A quantum ruler for orbital magnetism in moiré quantum matter.

For almost a century, magnetic oscillations have been a powerful "quantum ruler" for measuring Fermi surface topology. In this study, we used Landau-level spectroscopy to unravel the energy-resolved valley-contrasting orbital magnetism and large orbital magnetic susceptibility that contribute to the energies of Landau levels of twisted double-bilayer graphene. These orbital magnetism effects led to substantial deviations from the standard Onsager relation, which manifested as a breakdown in scaling of Landau-level orbits. These substantial magnetic responses emerged from the nontrivial quantum geometry of the electronic structure and the large length scale of the moiré lattice potential. Going beyond traditional measurements, Landau-level spectroscopy performed with a scanning tunneling microscope offers a complete quantum ruler that resolves the full energy dependence of orbital magnetic properties in moiré quantum matter.

Current-induced torques in magnetic Weyl semimetal tunnel junctions.

We study the current-induced torques in asymmetric magnetic tunnel junctions containing a conventional ferromagnet and a magnetic Weyl semimetal contact. The Weyl semimetal hosts chiral bulk states and topologically protected Fermi arc surface states which were found to govern the voltage behavior and efficiency of current-induced torques. We report how bulk chirality dictates the sign of the non-equilibrium torques acting on the ferromagnet and discuss the existence of large field-like torques acting on the magnetic Weyl semimetal which exceeds the theoretical maximum of conventional magnetic tunnel junctions. The latter are derived from the Fermi arc spin texture and display a counter-intuitive dependence on the Weyl nodes separation. Our results shed light on the new physics of multilayered spintronic devices comprising of magnetic Weyl semimetals, which might open doors for new energy efficient spintronic devices.

Gigantic tunneling magnetoresistance in magnetic Weyl semimetal tunnel junctions.

We investigate the tunneling magnetoresistance in magnetic tunnel junctions (MTJs) comprised of Weyl semimetal contacts. We show that chirality-magnetization locking leads to a gigantic tunneling magnetoresistance ratio, an effect that does not rely on spin filtering by the tunnel barrier. Our results indicate that the conductance in the anti-parallel configuration is more sensitive to magnetization fluctations than in MTJs with normal ferromagnets, and predicts a TMR as large as 104 % when realistic magnetization fluctuations are accounted for. In addition, we show that the Fermi arc states give rise to a non-monotonic dependence of conductance on the misalignment angle between the magnetizations of the two contacts.

Bidirectional switching assisted by interlayer exchange coupling in asymmetric magnetic tunnel junctions.

We study the combined effects of spin transfer torque, voltage modulation of interlayer exchange coupling and magnetic anisotropy on the switching behavior of perpendicular magnetic tunnel junctions (p-MTJs). In asymmetric p-MTJs, a linear-in-voltage dependence of interlayer exchange coupling enables the effective perpendicular anisotropy barrier to be lowered for both voltage polarities. This mechanism is shown to reduce the critical switching current and effective activation energy. Finally, we analyze the possibility of having switching via interlayer exchange coupling only.

Interfacial spin-orbit torques.

Spin-orbit torques offer a promising mechanism for electrically controlling magnetization dynamics in nanoscale heterostructures. While spin-orbit torques occur predominately at interfaces, the physical mechanisms underlying these torques can originate in both the bulk layers and at interfaces. Classifying spin-orbit torques based on the region that they originate in provides clues as to how to optimize the effect. While most bulk spin-orbit torque contributions are well studied, many of the interfacial contributions allowed by symmetry have yet to be fully explored theoretically and experimentally. To facilitate progress, we review interfacial spin-orbit torques from a semiclassical viewpoint and relate these contributions to recent experimental results. Within the same model, we show the relationship between different interface transport parameters. For charges and spins flowing perpendicular to the interface, interfacial spin-orbit coupling both modifies the mixing conductance of magnetoelectronic circuit theory and gives rise to spin memory loss. For in-plane electric fields, interfacial spin-orbit coupling gives rise to torques described by spin-orbit filtering, spin swapping and precession. In addition, these same interfacial processes generate spin currents that flow into the non-magnetic layer. For in-plane electric fields in trilayer structures, the spin currents generated at the interface between one ferromagnetic layer and the non-magnetic spacer layer can propagate through the non-magnetic layer to produce novel torques on the other ferromagnetic layer.

Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine.

BACKGROUND: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. METHODS: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. RESULTS: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. CONCLUSIONS: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. ClinicalTrials.gov Identifier: NCT01227889.

Changing exchange bias in spin valves with an electric current.

We show that a high-density electric current, injected from a point contact into an exchange-biased spin valve, systematically changes the exchange bias. The bias can either increase or decrease depending upon the current direction. This observation is not readily explained by the well-known spin-transfer torque effect in ferromagnetic metal circuits, but could be evidence for the recently predicted current-induced torques in antiferromagnetic metals.

SwellGel: an affinity chromatography technology for high-capacity and high-throughput purification of recombinant-tagged proteins.

The revolution in genomics and proteomics is having a profound impact on drug discovery. Today's protein scientist demands a faster, easier, more reliable way to purify proteins. A high capacity, high-throughput new technology has been developed in Perbio Sciences for affinity protein purification. This technology utilizes selected chromatography media that are dehydrated to form uniform aggregates. The SwellGel aggregates will instantly rehydrate upon addition of the protein sample, allowing purification and direct performance of multiple assays in a variety of formats. SwellGel technology has greater stability and is easier to handle than standard wet chromatography resins. The microplate format of this technology provides high-capacity, high-throughput features, recovering milligram quantities of protein suitable for high-throughput screening or biophysical/structural studies. Data will be presented applying SwellGel technology to recombinant 6x His-tagged protein and glutathione-S-transferase (GST) fusion protein purification.

Localization of the GLUT1 glucose transporter to brefeldin A-sensitive vesicles of differentiated CIT3 mouse mammary epithelial cells.

Glucose is a precursor of lactose, the major carbohydrate and osmotic constituent of human milk, which is synthesized in the Golgi. The GLUT1 glucose transporter is the only glucose transporter isoform expressed in the mammary gland. The hypothesis that lactogenic hormones induce GLUT1 and cause its localization to the Golgi of mammary epithelial cells was tested in CIT(3)mouse mammary epithelial cells. Treatment with prolactin and hydrocortisone caused a 15-fold induction of GLUT1 by Western blotting, but 2-deoxyglucose uptake decreased. Subcellular fractionation and density gradient centrifugation demonstrated enrichment of Golgi fractions with GLUT1. Lactogenic hormones enhanced GLUT1 glycosylation, but did not determine whether GLUT1 was targeted to plasma membrane or to Golgi. Confocal microscopy revealed that lactogenic hormones alter GLUT1 targeting from a plasma membrane pattern to a predominant perinuclear distribution with punctate scattering through the cytoplasm. GLUT1 is targeted to a compartment which is more sensitive to Brefeldin A than the compartments in which GM130 and beta-COP reside. Targeting of GLUT1 to endosomes was specifically excluded. We conclude that prolactin and hydrocortisone induce GLUT1, enhance GLUT1 glycosylation, and cause glycosylation-independent targeting of GLUT1 to Brefeldin A-sensitive vesicles which may represent a subcompartment of cis-Golgi. These results demonstrate a hormonally-regulated targeting mechanism for GLUT1 and are consistent with an important role for GLUT1 in the provision of substrate for lactose synthesis.

Golgi targeting of the GLUT1 glucose transporter in lactating mouse mammary gland.

Lactose, the major carbohydrate of human milk, is synthesized in the Golgi from glucose and UDP-galactose. The lactating mammary gland is unique in its requirement for the transport of glucose into Golgi. Glucose transporter-1 (GLUT1) is the only isoform of the glucose transporter family expressed in mammary gland. In most cells, GLUT1 is localized to the plasma membrane and is responsible for basal glucose uptake; in no other cell type is GLUT1 a Golgi resident. To test the hypothesis that GLUT1 is targeted to Golgi during lactation, the amount and subcellular distribution of GLUT1 were examined in mouse mammary gland at different developmental stages. Methods including immunohistochemistry, immunofluorescence, subcellular fractionation, density gradient centrifugation, and Western blotting yielded consistent results. In virgins, GLUT1 expression was limited to plasma membrane of epithelial cells. In late pregnant mice, GLUT1 expression was increased with targeting primarily to basolateral plasma membrane but also with some intracellular signal. During lactation, GLUT expression was further increased, and targeting to Golgi, demonstrated by colocalization with the 110-kD coatomer-associated protein beta-COP, predominated. Removal of pups 18 d after delivery resulted in retargeting of GLUT1 from Golgi to plasma membrane and a decline in total cellular GLUT1 within 3 h. In mice undergoing natural weaning, GLUT1 expression declined. Changes in the amount and targeting of GLUT1 during mammary gland development are consistent with a key role for GLUT1 in supplying substrate for lactose synthesis and milk production.

Development of an in vitro dissolution method using microdialysis sampling technique for implantable drug delivery systems.

The major challenge faced during the development of implantable dosage forms for site-specific delivery is monitoring the local concentration of the drug at or around the site of action. The tissue concentration at the site is generally measured by either sacrificing the animal at different points in time or by determining the amount of drug left in the implants at various time intervals. Unfortunately, there are no official in vitro dissolution methods available to study the release characteristics of drugs from this drug delivery system. The objective of this investigation was to develop a simple method using microdialysis sampling technique to serve as an in vitro dissolution method for implantable drug delivery systems. Ciprofloxacin implants were prepared by compressing ciprofloxacin microcapsules in poly(lactic acid) (PLA) and poly(lactic-glycolic acid) (PLGA). A sensitive HPLC method was developed and validated for the assay of Ciprofloxacin. An in vitro dissolution method was developed to study the release characteristics of drug from these implants. The method used a microdialysis sampling technique and a small sample volume of release medium. The various advantages and disadvantages of this method over other USP methods are discussed.

Analysis of thermal stabilizing interactions in mesophilic and thermophilic adenylate kinases from the genus Methanococcus.

Adenylate kinases (ADKs) from four closely related methanogenic members of the Archaea (the mesophile Methanococcus voltae (MVO), the thermopile Methanococcus thermolithotrophicus (MTH), and the extreme thermopiles Methanococcus igneus (MIG) and Methanococcus jannaschii (MJA)) were characterized for their resistance to thermal denaturation. Despite possessing between 68 and 81% sequence identity, the methanococcal ADKs significantly differed in their stability against thermal denaturation, with melting points ranging from 69 to 103 degrees C. The high sequence identity between these organisms allowed regions of the MVO and MJA ADKs to be exchanged, producing chimeric ADKs with significantly altered thermal stability. Up to a 20 degrees C increase or decrease in stability was achieved for chimeric ADKs, whereas 88% of the original protein sequence was maintained. Based on our previous structural modeling studies, we conclude that cooperative interactions within the hydrophobic protein core play an integral role in determining the differences in structural stability observed between the methanococcal ADKs. From comparisons of the effects of temperature on protein unfolding and optimal enzymatic activity, we also conclude that thermostability and enzymatic temperature optima are influenced differently by molecular modifications and thus that the protein flexibility required for activity and stability, respectively, is not unconditionally linked within the methanococcal ADKs.

Thermal adaptation analyzed by comparison of protein sequences from mesophilic and extremely thermophilic Methanococcus species.

The genome sequence of the extremely thermophilic archaeon Methanococcus jannaschii provides a wealth of data on proteins from a thermophile. In this paper, sequences of 115 proteins from M. jannaschii are compared with their homologs from mesophilic Methanococcus species. Although the growth temperatures of the mesophiles are about 50 degrees C below that of M. jannaschii, their genomic G+C contents are nearly identical. The properties most correlated with the proteins of the thermophile include higher residue volume, higher residue hydrophobicity, more charged amino acids (especially Glu, Arg, and Lys), and fewer uncharged polar residues (Ser, Thr, Asn, and Gln). These are recurring themes, with all trends applying to 83-92% of the proteins for which complete sequences were available. Nearly all of the amino acid replacements most significantly correlated with the temperature change are the same relatively conservative changes observed in all proteins, but in the case of the mesophile/thermophile comparison there is a directional bias. We identify 26 specific pairs of amino acids with a statistically significant (P < 0.01) preferred direction of replacement.

Cysteinyl-tRNA formation: the last puzzle of aminoacyl-tRNA synthesis.

With the exception of the methanogenic archaea Methanococcus jannaschii and Methanobacterium thermoautotrophicum deltaH, all organisms surveyed contain orthologs of Escherichia coli cysteinyl-tRNA synthetase (CysRS). The characterization of CysRS-encoding (cysS) genes and the demonstration of their ability to complement an E. coli cysSts mutant reveal that Methanococcus maripaludis and Methanosarcina barkeri, two other methanogenic archaea, possess canonical CysRS proteins. A molecular phylogeny inferred from 40 CysRS sequences indicates that the CysRS of M. maripaludis and Methanosarcina spp. are specific relatives of the CysRS of Pyrococcus spp. and Chlamydia, respectively. This result suggests that the CysRS gene was acquired by lateral gene transfer in at least one euryarchaeotic lineage.

Changing self-esteem in children and adolescents: a meta-analytic review.

Conducted a meta-analytic review of 116 studies, which indicated significant improvement in children's and adolescents' self-esteem and self-concept, and significant concomitant changes in behavioral, personality, and academic functioning. Interventions specifically focused on changing self-esteem and self-concept were significantly more effective (mean effect size = 0.57) than programs focused on another target, such as behavior or social skills (0.10). Treatment programs were also more effective (0.47) than primary prevention programs (0.09) in changing self-esteem. Four variables emerged as significant predictors of self-esteem outcomes: 2 methodological features (type of design and control group), the use of a theoretical or empirical rationale, and the type of program (treatment or prevention). Future research needs to examine the causal connection between changes occurring in self-esteem and other areas of adjustment, assess intervention success for different ethnic groups and for children of different ages and sex, and determine the long-term impact of interventions.

Anomalies of pulmonary veins: usefulness of spin-echo and gradient-echo MR images.

OBJECTIVE: We compared the value of spin-echo and gradient-echo MR images in the evaluation of anomalies of pulmonary veins. MATERIALS AND METHODS: Fourteen patients with a variety of developmental anomalies of pulmonary veins underwent MR imaging examination. Axial T1-weighted spin-echo and gradient-echo MR images were evaluated retrospectively on separate occasions during which visualization of normal and anomalous pulmonary veins was determined. RESULTS: Of 52 pulmonary veins, 46 (88%) were identified on T1-weighted spin-echo images and 50 (96%) on gradient-echo images. Two patients had atresia of both left pulmonary veins. Of 14 anomalous veins, 11 (79%) were revealed on spin-echo images and 13 (93%) on gradient-echo images. CONCLUSION: Both spin-echo and gradient-echo MR images were accurate in revealing anomalies of pulmonary veins. In our study, gradient-echo images were equal or superior to spin-echo images.

Summary of ocular genetic disorders and inherited systemic conditions with eye findings.

Of the close to 10,000 known inherited disorders that affect humankind, a disproportionately high number affect the eye. The total number of genes responsible for the normal structure, function, and differentiation of the eye is unknown, but the list of these genes is rapidly and constantly growing. The objective of this paper is to provide a current list of mapped and/or cloned human eye genes that are responsible for inherited diseases of the eye. The ophthalmologist should be aware of recent advances in molecular technology which have resulted in significant progress towards the identification of these genes. The implications of this new knowledge will be discussed herein.

An ecological model for school-based mental health services for urban low-income aggressive children.

An ecological model for school-based mental health services that targets urban low-income aggressive children--a highly vulnerable and underserved population--is presented. The goals of the model are to increase children's and teachers' involvement in the delivery of services and to increase the integration of these services into existing school resources and activities. The model proposes that mental health service providers work in collaboration with teachers to deliver services that (1) can be managed by existing school resources and personnel, (2) are related to empirically based factors associated with reduced aggression and increased social functioning, and (3) are group administered to increase the number of children served and to reduce stigmatization associated with mental health services. The model is individualized and flexible by acknowledging that contexts for aggression differ across classrooms and children and by providing services specific to those contexts. Two studies are presented illustrating the application of this model to decrease aggression and increase academic engagement in low-income urban public schools.

MR imaging of congenital anomalies of the thoracic veins.

Congenital anomalies of the thoracic veins are infrequent but important developmental abnormalities. Thoracic venous anomalies can be classified as systemic or pulmonary. Systemic venous anomalies are often incidental findings, whereas pulmonary venous anomalies are more likely to manifest with cyanosis and to be associated with congenital cardiac abnormalities, especially atrial septal defect. Magnetic resonance (MR) imaging provides excellent delineation of the abnormal vessels and associated cardiac defects. Conventional spin-echo (SE) techniques show blood flow as a signal void and are sufficient for demonstrating the aberrant venous anatomy in most cases. Gradient-echo images show flowing blood as high signal intensity and are useful for clarifying the course of anomalous veins when vessel walls are difficult to visualize on SE images. Phase-contrast images are valuable for ascertaining the direction of blood flow and thus provide a physiologic method of distinguishing the vertical vein of anomalous pulmonary venous return from a left superior vena cava. MR imaging is useful for delineating both the thoracic venous and accompanying intracardiac anomalies and is a valuable, complementary technique to echocardiography, angiography, and computed tomography in the evaluation of patients with these abnormalities.