Read-Across for Rat Oral Gavage Repeated-Dose Toxicity for Short-Chain Mono-Alkylphenols: A Case Study

Short-chain mono-alkylphenols provide an example of where a category-approach to read-across may be used to estimate the repeated-dose endpoint for a number of derivatives. Specifically, the NOAELs of 50 mg/kg bw/d for mono-methylphenols based on a LOAEL of very low systemic toxicity can be read across with confidence to untested mono-alkylphenols in the category. These simple alkylphenols are non-reactive and exhibit an unspecific, reversible polar narcosis mode of toxic action. Briefly, polar narcotics act via unspecific, reversible interactions with biological membranes in a manner similar to cataleptic anaesthetics. The read-across premise includes rapid and complete absorption via the gastrointestinal tract, distribution in the circulatory system, first-pass Phase 2 metabolism in the liver, and elimination of sulphates and glucuronides in the urine. Thus, toxicokinetic parameters are considered to be similar and have the same toxicological significance. Five analogues have high quality experimental oral repeated-dose toxicity data (i.e., OECD TG 408 or OECD TG 422). These repeated-dose toxicity test results exhibit qualitative consistency in symptoms. Typical findings include decreased body weight and slightly increased liver and kidney weights which are generally without concurrent histopathological effects. The sub-chronic findings are quantitatively consistent with the No Observed Adverse Effect Level (NOAEL) of ≥ 50 mg/kg bw/d. Chemical similarity between the analogues is readily defined, and data uncertainty associated with the similarities in toxicokinetic properties, as well as toxicodynamic properties, are low. Uncertainty associated with mechanistic relevance and completeness of the read-across is low-to-moderate, largely because there is no adverse outcome pathway or intermediate event data. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo, in vitro, USEPA toxicity forecaster (ToxCast) results, as well as the in silico data. The rat oral repeated-dose NOAEL values for the source substances can be read across to fill the data gaps of the untested analogues in this category with uncertainty deemed equivalent to results from a TG 408 assessment

Digital Health Intervention Design and Deployment for Engaging Demographic Groups Likely to Be Affected by the Digital Divide: Protocol for a Systematic Scoping Review

Background: Digital health interventions (DHIs) refer to interventions designed to support health-related knowledge transfer and delivered via digital technologies, such as mobile applications (apps). DHIs are a double-edged sword: they have the potential to reduce health inequalities, for example by making treatments available remotely to rural populations underserved by healthcare facilities or by helping to overcome language barriers via in-app translation services. However, if not designed and deployed with care, DHIs also have the potential to increase health inequalities and exacerbate effects of the digital divide. / Objective: The objective of this study was to review ways to mitigate the digital divide through DHI design, deployment and engagement mechanisms sensitive to the needs of digitally-excluded populations. / Methods: This protocol outlines the procedure for a systematic scoping review focussing on features of DHI design and deployment that enable or hinder access to and engagement with DHIs by people from demographic groups likely to be affected by the digital divide. / Results: The review is underway and is anticipated to be completed by the end of September 2021. / Conclusions: The results will have wider implications for researchers and policy makers using DHIs for health improvement peri-pandemic and post-pandemic and will inform best practices in the design and delivery of DHIs. Clinical Trial: A summary of the protocol and any supplementary material will be registered with the Open Science Framework (OSF) and assigned a Digital Object Identifier (DOI) for long-term retrieval

Определение скорости перемещения деформаций растяжений в массиве при подземной выемке угля

Приведена швидкість переміщення деформацій в непорушеному масиві. Встановлено, що швидкість в породах середнього ступеня метаморфізму складає 15 м/добу. Середня швидкість переміщення деформацій в сланцях – 10 м/добу, в піщаниках – 15 м/добу. При повторній підробці швидкість переміщення деформацій складає 17 м/добу.Deformation’s speed travel in the virgin rock massif is given in this article. It has been determined that deformation’s speed in the rocks of medium-scale metamorphism was 15 meters over the entire circadian period. The average speed of deformation’s travel in the shale rocks is 10 meters over the entire circadian period and in the sandstone is 15 meters over the entire circadian period. During the recurring undermining the speed travel of deformations is 17 meters over the entire circadian period

Mineralogy, early marine diagenesis, and the chemistry of shallow-water carbonate sediments

Shallow-water carbonate sediments constitute the bulk of sedimentary carbonates in the geologic record and are widely used archives of Earth’s chemical and climatic history. One of the main limitations in interpreting the geochemistry of ancient carbonate sediments is the potential for post-depositional diagenetic alteration. In this study, we use paired measurements of calcium (44Ca/40Ca or δ44Ca) and magnesium (26Mg/24Mg or δ26Mg) isotope ratios in sedimentary carbonates and associated pore-fluids as a tool to understand the mineralogical and diagenetic history of Neogene shallow-water carbonate sediments from the Bahamas and southwest Australia. We find that the Ca and Mg isotopic composition of bulk carbonate sediments at these sites exhibits systematic stratigraphic variability that is related to both mineralogy and early marine diagenesis. The observed variability in bulk sediment Ca isotopes is best explained by changes in the extent and style of early marine diagenesis from one where the composition of the diagenetic carbonate mineral is determined by the chemistry of the fluid (fluid-buffered) to one where the composition of the diagenetic carbonate mineral is determined by the chemistry of the precursor sediment (sediment-buffered). Our results indicate that this process, together with variations in carbonate mineralogy (aragonite, calcite, and dolomite), plays a fundamental and underappreciated role in determining the regional and global stratigraphic expressions of geochemical tracers (δ13C, δ18O, major, minor, and trace elements) in shallow-water carbonate sediments in the geologic record. Our results also provide evidence that a large shallow-water carbonate sink that is enriched in 44Ca can explain the mismatch between the δ44/40Ca value of rivers and deep-sea carbonate sediments and call into question the hypothesis that the δ44/40Ca value of seawater depends on the mineralogy of primary carbonate precipitations (e.g. ‘aragonite seas’ and ‘calcite seas’). Finally, our results for sedimentary dolomites suggest that paired measurements of Ca and Mg isotopes may provide a unique geochemical fingerprint of mass transfer during dolomitization to better understand the paleo-environmental information preserved in these enigmatic but widespread carbonate minerals

Decision making and experiences of young adults undergoing presymptomatic genetic testing for familial cancer: A longitudinal grounded theory study

Enabling informed choice is an essential component of care when offering young adults presymptomatic testing for a genetic condition. A systematic review on this topic revealed that many young adults grew up with little information regarding their genetic risk and that parents had applied pressure to them during the testing decision-making process. However, none of the studies retrieved were conducted in South European countries. To address this gap, we undertook a qualitative study based on grounded theory to explore the psychosocial implications of presymptomatic testing for hereditary cancer in Italian young adults aged 18-30 years. Interviews were conducted on three occasions: 1 month before counselling, and 2 weeks and 6 months after results. Data were coded and grouped under themes. A total of 42 interviews were conducted. Four themes emerged: knowledge, genetic counselling process, decision making and dealing with test results. Although participants grew up with little or no information about their genetic risk, none expressed regret at having the test at a young age. Pre-test counselling was appreciated as a source of information, rather than support for decision making. Decisions were often made autonomously and sometimes conflicted with parents' wishes. Participants reported no changes in health behaviours after testing. This evidence highlights the need for a comprehensive, longitudinal counselling process with appropriate timing and setting, which supports 'parent-to-offspring' risk communication first and decision making by young adults about presymptomatic testing and risk management afterwards. In conclusion, it is clear that counselling approaches for presymptomatic testing may require modification both for young adults and their parents. © 2017 European Society of Human Genetics

Permanence of the information given during oncogenetic counseling to persons at familial risk of breast/ovarian and/or colon cancer

How long counselees retain the information given during their genetic consultation is of major importance. To address this issue, we conducted a survey among the 3500 families that have been offered genetic counseling at our Center since 1988. In August 2007, we mailed a questionnaire to a representative subset of 579 persons belonging to breast/ovarian or colon cancer families seen in the last 10 years, either carrying an identified mutation or not. Targeted topics included the meaning of hereditary predisposition, the medical prevention related to the familial risk, the steps to undertake for a new family member to enter the genetic testing program and general knowledge of hereditary predisposition to cancer. A total of 91 randomized non-respondents were sent a second, more inciting letter, in order to assess any non-response bias. Overall, 337 questionnaires were collected: response rate was 58%. Standardized average knowledge was 7.28±1.52 of 10. Scores were lowest concerning medical prevention. The level of knowledge decreased with age (P<10−6), but increased with educational level (P<10−5) and mutation status (P=0.01). Surprisingly, no erosion of patients' knowledge over the time was observed (P=0.41). Among persons at hereditary risk of colon cancer, the level of knowledge tended to improve with time, in contrast to the breast/ovarian group (P=0.017). Among persons with a familial risk of breast/ovarian or colon cancer, a renewal of oncogenetic counseling does not seem necessary to maintain the level of specific knowledge. Measures to help patients follow their medical prevention, as organizing or checking their medical examinations, seem indicated

Proteomic analysis of the Plasmodium male gamete reveals the key role for glycolysis in flagellar motility.

BACKGROUND: Gametogenesis and fertilization play crucial roles in malaria transmission. While male gametes are thought to be amongst the simplest eukaryotic cells and are proven targets of transmission blocking immunity, little is known about their molecular organization. For example, the pathway of energy metabolism that power motility, a feature that facilitates gamete encounter and fertilization, is unknown. METHODS: Plasmodium berghei microgametes were purified and analysed by whole-cell proteomic analysis for the first time. Data are available via ProteomeXchange with identifier PXD001163. RESULTS: 615 proteins were recovered, they included all male gamete proteins described thus far. Amongst them were the 11 enzymes of the glycolytic pathway. The hexose transporter was localized to the gamete plasma membrane and it was shown that microgamete motility can be suppressed effectively by inhibitors of this transporter and of the glycolytic pathway. CONCLUSIONS: This study describes the first whole-cell proteomic analysis of the malaria male gamete. It identifies glycolysis as the likely exclusive source of energy for flagellar beat, and provides new insights in original features of Plasmodium flagellar organization

Environmental variables, habitat discontinuity and life history shaping the genetic structure of Pomatoschistus marmoratus

Coastal lagoons are semi-isolated ecosystems exposed to wide fluctuations of environmental conditions and showing habitat fragmentation. These features may play an important role in separating species into different populations, even at small spatial scales. In this study, we evaluate the concordance between mitochondrial (previous published data) and nuclear data analyzing the genetic variability of Pomatoschistus marmoratus in five localities, inside and outside the Mar Menor coastal lagoon (SE Spain) using eight microsatellites. High genetic diversity and similar levels of allele richness were observed across all loci and localities, although significant genic and genotypic differentiation was found between populations inside and outside the lagoon. In contrast to the FST values obtained from previous mitochondrial DNA analyses (control region), the microsatellite data exhibited significant differentiation among samples inside the Mar Menor and between lagoonal and marine samples. This pattern was corroborated using Cavalli-Sforza genetic distances. The habitat fragmentation inside the coastal lagoon and among lagoon and marine localities could be acting as a barrier to gene flow and contributing to the observed genetic structure. Our results from generalized additive models point a significant link between extreme lagoonal environmental conditions (mainly maximum salinity) and P. marmoratus genetic composition. Thereby, these environmental features could be also acting on genetic structure of coastal lagoon populations of P. marmoratus favoring their genetic divergence. The mating strategy of P. marmoratus could be also influencing our results obtained from mitochondrial and nuclear DNA. Therefore, a special consideration must be done in the selection of the DNA markers depending on the reproductive strategy of the species

Genes Are Often Sheltered from the Global Histone Hyperacetylation Induced by HDAC Inhibitors

Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (∼9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay