velocity (P sub n), the crustal thickness (H sub c) and the average seismic velocity of the crystalline crust (V sub p). Compressional wave parameters were compared with shear wave data derived from surface wave dispersion models and indicate an average value for Poisson's ratio of 0.252 for the crust and of 0.273 for the uppermost mantle. Contour maps illustrate lateral variations in crustal thickness, upper mantle velocity and average seismic velocity of the crystalline crust. The distribution of seismic parameters are compared with a smoothed free air anomaly map of North America and indicate that a complidated mechanism of isostatic compensation exists for the North American continent. Several features on the seismic contour maps also correlate with regional magnetic anomalies

The Anatomy of a Leading Case: \u3cem\u3eLawrence v. Fox\u3c/em\u3e in the Courts, the Casebooks, and the Commentaries

In spite of the wide diversity of training, practice, and location of lawyers throughout the United States, virtually all share one experience: the standard core curriculum of the first year of law school taught by the case method. The extent to which that experience in parsing cases in contracts, torts, and property shapes the American legal mentality is open to debate, but it undeniably has an impact. The first-year experience socializes law students in the culture of the law. During this period, students learn the language of the law and the ways that lawyers think. During this period, too, students absorb certain basic notions about legal analysis and the shape of the legal system, and begin to view the world as common lawyers. Included among these basic notions, the conventional wisdom of basic law training, is the concept of the leading case. This Article explores the notion of the leading case, and places the concept in an historical and jurisprudential framework

Laboratory selection for an accelerated mosquito sexual development rate

<p>Abstract</p> <p>Background</p> <p>Separating males and females at the early adult stage did not ensure the virginity of females of <it>Anopheles arabiensis </it>(Dongola laboratory strain), whereas two years earlier this method had been successful. In most mosquito species, newly emerged males and females are not able to mate successfully. For anopheline species, a period of 24 h post-emergence is generally required for the completion of sexual maturation, which in males includes a 180° rotation of the genitalia. In this study, the possibility of an unusually shortened sexual maturity period in the laboratory-reared colony was investigated.</p> <p>Methods</p> <p>The effect of two different sex-separation methods on the virginity of females was tested: females separated as pupae or less than 16 h post-emergence were mated with males subjected to various doses of radiation. T-tests were performed to compare the two sex-separation methods. The rate of genitalia rotation was compared for laboratory-reared and wild males collected as pupae in Dongola, Sudan, and analysed by Z-tests. Spermatheca dissections were performed on females mated with laboratory-reared males to determine their insemination status.</p> <p>Results</p> <p>When the sex-separation was performed when adults were less than 16 h post-emergence, expected sterility was never reached for females mated with radio-sterilized males. Expected sterility was accomplished only when sexes were separated at the pupal stage. Observation of genitalia rotation showed that some males from the laboratory strain Dongola were able to successfully mate only 11 h after emergence and 42% of the males had already completed rotation. A small proportion of the same age females were inseminated. Wild males showed a much slower genitalia rotation rate. At 17 h post-emergence, 96% of the laboratory-reared males had completed genitalia rotation whereas none of the wild males had.</p> <p>Conclusion</p> <p>This colony has been cultured in the laboratory for over one hundred generations, and now has accelerated sexual maturation when compared with the wild strain. This outcome demonstrates the kinds of selection that can be expected during insect colonization and maintenance, particularly when generations are non-overlapping and similar-age males must compete for mates.</p

A bibliography of mosquito writings of H. G. Dyar and Frederick Knab.

Volume:

New material of Alierasaurus ronchii (Synapsida, Caseidae) from the Permian of Sardinia (Italy), and its phylogenetic affinities

New characters of the giant caseid Alierasaurus ronchii are described here based on material recovered from the type locality in the Permian deposits of Cala del Vino Formation (Sardinia NW) and additional preparation of the previously collected material. All new described osteological elements are characterized by the same state of preservation and, given the absence of double elements and the total compatibility in absolute size, the new material can be attributed without doubt to the holotypic individual of A. ronchii. Highly diagnostic material includes a caudal neural spine with a broad bifid distal termination. This represents a synapomorphy characterizing the more derived caseids, thus fully confirming the attribution of the Sardinian specimen to Caseidae. Also the other vertebral material and newly collected ribs show a typical caseid structure, fully consistent with the previously published material. Despite the highly partial nature of Alierasaurus, the taxon was included in a recent phylogenetic analysis of caseids to investigate its phylogenetic position within the monophyletic Caseasauria. Alierasaurus falls as the sister taxon of Cotylorhynchus, and is autapomorphic in the general construction of MT-IV and proximal phalanx IV-I. The absolute size of the newly recovered material confirms a gigantic body size for Alierasaurus, comparable, if not greater, to that of the huge North American species Cotylorhynchus hancocki (up to 6 m in length). Such gigantic adult body size, closely correlated to its herbivorous lifestyle, must have been selected during evolution of caseids, leading to substantial advantages in terms of fitness

\u3cem\u3e1994-1995 Annual Report\u3c/em\u3e

The review presented in this Report is for the period 1994-1995 and summarizes the ongoing research, public service, and educational benefits of the Institute\u27s programs. Contents: Table of Contents.....p. iii Introduction.....p. 1 Administrative Division.....p. 7 Office of the State Archaeologist.....p. 11 Research Division.....p. 15 Underwater Archaeology Division.....p. 19 Savannah River Archaeological Research Program.....p. 25 Cultural Resources Consulting Division.....p. 31 Archaeological Society of South Carolina.....p. 35 Archaeological Research Trust.....p. 39 Staff.....p. 43 Appendix A - Publications.....p. 47 Appendix B - Editorships.....p. 52 Appendix C - Papers Presented.....p. 53 Appendix D - Refereed Reviews.....p. 57 Appendix E - Courses Taught.....p. 58 Appendix F - Theses and Dissertations.....p. 59 Appendix G - Research Affiliates.....p. 60 Appendix H - Institute, University and State Committees and Boards.....p. 62 Appendix I - Consultations.....p. 64 Appendix J - Public Education.....p. 66 Appendix K - Professional Committees and Offices.....p. 74 Appendix L - Awards.....p. 76 Appendix M - Grants and Contracts.....p. 77 Coda.....p. 7

Blood haemoglobin measurement as a predictive indicator for the progression of HIV/AIDS in resource-limited setting

<p>Abstract</p> <p>Background</p> <p>Anaemia is a frequent complication of infection with the human immunodeficiency virus (HIV) and may have multiple causes. The objective of this study was to find out if blood haemoglobin measurement could be used as an indicator for the progression of HIV/AIDS in resource-limited setting.</p> <p>Methods</p> <p>Two hundred and twenty-eight (228) consented People Living with HIV/AIDS (PLWHAs) who were placed in three groups according to their CD4 counts were used in the study. The three groups were those with CD4 counts (1) ≥ 500 mm-³; (2) 200-499 mm-³; and (3) <it><</it>200 mm-³. One hundred (100) sex, age-matched and healthy HIV-seronegative individuals were used as control subjects. Blood haemoglobin, blood haematocrit, Red cell indices which included Mean Cell Volume, Mean Cell Haemoglobin Concentration and Mean Cell Haemoglobin and CD4 count were analysed in all subjects.</p> <p>Results</p> <p>The mean blood haemoglobin concentrations in those with CD4 counts <it><</it>200 mm-³, 200-499 mm-³and ≥ 500 mm-³(8.83 ± 0.22 g/dl, 10.03 ± 0.31 g/dl and 11.3 ± 0.44 g/dl respectively) were significantly lower when compared with the control group (14.29 ± 0.77 g/dl) (<it>p </it>< 0.0001). The mean blood haematocrit levels in those with CD4 counts <it><</it>200 mm-³, 200-499 mm-³and ≥ 500 mm-³(23.53 ± 0.85%, 28.28 ± 0.77% and 33.54 ± 1.35% respectively) were also significantly lower when compared with the control group (41.15 ± 2.15%) (<it>p </it>< 0.0001). The red cell indices were also lower in the subjects when compared with the control group. Using the Pearson's correlation, there was a significant and positive correlation between the blood haemoglobin level and their CD4 counts <it>(</it>r²= 0.1755; <it>p < 0.0001)</it>.</p> <p>Conclusion</p> <p>Anaemia in People Living with HIV/AIDS, if persistent, is associated with substantially decreased survival. From our analysis, there was a decrease in the blood haemoglobin, levels as the HIV infection progressed and our findings are consistent with those of other studies of anaemia as a prognostic factor in HIV infection. Haemoglobin levels could be measured easily where resources for more sophisticated laboratory markers such as viral load or even CD4 lymphocyte count are not available given that measurement of the CD4 lymphocyte count requires flow cytometry, an expensive technique unavailable in many developing countries. Regular measurements could help to determine which patients are at greatest risk of disease progression, allowing these patients to be identified for closer monitoring or therapeutic intervention.</p

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders.Peer reviewe