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Working memory difficulties are common, debilitating, and may pose barriers to recovery for people who use methamphetamine. Yet, little is known regarding the neural dysfunctions accompanying these difficulties. Here, we acquired cross-sectional, functional magnetic resonance imaging while people with problematic methamphetamine-use experience (MA + , n = 65) and people without methamphetamine-use experience (MA - , n = 44) performed a parametric n-back task (0-back through 2-back). Performance on tasks administered outside of the scanner, together with n-back performance, afforded to determine a latent dimension of participants' working memory ability. Behavioural results indicated that MA + participants exhibited lower scores on this dimension compared to MA - participants (d = -1.39, p < .001). Whole-brain imaging results also revealed that MA + participants exhibited alterations in load-induced responses predominantly in frontoparietal and default-mode areas. Specifically, while the MA - group exhibited monotonic activation increases within frontoparietal areas and monotonic decreases within default-mode areas from 0-back to 2-back, MA + participants showed a relative attenuation of these load-induced activation patterns (d = -1.55, p < .001). Moreover, increased activations in frontoparietal areas from 0- to 2-back were related to greater working memory ability among MA + participants (r = .560, p = .004). No such effects were observed for default-mode areas. In sum, reductions in working memory ability were observed alongside load-induced dysfunctions in frontoparietal and default-mode areas for people with problematic methamphetamine-use experience. Among them, load-induced activations within frontoparietal areas were found to have a strong and specific relationship to individual differences in working memory ability, indicating a putative neural signature of the working memory difficulties associated with chronic methamphetamine use., (© 2024 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2-[ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography in vivo in 9-, 12-, and 18-month-old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9-month-old SHR decreasing) 2-[ 18 F] fluoro-2-deoxy-d-glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12-month-old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2-[ 18 F] fluoro-2-deoxy-d-glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

Particle identification and selection, which is a prerequisite for high-resolution structure determination of biological macromolecules via single-particle cryo-electron microscopy poses a major bottleneck for automating the steps of structure determination. Here, we present a generalized deep learning tool, CASSPER, for the automated detection and isolation of protein particles in transmission microscope images. This deep learning tool uses Semantic Segmentation and a collection of visually prepared training samples to capture the differences in the transmission intensities of protein, ice, carbon, and other impurities found in the micrograph. CASSPER is a semantic segmentation based method that does pixel-level classification and completely eliminates the need for manual particle picking. Integration of Contrast Limited Adaptive Histogram Equalization (CLAHE) in CASSPER enables high-fidelity particle detection in micrographs with variable ice thickness and contrast. A generalized CASSPER model works with high efficiency on unseen datasets and can potentially pick particles on-the-fly, enabling data processing automation.

Background In spontaneously hypertensive rats (SHR) we observed profound myocardial metabolic changes during early hypertension before development of cardiac dysfunction and left ventricular hypertrophy. In this study, we evaluated whether metformin improved myocardial metabolic abnormalities and simultaneously prevented contractile dysfunction and left ventricular hypertrophy in SHR. Methods and Results SHR and control Wistar-Kyoto rats were treated with metformin from 2 to 5 months of age, when SHR hearts exhibit metabolic abnormalities and develop cardiac dysfunction and left ventricular hypertrophy. We evaluated the effect of metformin on myocardial glucose uptake rates with dynamic 2-[ 18 F] fluoro-2-deoxy-D-glucose positron emission tomography. We used cardiac MRI in vivo to assess the effect of metformin on ejection fraction, left ventricular mass, and end-diastolic wall thickness, and also analyzed metabolites, AMP-activated protein kinase and mammalian target-of-rapamycin activities, and mean arterial blood pressure. Metformin-treated SHR had lower mean arterial blood pressure but remained hypertensive. Cardiac glucose uptake rates, left ventricular mass/tibia length, wall thickness, and circulating free fatty acid levels decreased to normal, and ejection fraction improved in treated SHR. Hearts of treated SHR exhibited increased AMP-activated protein kinase phosphorylation and reduced mammalian target-of-rapamycin activity. Cardiac metabolite profiling demonstrated that metformin decreased fatty acyl carnitines and markers of oxidative stress in SHR. Conclusions Metformin reduced blood pressure, normalized myocardial glucose uptake, prevented left ventricular hypertrophy, and improved cardiac function in SHR. Metformin may exert its effects by normalizing myocardial AMPK and mammalian target-of-rapamycin activities, improving fatty acid oxidation, and reducing oxidative stress. Thus, metformin may be a new treatment to prevent or ameliorate chronic hypertension-induced left ventricular hypertrophy.

We generate the equation of state (EOS) of solid parahydrogen (para-H 2 ) using a path-integral Monte Carlo (PIMC) simulation based on a highly accurate first-principles adiabatic hindered rotor potential energy curve for the para-H 2 dimer. The EOS curves for the fcc and hcp structures of solid para-H 2 near the equilibrium density show that the hcp structure is the more stable of the two, in agreement with experiment. To accurately reproduce the structural and energy properties of solid para-H 2 , we eliminated by extrapolation the systematic errors associated with the choice of simulation parameters used in the PIMC calculation. We also investigate the temperature dependence of the EOS curves, and the invariance of the equilibrium density with temperature is satisfyingly reproduced. The pressure as a function of density and the compressibility as a function of pressure are both calculated using the obtained EOS and are compared with previous simulation results and experiments. We also report the first ever a priori prediction of a vibrational matrix shift from first-principles two-body potential functions, and its result for the equilibrium state agrees well with experiment.

Helium (^{4}He) nanodroplets provide a unique environment to observe the microscopic origins of superfluidity. The search for another superfluid substance has been an ongoing quest in the field of quantum fluids. Nearly two decades ago, experiments on doped parahydrogen (p-H&#95;{2}) clusters embedded in ^{4}He droplets displayed anomalous spectroscopic signatures that were interpreted as a sign of the superfluidity of p-H&#95;{2} [S. Grebenev et al., Science 289, 1532 (2000)SCIEAS0036-807510.1126/science.289.5484.1532]. Here, we observe, using first-principles quantum Monte Carlo simulations, a phase separation between a symmetric and localized p-H&#95;{2} core and ^{4}He shells. The p-H&#95;{2} core has minimal superfluid response. These findings are consistent with the recorded spectra but not with their original interpretation, and lead us to conclude that doped p-H&#95;{2} clusters form a nonsuperfluid core in ^{4}He droplets.

Background Sustained pressure overload leads to changes in cardiac metabolism, function, and structure. Both time course and causal relationships between these changes are not fully understood. Therefore, we studied spontaneously hypertensive rats (SHR) during early hypertension development and compared them to control Wistar Kyoto rats. Methods and Results We serially evaluated myocardial glucose uptake rates (Ki) with dynamic 2-[ 18 F] fluoro-2-deoxy-D-glucose positron emission tomography, and ejection fraction and left ventricular mass to body weight ratios with cardiac magnetic resonance imaging in vivo, determined glucose uptake and oxidation rates in isolated perfused hearts, and analyzed metabolites, mammalian target of rapamycin activity and endoplasmic reticulum stress in dissected hearts. When compared with Wistar Kyoto rats, SHR demonstrated increased glucose uptake rates (Ki) in vivo, and reduced ejection fraction as early as 2 months of age when hypertension was established. Isolated perfused SHR hearts showed increased glucose uptake and oxidation rates starting at 1 month. Cardiac metabolite analysis at 2 months of age revealed elevated pyruvate, fatty acyl- and branched chain amino acid-derived carnitines, oxidative stress, and inflammation. Mammalian target of rapamycin activity increased in SHR beginning at 2 months. Left ventricular mass to body weight ratios and endoplasmic reticulum stress were elevated in 5 month-old SHR. Conclusions Thus, in a genetic hypertension model, chronic cardiac pressure overload promptly leads to increased myocardial glucose uptake and oxidation, and to metabolite abnormalities. These coincide with, or precede, cardiac dysfunction while left ventricular hypertrophy develops only later. Myocardial metabolic changes may thus serve as early diagnostic markers for hypertension-induced left ventricular hypertrophy.

Rodent models of liver tumorigenesis have reproducibly shown that dietary sugar intake is a powerful driver of liver tumor initiation and growth. In contrast, dietary sugar restriction with ketogenic diets or calorie restriction generally prevents liver tumor formation. Ketogenic diet is viewed positively as a therapeutic adjuvant; however, most ketogenic diet studies described to date have been performed in prevention mode rather than treatment mode. Therefore, it remains unclear whether a ketogenic diet can be administered in late stages of disease to stall or reverse liver tumor growth. To model the clinically relevant treatment mode, we administered a ketogenic diet to mice after liver tumor initiation and monitored tumor growth by magnetic resonance imaging (MRI). Male C57BL/6 mice were injected with diethylnitrosamine (DEN) at 2 weeks of age and fed a chow diet until 39 weeks of age, when they underwent MRI imaging to detect liver tumors. Mice were then randomised into two groups and fed either a chow diet or switched to a ketogenic diet from 40⁻48 weeks of age. Serial MRIs were performed at 44 and 48 weeks of age. All mice had tumors at study completion and there were no differences in total tumor burden between diet groups. Although a ketogenic diet has marked protective effects against DEN-induced liver tumourigenesis in this mouse model, these data demonstrate that ketogenic diet cannot stop the progression of established liver tumors.

Objective: The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA)., Methods: Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 μL of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 μL of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement., Results: Compared with the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 21, 28, and 100, respectively; P < .001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro-matrix metalloproteinase 9, interleukin-1β, interleukin-6, chemokine [C-C motif] ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100., Conclusions: A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

This article reviews the various modeling techniques for neuromonitoring depth of anesthesia (DOA). Traditional techniques such as parametric, predictive, optimal, and adaptive modeling; proportional, integral, derivative (PID) modeling; together with modern techniques such as bispectral-based, artificial neural-network-based, fuzzy logic, and neuro-fuzzy modeling, bring us to the current state of the art in DOA neuromonitoring. This article reviews historical information about each of the modern techniques and provides an example demonstrating its implementation; reviews drug pharmacokinetic/pharmacodynamic (PK/PD) and drug interaction PK/PD modeling techniques for a balanced total intravenous anesthesia (TIVA) administration; and discusses the existing technical problems and clinical challenges, suggesting new techniques necessary for the future development of a DOA monitoring and control system.

All available "conventional" absorption/emission spectroscopic data have been combined with photodissociation data and translational spectroscopy data in a global analysis that yields analytic potential energy and Born-Oppenheimer breakdown functions for the X(1)Σ(+) and A(1)Π states of CH(+) and its isotopologues that reproduce all of the data (on average) within their assigned uncertainties. For the ground X(1)Σ(+) state, this fully quantum mechanical "Direct-Potential-Fit" analysis yielded an improved empirical well depth of 𝔇e = 34 362.8(3) cm(-1) and equilibrium bond length of re = 1.128 462 5 (58) Å. For the A(1)Π state, the resulting well depth and equilibrium bond length are 𝔇e = 10 303.7(3) cm(-1) and re = 1.235 896 (14) Å, while the electronic isotope shift from the hydride to the deuteride is ΔTe = - 5.99(±0.08) cm(-1).

Raman vibrational shifts of small parahydrogen (pH2), orthodeuterium (oD2), and paratritium (pT2) clusters with respect to the free molecules are calculated by combining a first order perturbation theory approach with Langevin equation Path Integral Ground State (LePIGS) simulations [ J. Phys. Chem. A 2013 , 117 , 7461 ]. Our theoretical predictions are compared to existing cryogenic free jet expansion results for pure (pH2)N clusters [ Phys. Rev. Lett. 2004 , 92 , 223401 ] and to new measurements for (oD2)N clusters reported here. This method has been successfully used before to predict the Raman vibrational shifts of (pH2)N clusters [ J. Chem. Phys. 2014 , 141 , 014310 ]. The 6-D interaction potential of Hinde [ J. Chem. Phys. 2008 , 128 , 154308 ] is reduced to 1-D using the Adiabatic Hindered Rotor approximation to yield effective pair potentials for both molecules being in the ground vibrational state, and for one of them carrying one quantum of vibrational excitation. These reduced 1-D potentials are fitted to a Morse Long Range analytic form for later convenience. Good agreement between experiment and theory is found for the smaller clusters, but significant deviations remain for the larger ones.

Purpose: Gene-modified mice may be used to elucidate molecular mechanisms underlying abnormal myocardial blow flow (MBF). We sought to develop a quantitative myocardial perfusion imaging technique for mice and to test the hypothesis that myocardial perfusion reserve (MPR) is reduced in a mouse model of diet-induced obesity (DIO)., Methods: A dual-contrast saturation-recovery sequence with ky -t undersampling and a motion-compensated compressed sensing reconstruction algorithm was developed for first-pass MRI on a small-bore 7 Tesla system. Control mice were imaged at rest and with the vasodilators ATL313 and Regadenoson (n = 6 each). In addition, we imaged mice fed a high-fat diet (HFD) for 24 weeks., Results: In control mice, MBF was 5.7 ± 0.8 mL/g/min at rest and it increased to 11.8 ± 0.6 mL/g/min with ATL313 and to 10.4 ± 0.3 mL/g/min with Regadenoson. In HFD mice, we detected normal resting MBF (5.6 ± 0.4 versus 5.0 ± 0.3 on control diet), low MBF at stress (7.7 ± 0.4 versus 10.4 ± 0.3 on control diet, P < 0.05), and reduced MPR (1.4 ± 0.2 versus 2.0 ± 0.3 on control diet, P < 0.05)., Conclusion: Accelerated dual-contrast first-pass MRI with motion-compensated compressed sensing provides spatiotemporal resolution suitable for measuring MBF in free-breathing mice, and detected reduced MPR in DIO mice. These techniques may be used to study molecular mechanisms that underlie abnormal myocardial perfusion., (© 2014 Wiley Periodicals, Inc.)

A direct-potential-fit analysis of all accessible data for the A (1)Σ(+) - X (1)Σ(+) system of NaH and NaD is used to determine analytic potential energy functions incorporating the correct theoretically predicted long-range behaviour. These potentials represent all of the data (on average) within the experimental uncertainties and yield an improved estimate for the ground-state NaH well depth of 𝔇e = 15797.4 (±4.3) cm(-1), which is ∼20 cm(-1) smaller than the best previous estimate. The present analysis also yields the first empirical determination of centrifugal (non-adiabatic) and potential-energy (adiabatic) Born-Oppenheimer breakdown correction functions for this system, with the latter showing that the A-state electronic isotope shift is -1.1(±0.6) cm(-1) going from NaH to NaD.