A review of fMRI simulation studies

Simulation studies that validate statistical techniques for fMRI data are challenging due to the complexity of the data. Therefore, it is not surprising that no common data generating process is available (i.e. several models can be found to model BOLD activation and noise). Based on a literature search, a database of simulation studies was compiled. The information in this database was analysed and critically evaluated focusing on the parameters in the simulation design, the adopted model to generate fMRI data, and on how the simulation studies are reported. Our literature analysis demonstrates that many fMRI simulation studies do not report a thorough experimental design and almost consistently ignore crucial knowledge on how fMRI data are acquired. Advice is provided on how the quality of fMRI simulation studies can be improved

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

The socioeconomic gradient and chronic illness and associated risk factors in Australia

OBJECTIVE: To examine the prevalence of major chronic diseases and their risk factors in different socioeconomic groups in the Australian population, in order to highlight the need for public policy initiatives to reduce socioeconomic inequalities in health. METHODS: Data were provided by the Australian Bureau of Statistics (ABS) from the 2001 National Health Survey (NHS) for selected chronic diseases and associated risk factors. Conditions selected were those, which form the National Health Priority Area (NHPA) conditions (other than injury, which has not been included in this paper, with its focus on chronic disease); plus other 'serious' chronic conditions, in line with the classification developed by Mathers; and for which sufficient cases were available for analysis by socioeconomic status. Indirectly age-standardised prevalence rates were calculated by broad age group for Australia and for five groups of socioeconomic status; rate ratios were calculated to show variations in prevalence between these groups. RESULTS: Significant socioeconomic inequalities were evident for many of the major chronic diseases; the largest was for diabetes mellitus (at ages 25 to 64 years); and for many diseases, there was also a strong, continuous socioeconomic gradient in the rates. Circulatory system diseases (in particular, hypertensive disease) and digestive system diseases also exhibited a strong differential in the 25 to 64 year age group. In the 65 years and over age group, the strongest inequalities were evident for mental and behavioural problems, diabetes (with a continuous socioeconomic gradient in rates) and respiratory system diseases. A number of risk factors for chronic diseases, namely self-reported smoking, alcohol misuse, physical inactivity and excess weight showed a striking association with socioeconomic status, in particular for people who were smokers and those who did not exercise. CONCLUSION: This analysis shows that the prevalence of chronic disease varies across the socioeconomic gradient for a number of specific diseases, as well as for important disease risk factors. Therefore, any policy interventions to address the impact of chronic disease, at a population level, need to take into account these socioeconomic inequalities

Higgs Low-Energy Theorem (and its corrections) in Composite Models

The Higgs low-energy theorem gives a simple and elegant way to estimate the couplings of the Higgs boson to massless gluons and photons induced by loops of heavy particles. We extend this theorem to take into account possible nonlinear Higgs interactions resulting from a strong dynamics at the origin of the breaking of the electroweak symmetry. We show that, while it approximates with an accuracy of order a few percents single Higgs production, it receives corrections of order 50% for double Higgs production. A full one-loop computation of the gg->hh cross section is explicitly performed in MCHM5, the minimal composite Higgs model based on the SO(5)/SO(4) coset with the Standard Model fermions embedded into the fundamental representation of SO(5). In particular we take into account the contributions of all fermionic resonances, which give sizeable (negative) corrections to the result obtained considering only the Higgs nonlinearities. Constraints from electroweak precision and flavor data on the top partners are analyzed in detail, as well as direct searches at the LHC for these new fermions called to play a crucial role in the electroweak symmetry breaking dynamics.Comment: 30 pages + appendices and references, 12 figures. v2: discussion of flavor constraints improved; references added; electroweak fit updated, results unchanged. Matches published versio

Utilising daily diaries to examine oral health experiences associated with dentine hypersensitivity

Background: The current investigation examined the determinants of oral health experiences associated with dentine hypersensitivity using prospective diary methodology. Methods: Staff and students from a large UK university who had self-diagnosed dentine hypersensitivity completed an online daily diary and text survey for two weeks recording their mood, oral health-related coping behaviours, coping and pain appraisals, pain experiences and functional limitations. Cross sectional and lagged path analyses were employed to examine relationships. Results: 101 participants took part in the diary study. Participants had a mean age of 26.3 years (range=18-63) and most were female (N=69). Individuals who used more oral health-related coping behaviours predicted and experienced greater levels of pain on subsequent days. Negative mood also predicted worse pain outcomes. The daily diary method provided a useful avenue for investigating variations in oral health experiences and relationships between variables that can fluctuate daily. Conclusions: Psychological variables such as coping and mood play an important role in the pain experiences of people with dentine hypersensitivity. The study highlights the benefits of using prospective methods to elucidate the experiences of people with oral condition

Prostate cancer disparities in Black men of African descent: a comparative literature review of prostate cancer burden among Black men in the United States, Caribbean, United Kingdom, and West Africa

<p>Abstract</p> <p>Background</p> <p>African American men have the highest prostate cancer morbidity and mortality rates than any other racial or ethnic group in the US. Although the overall incidence of and mortality from prostate cancer has been declining in White men since 1991, the decline in African American men lags behind White men. Of particular concern is the growing literature on the disproportionate burden of prostate cancer among other Black men of West African ancestry in the Caribbean Islands, United Kingdom and West Africa. This higher incidence of prostate cancer observed in populations of African descent may be attributed to the fact that these populations share ancestral genetic factors. To better understand the burden of prostate cancer among men of West African Ancestry, we conducted a review of the literature on prostate cancer incidence, prevalence, and mortality in the countries connected by the Transatlantic Slave Trade.</p> <p>Results</p> <p>Several published studies indicate high prostate cancer burden in Nigeria and Ghana. There was no published literature for the countries Benin, Gambia and Senegal that met our review criteria. Prostate cancer morbidity and/or mortality data from the Caribbean Islands and the United Kingdom also provided comparable or worse prostate cancer burden to that of US Blacks.</p> <p>Conclusion</p> <p>The growing literature on the disproportionate burden of prostate cancer among other Black men of West African ancestry follows the path of the Transatlantic Slave Trade. To better understand and address the global prostate cancer disparities seen in Black men of West African ancestry, future studies should explore the genetic and environmental risk factors for prostate cancer among this group.</p

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.National Institutes of Health (U.S.) (Grant HG002668)National Institutes of Health (U.S.) (Grant CA109901

Nanoscale magnetic imaging of a single electron spin under ambient conditions

The detection of ensembles of spins under ambient conditions has revolutionized the biological, chemical and physical sciences through magnetic resonance imaging and nuclear magnetic resonance . Pushing sensing capabilities to the individual-spin level would enable unprecedented applications such as single-molecule structural imaging; however, the weak magnetic fields from single spins are undetectable by conventional far-field resonance techniques . In recent years, there has been a considerable effort to develop nanoscale scanning magnetometers , which are able to measure fewer spins by bringing the sensor in close proximity to its target. The most sensitive of these magnetometers generally require low temperatures for operation, but the ability to measure under ambient conditions (standard temperature and pressure) is critical for many imaging applications, particularly in biological systems. Here we demonstrate detection and nanoscale imaging of the magnetic field from an initialized single electron spin under ambient conditions using a scanning nitrogen-vacancy magnetometer. Real-space, quantitative magnetic-field images are obtained by deterministically scanning our nitrogen-vacancy magnetometer 50 nm above a target electron spin, while measuring the local magnetic field using dynamically decoupled magnetometry protocols. We discuss how this single-spin detection enables the study of a variety of room-temperature phenomena in condensed-matter physics with an unprecedented combination of spatial resolution and spin sensitivity

AglH, a thermophilic UDP‑<i>N</i>‑acetylglucosamine‑1‑phosphate:dolichyl phosphate GlcNAc‑1‑phosphotransferase initiating protein<i> N</i>‑glycosylation pathway in <i>Sulfolobus acidocaldarius</i>, is capable of complementing the eukaryal Alg7

AglH, a predicted UDP-GlcNAc-1-phosphate:dolichyl phosphate GlcNAc-1-phosphotransferase, is initiating the protein N-glycosylation pathway in the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius. AglH successfully replaced the endogenous GlcNAc-1-phosphotransferase activity of Alg7 in a conditional lethal Saccharomyces cerevisiae strain, in which the first step of the eukaryal protein N-glycosylation process was repressed. This study is one of the few examples of cross-domain complementation demonstrating a conserved polyprenyl phosphate transferase reaction within the eukaryal and archaeal domain like it was demonstrated for Methanococcus voltae (Shams-Eldin et al. 2008). The topology prediction and the alignment of the AglH membrane protein with GlcNAc-1-phosphotransferases from the three domains of life show significant conservation of amino acids within the different proposed cytoplasmic loops. Alanine mutations of selected conserved amino acids in the putative cytoplasmic loops II (D(100)), IV (F(220)) and V (F(264)) demonstrated the importance of these amino acids for cross-domain AlgH activity in in vitro complementation assays in S. cerevisiae. Furthermore, antibiotic treatment interfering directly with the activity of dolichyl phosphate GlcNAc-1-phosphotransferases confirmed the essentiality of N-glycosylation for cell survival

Simple isatin derivatives as free radical scavengers: Synthesis, biological evaluation and structure-activity relationship

To develop more potent small molecules with enhanced free radical scavenger properties, a series of N-substituted isatin derivatives was synthesized, and the cytoprotective effect on the apoptosis of PC12 cells induced by H2O2 was screened. All these compounds were found to be active, and N-ethyl isatin was found with the most potent activity of 69.7% protective effect on PC12 cells. Structure-activity relationship analyses showed the bioactivity of N-alkyl isatins decline as the increasing of the chain of the alkyl group, furthermore odd-even effect was found in the activity, which is interesting for further investigation