Molecular dynamics of ion transport through the open conformation of a bacterial voltage-gated sodium channel

The crystal structure of the open conformation of a bacterial voltage-gated sodium channel pore from Magnetococcus sp. (NaVMs) has provided the basis for a molecular dynamics study defining the channel’s full ion translocation pathway and conductance process, selectivity, electrophysiological characteristics, and ion-binding sites. Microsecond molecular dynamics simulations permitted a complete time-course characterization of the protein in a membrane system, capturing the plethora of conductance events and revealing a complex mixture of single and multi-ion phenomena with decoupled rapid bidirectional water transport. The simulations suggest specific localization sites for the sodium ions, which correspond with experimentally determined electron density found in the selectivity filter of the crystal structure. These studies have also allowed us to identify the ion conductance mechanism and its relation to water movement for the NavMs channel pore and to make realistic predictions of its conductance properties. The calculated single-channel conductance and selectivity ratio correspond closely with the electrophysiology measurements of the NavMs channel expressed in HEK 293 cells. The ion translocation process seen in this voltage-gated sodium channel is clearly different from that exhibited by members of the closely related family of voltage-gated potassium channels and also differs considerably from existing proposals for the conductance process in sodium channels. These studies simulate sodium channel conductance based on an experimentally determined structure of a sodium channel pore that has a completely open transmembrane pathway and activation gate

Mantle Sources and Geochemical Evolution of the Picture Gorge Basalt, Columbia River Basalt Group

The Columbia River Basalt Group (CRBG) is the youngest continental flood basalt province, proposed to be sourced from the deep-seated plume that currently resides underneath Yellowstone National Park. If so, the earliest erupted basalts from this province, such as those in the Picture Gorge Basalt (PGB), aid in understanding and modeling plume impingement and the subsequent evolution of basaltic volcanism. Using geochemical and isotopic data, this study explores potential mantle sources and magma evolution of the PGB. Long known geochemical signatures of the PGB include overall large ion lithophile element (LILE) enrichment and relative depletion of high field strength elements (HFSE) typical of other CRBG main-phase units. Basaltic samples of the PGB have 87Sr/86Sr ratios on the low end of the range displayed by other CRBG lavas and mantle-like δ18O values. The relatively strong enrichment of LILE and depletion of HFSE coupled with depleted isotopic signatures suggest a metasomatized upper mantle as the most likely magmatic source for the PGB. Previous geochemical modeling of the PGB utilized the composition of two high-MgO primitive dikes exposed in the northern portion of the Monument Dike swarm as parental melt. However, fractionation of these dike compositions cannot generate the compositional variability illustrated by basaltic lavas and dikes of the PGB. This study identifies a second potential parental PGB composition best represented by basaltic flows in the extended spatial distribution of the PGB. This composition also better reflects the lowest stratigraphic flows identified in the previously mapped extent of the PGB. Age data reveal that PGB lavas erupted first and throughout eruptions of main-phase CRBG units (Steens, Imnaha, Grande Ronde Basalt). Combining geochemical signals with these age data indicates cyclical patterns in the amounts of contributing mantle components. Eruption of PGB material occurred in two pulses, demonstrated by a ~0.4 Ma temporal gap in reported ages, 16.62 to 16.23 Ma. Coupling ages with observed geochemical signals, including relative elemental abundances of LILE, indicates increased influence of a more primitive, potentially plume-like source with time

Metacognitive deficits and social functioning in schizophrenia across symptom profiles: A latent class analysis

Functional deficits are a hallmark of schizophrenia spectrum disorders, but much debate still exists over why and how they originate. One model suggests that disturbances in social functioning are a result of metacognitive deficits or a failure to integrate information to form more complex ideas of themselves and others. It is unclear if this social dysfunction is present across different symptom presentations. We examined the relationship of metacognition, symptoms, and social functioning among a sample of adults with schizophrenia spectrum disorders (N ¼ 334). A latent class analysis produced a four-class model. Groups were classified as follows: diffuse symptoms/moderately impaired social functioning (Class 1), positive and hostility symptoms/mildly impaired social functioning (Class 2), minimal symptoms/good social functioning (Class 3), and negative and cognitive symptoms/severely impaired social functioning (Class 4). Class 3 demonstrated better overall metacognitive capacity than both Classes 1 and 4 but did not differ significantly from Class 2. Classes 2 and 3 both demonstrated better interpersonal functioning than Classes 1 and 4. Together, these findings provide support for models of poor functioning that stem from fragmentation of an individual’s experience, leading to diminished abilities to form meaningful connections with others. Additional interpretations, limitations, and research implications are discussed

Effect of Sodium Saccharin on the Neonatal Rat Bladder

In a two-generation bioassay, high doses of dietary sodium saccharin (NaSac) produce bladder carcinoma in rats, whereas acid saccharin (HSac) does not effect the urothelium. NaSac and HSac administered as 5% of the diet to F0 Sprague-Dawley (SD) and F344 rats, continued through to the weaned male rats for ten additional weeks. Control 3H-thymidine labeling index (LI) was high prior to and at birth (approximately 11%), declining rapidly by weaning (to \u3c 0.2). Neither NaSac nor HSac increased proliferation through 7 days of age. NaSac increased the proliferation rate at later times, whereas HSac did not. The LI decreased to control levels in NaSac-fed rats switched to control diet after weaning and increased in control-fed rats switched to NaSac after birth or weaning. In a second experiment, 5% NaSac did not affect urothelial morphology of SD rats through 7 days. By 21 days post-birth, urothelial hyperplasia occurred in NaSac-fed rat. The LI in treated versus control was similar through gestation, with a slight difference by 7 days. LI was significantly different by 21 days post-birth, but was similar between males and females. These results provide additional evidence for the increased cell proliferative effects of NaSac during the neonatal period, but not during gestation

Happy Soldiers are Highest Performers

17 USC 105 interim-entered record; under review.The article of record as published may be found at: https://doi.org/10.1007/s10902-021-00441-xWe examined the prediction of affective well-being to work performance in the United States Army. We found that high positive affect (PA), low negative affect (NA), and high optimism predicted awards for performance and heroism in a sample of 908,096 U.S. Army soldiers (mean age 29.60 years old, SD = 9.16 years; with over 1⁄4 of a million ethnic minor- ities and over 150,000 women). Baseline high PA, low NA, and high optimism predicted awards over a four-year follow up window, in which 114,443 soldiers (12.60%) received an award. Each well-being variable predicted future awards for both women and men, for enlisted soldiers as well as officers, for several ethnicities, for varying levels of education, and controlling for a number of other potential explanatory variables. The effects of high positive and low negative affect were additive, with each predicting significantly beyond the other. Comparing the soldiers highest vs. lowest in well-being predicted an almost four- fold greater award recognition in the high group. Awards were predicted by both high and low arousal positive emotions, as well as low sadness and low anger. The relations between PA, NA, and optimism with award attainment were curvilinear, with the greatest difference in award attainment occurring between low and moderate levels of affective well-being, with little effect between moderate and high well-being.Identified in text as U.S. Government work

Thermal annealing behaviour and gel to crystal transition of a low molecular weight hydrogelator

The thermal annealing behaviour of an electrolyte-triggered calixarene hydrogelator is found to depend strongly on the specific metal chloride used. While the lithium chloride gel showed typical gel-sol transitions as a function of temperature, the magnesium chloride gel was found to repeatedly strengthen with heat-cool cycles. Structural investigations using small-angle neutron scattering, and scanning probe microscopy, suggest that the annealing behaviour is associated with a change in morphology of the fibrous structures supporting the gel. On prolonged standing at room temperature, the magnesium chloride gel underwent a gel-crystal transition, with the collapsing gel accompanied by the deposition of crystals of a magnesium complex of the proline-functionalised calix[4]arene gelator

Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice

Background Sirtuins are important regulators of glucose and fat metabolism, and sirtuin activation has been proposed as a therapeutic target for insulin resistance and diabetes. We have shown leucine to increase mitochondrial biogenesis and fat oxidation via Sirt1 dependent pathways. Resveratrol is a widely recognized activator of Sirt; however, the biologically-effective high concentrations used in cell and animal studies are generally impractical or difficult to achieve in humans. Accordingly, we sought to determine whether leucine would exhibit synergy with low levels of resveratrol on sirtuin-dependent outcomes in adipocytes and in diet-induced obese (DIO) mice. Methods 3T3-L1 mouse adipocytes were treated with Leucine (0.5 mM), β-hydroxy-β-methyl butyrate (HMB) (5 μM) or Resveratrol (200 nM) alone or in combination. In addition, diet-induced obese mice were treated for 6-weeks with low (2 g/kg diet) or high (10 g/kg diet) dose HMB, Leucine (24 g/kg diet; 200% of normal level) or low (12.5 mg/kg diet) or high (225 mg/kg diet) dose resveratrol, alone or as combination with leucine-resveratrol or HMB-resveratrol. Results Fatty acid oxidation, AMPK, Sirt1 and Sirt3 activity in 3T3-L1 adipocytes and in muscle cells, were significantly increased by the combinations compared to the individual treatments. Similarly, 6-week feeding of low-dose resveratrol combined with either leucine or its metabolite HMB to DIO mice increased adipose Sirt1 activity, muscle glucose and palmitate uptake (measured via PET/CT), insulin sensitivity (HOMAIR), improved inflammatory stress biomarkers (CRP, IL-6, MCP-1, adiponectin) and reduced adiposity comparable to the effects of high dose resveratrol, while low-dose resveratrol exerted no independent effect. Conclusion These data demonstrate that either leucine or its metabolite HMB may be combined with a low concentration of resveratrol to exert synergistic effects on Sirt1-dependent outcomes; this may result in more practical dosing of resveratrol in the management of obesity, insulin-resistance and diabetes

Calcium, magnesium and potassium intake and mortality in women with heart failure: The Women\u27s Health Initiative

Although diet is thought to affect the natural history of heart failure (HF), nutrient intake in HF patients has not been well studied. Based on prior research linking high intake of Ca, Mg and K to improved cardiovascular health, we hypothesised that these nutrients would be inversely associated with mortality in people with HF. Of the 161 808 participants in the Women\u27s Health Initiative (WHI), we studied 3340 who experienced a HF hospitalisation. These participants were followed for post-hospitalisation all-cause mortality. Intake was assessed using questionnaires on food and supplement intake. Hazard ratios (HR) and 95 % CI were calculated using Cox proportional hazards models adjusted for demographics, physical function, co-morbidities and dietary covariates. Over a median of 4·6 years of follow-up, 1433 (42·9 %) of the women died. HR across quartiles of dietary Ca intake were 1·00 (referent), 0·86 (95 % CI 0·73, 1·00), 0·88 (95 % CI 0·75, 1·04) and 0·92 (95 % CI 0·76, 1·11) (P for trend = 0·63). Corresponding HR were 1·00 (referent), 0·86 (95 % CI 0·71, 1·04), 0·88 (95 % CI 0·69, 1·11) and 0·84 (95 % CI 0·63, 1·12) (P for trend = 0·29), across quartiles of dietary Mg intake, and 1·00 (referent), 1·20 (95 % CI 1·01, 1·43), 1·06 (95 % CI 0·86, 1·32) and 1·16 (95 % CI 0·90, 1·51) (P for trend = 0·35), across quartiles of dietary K intake. Results were similar when total (dietary plus supplemental) nutrient intakes were examined. In summary, among WHI participants with incident HF hospitalisation, intakes of Ca, Mg and K were not significantly associated with subsequent mortality