Control of motivation for sucrose in the paraventricular hypothalamic nucleus by dynorphin peptides and the kappa opioid receptor.

The dynorphin peptides are the endogenous ligands for the kappa opioid receptor (KOR) and regulate food intake. Administration of dynorphin-A1-13 (DYN) in the paraventricular hypothalamic nucleus (PVN) increases palatable food intake, and this effect is blocked by co-administration of the orexin-A neuropeptide, which is co-released with DYN in PVN from neurons located in the lateral hypothalamus. While PVN administration of DYN increases palatable food intake, whether it increases food-seeking behaviors has yet to be examined. We tested the effects of DYN and norBNI (a KOR antagonist) on the seeking and consumption of sucrose using a progressive ratio (PR) and demand curve (DC) tasks. In PVN, DYN did not alter the sucrose breaking point (BP) in the PR task nor the elasticity or intensity of demand for sucrose in the DC task. Still, DYN reduced the delay in obtaining sucrose and increased licks during sucrose intake in the PR task, irrespective of the co-administration of orexin-A. In PVN, norBNI increased the delay in obtaining sucrose and reduced licks during sucrose intake in the PR task while increasing elasticity without altering intensity of demand in the DC task. However, subcutaneous norBNI reduced the BP for sucrose and increased the delay in obtaining sucrose in the PR task while reducing the elasticity of demand. Together, these data show different effects of systemic and PVN blockade of KOR on food-seeking, consummatory behaviors, and incentive motivation for sucrose and suggest that KOR activity in PVN is necessary but not sufficient to drive seeking behaviors for palatable food.

Meta-analysis of pre-clinical studies on the effects of opioid receptor ligands on food intake, motivation, and choice.

The opioid receptors (OR) regulate food intake. Still, despite extensive pre-clinical research, the overall effects and individual contribution of the mu (MOR), kappa (KOR), and delta (DOR) OR subtypes to feeding behaviors and food intake remain unclear. To address this, we conducted a pre-registered systematic search and meta-analysis of rodent dose-response studies to evaluate the impact of central and peripheral administration of non-selective and selective OR ligands on intake, motivation, and choice of food. All studies had a high bias risk. Still, the meta-analysis confirmed the overall orexigenic and anorexigenic effects of OR agonists and antagonists, respectively. Our results support a larger orexigenic role for central MOR agonists among OR subtypes and that peripheral OR antagonists reduce motivation for and intake of preferred foods. In binary food choice studies, peripheral OR agonists selectively increase the intake of fat-preferred foods; in contrast, they did not increase the intake of sweet carbohydrate-preferred foods. Overall, these data support that OR regulation of intake, motivation, and choice is influenced by food macronutrient composition.

Collective Ferromagnetism of Artificial Square Spin Ice.

We study the temperature and magnetic field dependence of the total magnetic moment of large-area permalloy artificial square spin ice arrays. The temperature dependence and hysteresis behavior are consistent with the coherent magnetization reversal expected in the Stoner-Wohlfarth model, with clear deviations due to interisland interactions at small lattice spacing. Through micromagnetic simulations, we explore this behavior and demonstrate that the deviations result from increasingly complex magnetization reversal at small lattice spacing, induced by interisland interactions, and depending critically on details of the island shapes. These results establish new means to tune the physical properties of artificial spin ice structures and other interacting nanomagnet systems, such as patterned magnetic media.

Finite-Size Effect in Phonon-Induced Elliott-Yafet Spin Relaxation in Al.

The Elliott-Yafet theory of spin relaxation in nonmagnetic metals predicts proportionality between spin and momentum relaxation times for scattering centers such as phonons. Here, we test this theory in Al nanowires over a very large thickness range (8.5-300 nm), finding that the Elliott-Yafet proportionality "constant" for phonon scattering in fact exhibits a large, unanticipated finite-size effect. Supported by analytical and numerical modeling, we explain this via strong phonon-induced spin relaxation at surfaces and interfaces, driven in particular by enhanced spin-orbit coupling.

Brain site-specific regulation of hedonic intake by orexin and DYN peptides: role of the PVN and obesity.

The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A1-13 (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A1-13. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A1-13 increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.

Enhanced superconductivity and ferroelectric quantum criticality in plastically deformed strontium titanate.

The properties of quantum materials are commonly tuned using experimental variables such as pressure, magnetic field and doping. Here we explore a different approach using irreversible, plastic deformation of single crystals. We show that compressive plastic deformation induces low-dimensional superconductivity well above the superconducting transition temperature (Tc) of undeformed SrTiO3, with evidence of possible superconducting correlations at temperatures two orders of magnitude above the bulk Tc. The enhanced superconductivity is correlated with the appearance of self-organized dislocation structures, as revealed by diffuse neutron and X-ray scattering. We also observe deformation-induced signatures of quantum-critical ferroelectric fluctuations and inhomogeneous ferroelectric order using Raman scattering. Our results suggest that strain surrounding the self-organized dislocation structures induces local ferroelectricity and quantum-critical dynamics that strongly influence Tc, consistent with a theory of superconductivity enhanced by soft polar fluctuations. Our results demonstrate the potential of plastic deformation and dislocation engineering for the manipulation of electronic properties of quantum materials.

Experimental Realization of the 1D Random Field Ising Model.

We have measured magnetic-field-induced avalanches in a square artificial spin ice array of interacting nanomagnets. Starting from the ground state ordered configuration, we imaged the individual nanomagnet moments after each successive application of an incrementally increasing field. The statistics of the evolution of the moment configuration show good agreement with the canonical one-dimensional random field Ising model. We extract information about the microscopic structure of the arrays from our macroscopic measurements of their collective behavior, demonstrating a process that could be applied to other systems exhibiting avalanches.

Universal superconducting precursor in three classes of unconventional superconductors.

A pivotal challenge posed by unconventional superconductors is to unravel how superconductivity emerges upon cooling from the generally complex normal state. Here, we use nonlinear magnetic response, a probe that is uniquely sensitive to the superconducting precursor, to uncover remarkable universal behaviour in three distinct classes of oxide superconductors: strontium titanate, strontium ruthenate, and the cuprate high-Tc materials. We find unusual exponential temperature dependence of the diamagnetic response above the transition temperature Tc, with a characteristic temperature scale that strongly varies with Tc. We correlate this scale with the sensitivity of Tc to local stress and show that it is influenced by intentionally-induced structural disorder. The universal behaviour is therefore caused by intrinsic, self-organized structural inhomogeneity, inherent to the oxides' perovskite-based structure. The prevalence of such inhomogeneity has far-reaching implications for the interpretation of electronic properties of perovskite-related oxides in general.

Policies Affecting Medicaid Beneficiaries' Smoking Cessation Behaviors.

Introduction: Smoking rates for Medicaid beneficiaries have remained flat in recent years. Medicaid may support smokers in quitting by covering a broad array of tobacco cessation services without barriers such as copays. This study examines the impact of increasing generosity in Medicaid tobacco cessation coverage policies on smoking and cessation behaviors. Methods: We used 2010 and 2015 National Health Interview Survey data merged with information on state tobacco, Medicaid cessation, and Medicaid eligibility policies to estimate state fixed effects models of cessation medication use, counseling use, quit attempts, and current smoking. Results: Smokers living in states that cover cessation medications but not counseling services were less likely to use counseling. Smokers were more likely to report having tried to quit in states with higher rates of use of cessation medications among Medicaid beneficiaries. We found no impact of Medicaid policies on use of cessation medications. States that impose copays had higher rates of smoking, while those that require counseling as a condition of receiving medication had lower rates of smoking. Additionally, we found that expanding Medicaid eligibility under the Affordable Care Act is associated with decreased smoking prevalence among Medicaid beneficiaries. Conclusion: Covering cessation counseling may encourage smokers that want to quit to use this service. Promoting the use of cessation medications may improve the likelihood that smokers try to quit. Medicaid coverage of cessation services is an important but incomplete strategy in addressing smoking among low-income populations. Implications: States may be able to improve utilization of cessation counseling by providing Medicaid reimbursement for this service. Encouraging utilization of tobacco cessation medications may help more smokers quit. States should consider how to promote effective cessation methods among clinicians and patients.

Effects on Hedonic Feeding, Energy Expenditure and Balance of the Non-opioid Peptide DYN-A2-17.

The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A2-17 on food intake and energy expenditure. Injection of DYN-A2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A2-17 on food intake while injection of DYN-A2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides, we compared the effects of DYN-A2-17 to orexin-A and the opioid peptide DYN-A1-13 on food choice and intake in PVN when palatable snacks and chow were available. DYN-A1-13 selectively increased intake of palatable snacks. DYN-A2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available.

Theory of Kondo suppression of spin polarization in nonlocal spin valves.

We theoretically analyze contributions from the Kondo effect to the spin polarization and spin diffusion length in all-metal nonlocal spin valves. Interdiffusion of ferromagnetic atoms into the normal metal layer creates a region in which Kondo physics plays a significant role, giving discrepancies between experiment and existing theory. We start from a simple model and construct a modified spin drift-diffusion equation which clearly demonstrates how the Kondo physics not only suppresses the electrical conductivity but even more strongly reduces the spin diffusion length. We also present an explicit expression for the suppression of spin polarization due to Kondo physics in an illustrative regime. We compare this theory to previous experimental data to extract an estimate of the Elliot-Yafet probability for Kondo spin flip scattering of 0.7 ± 0.4, in good agreement with the value of 2/3 derived in the original theory of Kondo.

A Pilot Study of Stereotactic Body Radiation Therapy Combined with Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma.

Purpose: While stereotactic body radiotherapy (SBRT) can reduce tumor volumes in patients with metastatic renal cell carcinoma (mRCC), little is known regarding the immunomodulatory effects of high-dose radiation in the tumor microenvironment. The main objectives of this pilot study were to assess the safety and feasibility of nephrectomy following SBRT treatment of patients with mRCC and analyze the immunological impact of high-dose radiation.Experimental Design: Human RCC cell lines were irradiated and evaluated for immunomodulation. In a single-arm feasibility study, patients with mRCC were treated with 15 Gray SBRT at the primary lesion in a single fraction followed 4 weeks later by cytoreductive nephrectomy. RCC specimens were analyzed for tumor-associated antigen (TAA) expression and T-cell infiltration. The trial has reached accrual (ClinicalTrials.gov identifier: NCT01892930).Results: RCC cells treated in vitro with radiation had increased TAA expression compared with untreated tumor cells. Fourteen patients received SBRT followed by surgery, and treatment was well-tolerated. SBRT-treated tumors had increased expression of the immunomodulatory molecule calreticulin and TAA (CA9, 5T4, NY-ESO-1, and MUC-1). Ki67+ -proliferating CD8+ T cells and FOXP3+ cells were increased in SBRT-treated patient specimens in tumors and at the tumor-stromal interface compared with archived patient specimens.Conclusions: It is feasible to perform nephrectomy following SBRT with acceptable toxicity. Following SBRT, patient RCC tumors have increased expression of calreticulin, TAA, as well as a higher percentage of proliferating T cells compared with archived RCC tumors. Collectively, these studies provide evidence of immunomodulation following SBRT in mRCC. Clin Cancer Res; 23(17); 5055-65. ©2017 AACR.

Percolation via Combined Electrostatic and Chemical Doping in Complex Oxide Films.

Stimulated by experimental advances in electrolyte gating methods, we investigate theoretically percolation in thin films of inhomogeneous complex oxides, such as La_{1-x}Sr_{x}CoO_{3} (LSCO), induced by a combination of bulk chemical and surface electrostatic doping. Using numerical and analytical methods, we identify two mechanisms that describe how bulk dopants reduce the amount of electrostatic surface charge required to reach percolation: (i) bulk-assisted surface percolation and (ii) surface-assisted bulk percolation. We show that the critical surface charge strongly depends on the film thickness when the film is close to the chemical percolation threshold. In particular, thin films can be driven across the percolation transition by modest surface charge densities. If percolation is associated with the onset of ferromagnetism, as in LSCO, we further demonstrate that the presence of critical magnetic clusters extending from the film surface into the bulk results in considerable enhancement of the saturation magnetization, with pronounced experimental consequences. These results should significantly guide experimental work seeking to verify gate-induced percolation transitions in such materials.

Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A(2-17)) in food intake and physical activity, and its interaction with orexin-A.

Food intake and physical activity are regulated by multiple neuropeptides, including orexin and dynorphin (DYN). Orexin-A (OXA) is one of two orexin peptides with robust roles in regulation of food intake and spontaneous physical activity (SPA). DYN collectively refers to several peptides, some of which act through opioid receptors (opioid DYN) and some whose biological effects are not mediated by opioid receptors (non-opioid DYN). While opioid DYN is known to increase food intake, the effects of non-opioid DYN peptides on food intake and SPA are unknown. Neurons that co-express and release OXA and DYN are located within the lateral hypothalamus. Limited evidence suggests that OXA and opioid DYN peptides can interact to modulate some aspects of behaviors classically related to orexin peptide function. The paraventricular hypothalamic nucleus (PVN) is a brain area where OXA and DYN peptides might interact to modulate food intake and SPA. We demonstrate that injection of des-Tyr-dynorphin (DYN-A(2-17), a non opioid DYN peptide) into the PVN increases food intake and SPA in adult mice. Co-injection of DYN-A(2-17) and OXA in the PVN further increases food intake compared to DYN-A(2-17) or OXA alone. This is the first report describing the effects of non-opioid DYN-A(2-17) on food intake and SPA, and suggests that DYN-A(2-17) interacts with OXA in the PVN to modulate food intake. Our data suggest a novel function for non-opioid DYN-A(2-17) on food intake, supporting the concept that some behavioral effects of the orexin neurons result from combined actions of the orexin and DYN peptides.

Behavioral characterization of a model of differential susceptibility to obesity induced by standard and personalized cafeteria diet feeding.

Despite the increase in obesity prevalence over the last decades, humans show large inter-individual variability for susceptibility to diet-induced obesity. Understanding the biological basis of this susceptibility could identify new therapeutic alternatives against obesity. We characterized behavioral changes associated with propensity to obesity induced by cafeteria (CAF) diet consumption in mice. We show that Balb/c mice fed a CAF diet display a large inter-individual variability in susceptibility to diet-induced obesity, such that based on changes in adiposity we can classify mice as obesity prone (OP) or obesity resistant (OR). Both OP and OR were hyperphagic relative to control-fed mice but caloric intake was similar between OP and OR mice. In contrast, OR had a larger increase in locomotor activity following CAF diet compared to OP mice. Obesity resistant and prone mice showed similar intake of sweet snacks, but OR ate more savory snacks than OP mice. Two bottle sucrose preference tests showed that OP decreased their sucrose preference compared to OR mice after CAF diet feeding. Finally, to test the robustness of the OR phenotype in response to further increases in caloric intake, we fed OR mice with a personalized CAF (CAF-P) diet based on individual snack preferences. When fed a CAF-P diet, OR increased their calorie intake compared to OP mice fed the standard CAF diet, but did not reach adiposity levels observed in OP mice. Together, our data show the contribution of hedonic intake, individual snack preference and physical activity to individual susceptibility to obesity in Balb/c mice fed a standard and personalized cafeteria-style diet.

High conductance 2D transport around the Hall mobility peak in electrolyte-gated rubrene crystals.

We report the observation of the Hall effect at hole densities up to 6×10¹³ cm⁻² (0.3 holes/molecule) on the surface of electrolyte-gated rubrene crystals. The perplexing peak in the conductance as a function of gate voltage is confirmed to result from a maximum in mobility, which reaches 4 cm² V⁻¹ s⁻¹ at 2.5×10¹³ cm⁻². Measurements to liquid helium temperatures reveal that this peak is markedly asymmetric, with bandlike and hopping-type transport occurring on the low density side, while unconventional, likely electrostatic-disorder-affected transport dominates the high density side. Most significantly, near the mobility peak the temperature coefficient of the resistance remains positive to as low as 120 K, the low temperature resistance becomes weakly temperature dependent, and the conductance reaches within a factor of 2 of e²/h, revealing conduction unprecedentedly close to a two-dimensional metallic state.

Optimization of long-range order in solvent vapor annealed poly(styrene)-block-poly(lactide) thin films for nanolithography.

Detailed experiments designed to optimize and understand the solvent vapor annealing of cylinder-forming poly(styrene)-block-poly(lactide) thin films for nanolithographic applications are reported. By combining climate-controlled solvent vapor annealing (including in situ probes of solvent concentration) with comparative small-angle X-ray scattering studies of solvent-swollen bulk polymers of identical composition, it is concluded that a narrow window of optimal solvent concentration occurs just on the ordered side of the order-disorder transition. In this window, the lateral correlation length of the hexagonally close-packed ordering, the defect density, and the cylinder orientation are simultaneously optimized, resulting in single-crystal-like ordering over 10 µm scales. The influences of polymer synthesis method, composition, molar mass, solvent vapor pressure, evaporation rate, and film thickness have all been assessed, confirming the generality of this behavior. Analogies to thermal annealing of elemental solids, in combination with an understanding of the effects of process parameters on annealing conditions, enable qualitative understanding of many of the key results and underscore the likely generality of the main conclusions. Pattern transfer via a Damascene-type approach verified the applicability for high-fidelity nanolithography, yielding large-area metal nanodot arrays with center-to-center spacing of 38 nm (diameter 19 nm). Finally, the predictive power of our findings was demonstrated by using small-angle X-ray scattering to predict optimal solvent annealing conditions for poly(styrene)-block-poly(lactide) films of low molar mass (18 kg mol(-1)). High-quality templates with cylinder center-to-center spacing of only 18 nm (diameter of 10 nm) were obtained. These comprehensive results have clear and important implications for optimization of pattern transfer templates and significantly advance the understanding of self-assembly in block copolymer thin films.

Magnetocaloric effect and critical behavior in Pr0.5Sr0.5MnO3: an analysis of the validity of the Maxwell relation and the nature of the phase transitions.

The Maxwell relation, the Clausius-Clapeyron equation, and a non-iterative method to obtain the critical exponents have been used to characterize the magnetocaloric effect (MCE) and the nature of the phase transitions in Pr0.5Sr0.5MnO3, which undergoes a second-order paramagnetic to ferromagnetic (PM-FM) transition at TC ~ 247 K, and a first-order ferromagnetic to antiferromagnetic (FM-AFM) transition at TN ~ 165 K. We find that around the second-order PM-FM transition, the MCE (as represented by the magnetic entropy change, ΔSM) can be precisely determined from magnetization measurements using the Maxwell relation. However, around the first-order FM-AFM transition, values of ΔSM calculated with the Maxwell relation deviate significantly from those calculated by the Clausius-Clapeyron equation at the magnetic field and temperature ranges where a conversion between the AFM and FM phases occurs. A detailed analysis of the critical exponents of the second-order PM-FM transition allows us to correlate the short-range type magnetic interactions with the MCE. Using the Arrott-Noakes equation of state with the appropriate values of the critical exponents, the field- and temperature-dependent magnetization [Formula: see text] curves, and hence the [Formula: see text] curves, have been simulated and compared with experimental data. A good agreement between the experimental and simulated data has been found in the vicinity of the Curie temperature TC, but a noticeable discrepancy is present for [Formula: see text]. This discrepancy arises mainly from the coexistence of AFM and FM phases and the presence of ferromagnetic clusters in the AFM matrix.

Kondo physics in non-local metallic spin transport devices.

The non-local spin-valve is pivotal in spintronics, enabling separation of charge and spin currents, disruptive potential applications and the study of pressing problems in the physics of spin injection and relaxation. Primary among these problems is the perplexing non-monotonicity in the temperature-dependent spin accumulation in non-local ferromagnetic/non-magnetic metal structures, where the spin signal decreases at low temperatures. Here we show that this effect is strongly correlated with the ability of the ferromagnetic to form dilute local magnetic moments in the NM. This we achieve by studying a significantly expanded range of ferromagnetic/non-magnetic combinations. We argue that local moments, formed by ferromagnetic/non-magnetic interdiffusion, suppress the injected spin polarization and diffusion length via a manifestation of the Kondo effect, thus explaining all observations. We further show that this suppression can be completely quenched, even at interfaces that are highly susceptible to the effect, by insertion of a thin non-moment-supporting interlayer.

Persistent optically induced magnetism in oxygen-deficient strontium titanate.

Strontium titanate (SrTiO3) is a foundational material in the emerging field of complex oxide electronics. Although its bulk electronic and optical properties are rich and have been studied for decades, SrTiO3 has recently become a renewed focus of materials research catalysed in part by the discovery of superconductivity and magnetism at interfaces between SrTiO3 and other non-magnetic oxides. Here we illustrate a new aspect to the phenomenology of magnetism in SrTiO3 by reporting the observation of an optically induced and persistent magnetization in slightly oxygen-deficient bulk SrTiO3-δ crystals using magnetic circular dichroism (MCD) spectroscopy and SQUID magnetometry. This zero-field magnetization appears below ~18 K, persists for hours below 10 K, and is tunable by means of the polarization and wavelength of sub-bandgap (400-500 nm) light. These effects occur only in crystals containing oxygen vacancies, revealing a detailed interplay between magnetism, lattice defects, and light in an archetypal complex oxide material.