Isolated pores dissected from human two-pore channel 2 are functional.

Multi-domain voltage-gated ion channels appear to have evolved through sequential rounds of intragenic duplication from a primordial one-domain precursor. Whereas modularity within one-domain symmetrical channels is established, little is known about the roles of individual regions within more complex asymmetrical channels where the domains have undergone substantial divergence. Here we isolated and characterised both of the divergent pore regions from human TPC2, a two-domain channel that holds a key intermediate position in the evolution of voltage-gated ion channels. In HeLa cells, each pore localised to the ER and caused Ca2+ depletion, whereas an ER-targeted pore mutated at a residue that inactivates full-length TPC2 did not. Additionally, one of the pores expressed at high levels in E. coli. When purified, it formed a stable, folded tetramer. Liposomes reconstituted with the pore supported Ca2+ and Na+ uptake that was inhibited by known blockers of full-length channels. Computational modelling of the pore corroborated cationic permeability and drug interaction. Therefore, despite divergence, both pores are constitutively active in the absence of their partners and retain several properties of the wild-type pore. Such symmetrical 'pore-only' proteins derived from divergent channel domains may therefore provide tractable tools for probing the functional architecture of complex ion channels.This work was supported by BBSRC studentship BB/J014567 (CJP) and BBSRC grants BB/L006790 (BAW), BB/J019135 (BAW), BB/N01524X (SP) and BB/K000942 (SP). TR was supported by Royal Society grants RG69132 and RG65196. The SRCD studies were enabled by beamtime grants from the Soleil Synchrotron, France (to BAW)

Inclusions in super-deep diamonds

Super-deep diamonds may originate from a depth of between 300 and 800 km, although their precise depth of origin remains uncertain. When growing, they trap other minerals from their surroundings, which remain unaltered in their diamond capsule on their journey up to the surface of our planet. Through the study of these inclusions it is thus possible to reveal the secrets of deep unseen environments. In this study we aim to determine the formation pressure of super- deep diamonds for the first time by characterising two types of inclusions: CaSiO3-walstromite and ferropericlase. To achieve this goal we investigated CaSiO3-walstromite inclusions by a combination of in situ single-crystal X-ray diffraction, \u201csingle-inclusion elastic barometry\u201d and in situ micro-Raman spectroscopy and we obtained an apparent entrapment pressure of 3c7.1 GPa, corresponding to 3c250 km, at a temperature of 1500 K. In addition, thermodynamic calculations suggested that single inclusions of CaSiO3-walstromite cannot derive from CaSiO3-perovskite. Preliminary X-ray micro-tomography and nuclear resonance scattering data were also collected on ferropericlase-bearing diamonds in order to detect micro-fractures around the inclusions and to determine whether the Fe3+/ 11Fe ratios are in agreement with lower mantle values or not

Connecting our world

This workshop will give participants the opportunity to build physical interfaces using a wide range of materials and calibrate them to enhance the existing capabilities of the Scratch Picoboard

Comparative study on energy consumption at the University of Johannesburg residences

Abstract: This study evaluates the pattern of energy usage at the twenty-eight residences of the University of Johannesburg during the 2016 academic year. The study investigates the trend of energy consumption based on total energy usage per residence in terms of the number of students at each of the residences on a monthly and daily basis. The data employed in this study were collected over a period of eleven months which is the overall effective academic calendar. The results obtained showed a contrast between the total energy usage per residence and energy usage per student. Sophia town residence recorded the highest total annual energy usage of 149286 kWh while Takalani residence recorded the least which was 97093 kWh of all the residences considered in this study. However, when energy consumption was measured as a function of number of students in each residence, Goudstad residence recorded the highest monthly energy usage per student (450.69 kWh), followed by YMCA (389.09 kWh) while the least monthly energy usage of 51.30 kWh was recorded in Maqhawe residence. Similarly, results obtained from the study on daily energy usage per student in the last five months of the 2016 academic year showed Goudstad residence (23.32 kWh) and YMCA (20.34) as the two residences with the highest daily energy usage per student respectively. However, the energy usage does not follow a regular pattern within the period under consideration

Uterine Torsion Dystocia Complicated by Perosomus Elumbis in an Angus Calf Associated with a Consanguineous Mating

A six-year-old multiparous Angus cow was presented for dystocia. Vaginal and rectal examinations revealed an approximately 360° counterclockwise uterine torsion. The torsion was corrected by rolling the cow counterclockwise (three episodes) with the aid of a plank coupled with manual detorsion via the vagina. The placement of obstetric chains followed by manual traction ultimately delivered a stillborn male calf with evidence of vertebral aplasia, arthrogryposis, and abdominal organ herniation. Patient history and subsequent parentage verification revealed that the calf was the result of a consanguineous (mother to son) mating. Tissue samples from the affected calf and blood samples from the dam, sire, and ten half siblings were collected for genetic testing and parentage verification. Necropsy, radiographic, and computed tomography examinations all supported a diagnosis of perosomus elumbis. Perosomus elumbis is a congenital abnormality of unknown origin(s), and this is the first report of a case associated with a consanguineous mating

Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases

The 1-aryl-tetrahydroisoquinoline (1-aryl-THIQ) moiety is found in many biologically active molecules. Single enantiomer chemical syntheses are challenging and although some biocatalytic routes have been reported, the substrate scope is limited to certain structural motifs. The enzyme norcoclaurine synthase (NCS), involved in plant alkaloid biosynthesis, has been shown to perform stereoselective Pictet–Spengler reactions between dopamine and several carbonyl substrates. Here, benzaldehydes are explored as substrates and found to be accepted by both wild-type and mutant constructs of NCS. In particular, the variant M97V gives a range of (1 S)-aryl-THIQs in high yields (48–99%) and e.e.s (79–95%). A co-crystallised structure of the M97V variant with an active site reaction intermediate analogue is also obtained with the ligand in a pre-cyclisation conformation, consistent with (1 S)-THIQs formation. Selected THIQs are then used with catechol O-methyltransferases with exceptional regioselectivity. This work demonstrates valuable biocatalytic approaches to a range of (1 S)-THIQs

Impact of the COVID-19 pandemic on chronic disease management and patient reported outcomes in patients with pulmonary hypertension: The Pulmonary Hypertension Association Registry

To better understand the impact of the COVID-19 pandemic on the care of patients with pulmonary hypertension, we conducted a retrospective cohort study evaluating health insurance status, healthcare access, disease severity, and patient reported outcomes in this population. Using the Pulmonary Hypertension Association Registry (PHAR), we defined and extracted a longitudinal cohort of pulmonary arterial hypertension (PAH) patients from the PHAR\u27s inception in 2015 until March 2022. We used generalized estimating equations to model the impact of the COVID-19 pandemic on patient outcomes, adjusting for demographic confounders. We assessed whether insurance status modified these effects via covariate interactions. PAH patients were more likely to be on publicly-sponsored insurance during the COVID-19 pandemic compared with prior, and did not experience statistically significant delays in access to medications, increased emergency room visits or nights in the hospital, or worsening of mental health metrics. Patients on publicly-sponsored insurance had higher healthcare utilization and worse objective measures of disease severity compared with privately insured individuals irrespective of the COVID-19 pandemic. The relatively small impact of the COVID-19 pandemic on pulmonary hypertension-related outcomes was unexpected but may be due to pre-established access to high quality care at pulmonary hypertension comprehensive care centers. Irrespective of the COVID-19 pandemic, patients who were on publicly-sponsored insurance seemed to do worse, consistent with prior studies highlighting outcomes in this population. We speculate that previously established care relationships may lessen the impact of an acute event, such as a pandemic, on patients with chronic illness

Hanford radiological protection support services annual report for 1988

The report documents the performance of certain radiological protection sitewide services during calendar year (CY) 1988 by Pacific Northwest Laboratory (PNL) in support of the US Department of Energy-Richland Operations Office (DOE-RL) and contractor activities on the Hanford Site. The routine program for each service is discussed along with any significant program changes and tasks, investigations, and studies performed in support of each program. Other related activities such as publications, presentations, and memberships on standard or industry committees are also listed. The programs covered provide services in the areas of (1) internal dosimetry, (2) in vivo measurements, (3) external dosimetry, (4) instrument calibration and evaluation, (5) calibration of radiation sources traceable to the National Institute of Standards and Technology (NIST) (formerly the National Bureau of Standards), and (6) radiological records. 23 refs., 15 figs., 15 tabs

Assessment of Unabated Facility Emission Potentials for Evaluating Airborne Radionuclide Monitoring Requirements at Pacific Northwest National Laboratory - 2003

Assessments were performed to evaluate compliance with the airborne radionuclide emission monitoring requirements in the National Emission Standards for Hazardous Air Pollutants (NESHAP - U.S. Code of Federal Regulations, Title 40, Part 61, Subpart H) and Washington Administrative Code (WAC) 246-247: Radiation Protection - Air Emissions. In these assessments, potential unabated offsite doses were evaluated for emission locations at facilities owned by the U.S. Department of Energy and operated by Pacific Northwest National Laboratory (PNNL) on the Hanford Site. This report describes the inventory-based methods and provides the results for the assessment performed in 2003

Crystallographic relationships between diamond and its inclusions

The study of the crystallographic orientations of minerals included in diamonds can provide an insight into the mechanisms of their incorporation and the timing of their formation relative to the host diamond. The reported occurrence of non-trivial orientations for some minerals in some diamonds, suggesting an epitactic relationship, has long been considered to reflect contemporaneous growth of the diamond and the inclusion (= syngenesis). Correct interpretation of such orientations requires (i) a statistically significant data set, i.e. crystallographic data for single and multiple inclusions in a large number of diamonds, and (ii) a robust data-processing method, capable of removing ambiguities derived from the high symmetry of the diamond and the inclusion. We have developed software which performs such processing, starting from crystallographic orientation matrixes obtained by X-ray diffractometry. Preliminary studies indicate a wide variety of trends in the orientations of different inclusion phases in diamonds. In contrast to previous claims, olivine inclusions in lithospheric diamonds from Udachnaya do not show any preferred orientations with respect to their diamond hosts, but multiple inclusions in a single diamond often show very similar orientations within a few degrees (Nestola et al. 2014). Chromite (spinel) inclusions exhibit a strong tendency for a single (111) plane of each inclusion to be parallel to a (111) plane of their diamond host, but without any statistically significant orientation of the crystallographic axes a, b, and c. By contrast, 7 inclusions of ferropericlase studied in 2 different super deep diamonds (four inclusions in one diamond and three inclusions in the second diamond) from Brazil all exhibit the same orientation with their axes practically coincident with those of diamonds regardless of the position and the shape of the inclusions. The implications of these observations for the mechanisms of diamond growth will be explored