Provenance and Paleogeography of the 25-17 Ma Rainbow Gardens Formation: Evidence for Tectonic Activity at Ca. 19 Ma and Internal Drainage rather than Throughgoing Paleorivers on the Southwestern Colorado Plateau

The paleogeographic evolution of the Lake Mead region of southern Nevada and northwest Arizona is crucial to understanding the geologic history of the U.S. Southwest, including the evolution of the Colorado Plateau and formation of the Grand Canyon. The ca. 25–17 Ma Rainbow Gardens Formation in the Lake Mead region, the informally named, roughly coeval Jean Conglomerate, and the ca. 24–19 Ma Buck and Doe Conglomerate southeast of Lake Mead hold the only stratigraphic evidence for the Cenozoic pre-extensional geology and paleogeography of this area. Building on prior work, we present new sedimentologic and stratigraphic data, including sandstone provenance and detrital zircon data, to create a more detailed paleogeographic picture of the Lake Mead, Grand Wash Trough, and Hualapai Plateau region from 25 to 18 Ma. These data confirm that sediment was sourced primarily from Paleozoic strata exposed in surrounding Sevier and Laramide uplifts and active volcanic fields to the north. In addition, a distinctive signal of coarse sediment derived from Proterozoic crystalline basement first appeared in the southwestern corner of the basin ca. 25 Ma at the beginning of Rainbow Gardens Formation deposition and then prograded north and east ca. 19 Ma across the southern half of the basin. Regional thermochronologic data suggest that Cretaceous deposits likely blanketed the Lake Mead region by the end of Sevier thrusting. Post-Laramide northward cliff retreat off the Kingman/Mogollon uplifts left a stepped erosion surface with progressively younger strata preserved northward, on which Rainbow Gardens Formation strata were deposited. Deposition of the Rainbow Gardens Formation in general and the 19 Ma progradational pulse in particular may reflect tectonic uplift events just prior to onset of rapid extension at 17 Ma, as supported by both thermochronology and sedimentary data. Data presented here negate the California and Arizona River hypotheses for an “old” Grand Canyon and also negate models wherein the Rainbow Gardens Formation was the depocenter for a 25–18 Ma Little Colorado paleoriver flowing west through East Kaibab paleocanyons. Instead, provenance and paleocurrent data suggest local to regional sources for deposition of the Rainbow Gardens Formation atop a stripped low-relief western Colorado Plateau surface and preclude any significant input from a regional throughgoing paleoriver entering the basin from the east or northeast

Structural Adaptability Facilitates Histidine Heme Ligation in a Cytochrome P450

Almost all known members of the cytochrome P450 (CYP) superfamily conserve a key cysteine residue that coordinates the heme iron. Although mutation of this residue abolishes monooxygenase activity, recent work has shown that mutation to either serine or histidine unlocks non-natural carbene- and nitrene-transfer activities. Here we present the first crystal structure of a histidine-ligated P450. The T213A/C317H variant of the thermostable CYP119 from Sulfolobus acidocaldarius maintains heme iron coordination through the introduced ligand, an interaction that is accompanied by large changes in the overall protein structure. We also find that the axial cysteine C317 may be substituted with any other amino acid without abrogating folding and heme cofactor incorporation. Several of the axial mutants display unusual spectral features, suggesting that they have active sites with unique steric and electronic properties. These novel, highly stable enzyme active sites will be fruitful starting points for investigations of non-natural P450 catalysis and mechanisms

Using Light Charged Particles to Probe the Asymmetry Dependence of the Nuclear Caloric Curve

Recently, we observed a clear dependence of the nuclear caloric curve on neutron-proton asymmetry $\frac{N-Z}{A}$ through examination of fully reconstructed equilibrated quasi-projectile sources produced in heavy ion collisions at E/A = 35 MeV. In the present work, we extend our analysis using multiple light charged particle probes of the temperature. Temperatures are extracted with five distinct probes using a kinetic thermometer approach. Additionally, temperatures are extracted using two probes within a chemical thermometer approach (Albergo method). All seven measurements show a significant linear dependence of the source temperature on the source asymmetry. For the kinetic thermometer, the strength of the asymmetry dependence varies with the probe particle species in a way which is consistent with an average emission-time ordering.Comment: 7 pages, 4 figure

Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4* Nicotinic Acetylcholine Receptors

Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6^(L9’S*) receptors. α6^(L9’S) mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6 α4* pentamers, as α6^(L9’S) mice lacking α4 subunits displayed essentially normal behavior. In α6^(L9’S) mice, receptor numbers are normal, but loss of α4 subunits leads to fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits, implicating α6α4β2* nAChRs in α6^(L9’S) mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by α6^(L9’S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in α6^(L9’S), but not WT or α4KO/ α6^(L9’S), mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6^(L9’S) presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system

Comparison of lithomarge and cement-based mortars performance in aggressive aqueous environments

The resistance of room temperature cured geopolymer mortar (GPM) against chemical attacks, i.e. sodium and magnesium sulfate solutions, and sulfuric and hydrochloric acid solutions, was evaluated. GPM was formulated using a lithomarge precursor (low-purity kaolin) to achieve 28-day characteristic compressive strength of 60 MPa. Its performance was compared with an equivalent Portland cement mortar (PCM) having the same paste volume and strength grade. 28-day old bar samples were stored in 0.352 mol/L sulfate solutions for 52 weeks whereas 28-day old cube samples were exposed for 8 weeks to acid solutions with concentration of 0.52 mol/L. GPM showed superior performance against sulfate attack when compared to PCM. No visual deterioration was observed in GPM, the length changes were relatively small, and no changes to the microstructure were detected – in contrast to severely deteriorated PCM. As confirmed by visual observations and lower mass loss, GPM showed better resistance to attack by both acids than PCM. GPM provided a better quality (lower permeability) of an acid-degraded layer, lowering the degree of further deterioration. The main mechanisms of the matrix deterioration of GPM in both acids was dealumination of the hardened binder, with a higher degree of changes detected for sulfuric acid

Why do men with prostate cancer discontinue active surveillance for definitive treatment? A mixed methods investigation

Objectives: To explore the personal and/or medical reasons patients on active surveillance (AS) have, or consider having, further definitive treatment for their prostate cancer. Research suggests up to 50% of patients on AS will discontinue within 5 years, though reasons for discontinuation from the patient\u27s perspective is under-explored. Methods: Prostate cancer patients who were or had been on AS for at least 6 months were recruited. A questionnaire assessed reasons for receiving/considering definitive treatment and the extent to which reasons were personal or medical. Clinical information was extracted from a state-level population registry. A subset of participants were interviewed to further explore questionnaire responses. Results: One-hundred and-three individuals completed the survey; 33 were also interviewed. Fifty-four survey participants (52%) had discontinued AS for definitive treatment. Common reasons for discontinuation were evidence of disease progression, doctor recommendation, desire to act, and fear of progression. Many participants who considered or had treatment reported weighing medical and personal factors equally in their decision. Interview participants described strongly considering any amount of disease progression and personal factors such as fear of progression, family concerns, and adverse vicarious experiences when deciding whether to pursue treatment. Conclusion: Both medical and personal factors are considered when deciding whether to discontinue AS. Identifying predictors of discontinuation is essential for informing supportive care services to improve AS management

Impact of different unconditional monetary incentives on survey response rates in men with prostate cancer: A 2-arm randomised trial

Background: Men are often viewed as a difficult group to recruit for psychological research, including in psycho-oncology. Whilst research has demonstrated the effectiveness of small monetary incentives for encouraging research participation, little research has examined different large unconditional incentive amounts. Larger unconditional incentives may result in increased participation of men in psychological research. This randomised study within a case–control trial of men diagnosed with early-stage prostate cancer aimed to investigate whether (a) response rates to a 30-min questionnaire completed via mail, online, or phone would vary with different unconditional incentive amounts, and (b) demographics would vary in those who responded within the different incentive groups. Methods: We conducted this randomised study within a case–control cross-sectional study aiming to identify the social-ecological factors influencing treatment discontinuation in prostate cancer patients. A total of 238 participants from the cross-sectional study were randomised to receive one of two unconditional incentives (n = 121 received AUD $10, n = 117 received AUD$20) with the study materials (consent form and survey). Results: Overall, 113 (47 %) responded; n = 61/121 (50.4 %) in the AUD $10 group, and n = 52/117 (44.4$20 group. No evidence of a difference was found in response rates by incentive group (odds ratio 1.27, 95 % CI = 0.76 – 2.12, p = 0.36). Additionally, there were no evident differences in the demographics of the responders vs. non-responders within each incentive group (all p \u3e 0.05). Conclusions: Unlike previous research, we were unable to show that higher monetary incentives were more effective for increasing response rates. An AUD $20 unconditional incentive may be no more effective than a lesser amount for encouraging prostate cancer survivors to participate in research involving long questionnaires. Future research should consider the cost-benefits of providing large unconditional incentives, as non-responses will result in lost resources perhaps better utilised in other engagement strategies

Cohort profile:The Scottish SHARE Mental Health (SHARE-MH) cohort - linkable survey, genetic and routinely collected data for mental health research

PURPOSE: The SHARE Mental Health (SHARE-MH) cohort was established to address the paucity of clinical and genetic data available for mental health research. The cohort brings together detailed mental health questionnaire responses, routinely collected electronic health data and genetic data to provide researchers with an unprecedented linkable dataset. This combination of data sources allows researchers to track mental health longitudinally, across multiple settings. It will be of interest to researchers investigating the genetic and environmental determinants of mental health, the experiences of those interacting with healthcare services, and the overlap between self-reported and clinically derived mental health outcomes.PARTICIPANTS: The cohort consists of individuals sampled from the Scottish Health Research Register (SHARE). To register for SHARE, individuals had to be over the age of 16 years and living in Scotland. Cohort participants were recruited by email and invited to take part in an online mental health survey. When signing up for SHARE, participants also provided written consent to the use of their electronic health records and genetic data-derived from spare blood samples-for research purposes.FINDINGS TO DATE: From 5 February 2021 to 27 November 2021, 9829 individuals completed a survey of various mental health topics, capturing information on symptoms, diagnoses, impact and treatment. Survey responses have been made linkable to electronic health records and genetic data using a single patient identifier. Linked data have been used to describe the cohort in terms of their demographics, self-reported mental health, inpatient and outpatient hospitalisations and dispensed prescriptions.FUTURE PLANS: The cohort will be improved through linkage to a broader variety of routinely collected data and to increasing amounts of genetic data obtained through blood sample diversion. We see the SHARE-MH cohort being used to drive forward novel areas of mental health research and to contribute to global efforts in psychiatric genetics.</p

Structural Basis for α-Conotoxin Potency and Selectivity

Parkinson\u27s disease is a debilitating movement disorder characterized by altered levels of α6β2* nicotinic acetylcholine receptors (nAChRs) localized on presynaptic striatal catecholaminergic neurons. α-Conotoxin MII (α-CTx MII) is a highly useful ligand to probe α6ß2 nAChRs structure and function, but it does not discriminate among closely related α6* nAChR subtypes. Modification of the α-CTx MII primary sequence led to the identification of α-CTx MII[E11A], an analog with 500-5300 fold discrimination between α6* subtypes found in both human and non-human primates. α-CTx MII[E11A] binds most strongly (femtomolar dissociation constant) to the high affinity α6* nAChR, a subtype that is selectively lost in Parkinson\u27s disease. Here we present the three-dimensional solution structure for α-CTx MII[E11A] as determined by two-dimensional 1H NMR spectroscopy to 0.13 +/- 0.09 Ǻ backbone and 0.45 +/- 0.08 Ǻ heavy atom root mean square deviation from mean structure. Structural comparisons suggest that the increased hydrophobic area of α-CTx MII[E11A] relative to other members of the α-CTx family may be responsible for its exceptionally high affinity for α6α4β2* nAChR as well as discrimination between α6ß2 and α3β2 containing nAChRs. This finding may enable the rational design of novel peptide analogs that demonstrate enhanced specificity for α6* nAChR subunit interfaces and provide a means to better understand nAChR structural determinants that modulate brain dopamine levels and the pathophysiology of Parkinson\u27s disease