THz-Driven Ultrafast Spin-Lattice Scattering in Amorphous Metallic Ferromagnets.

We use single-cycle THz fields and the femtosecond magneto-optical Kerr effect to, respectively, excite and probe the magnetization dynamics in two thin-film ferromagnets with different lattice structures: crystalline Fe and amorphous CoFeB. We observe Landau-Lifshitz-torque magnetization dynamics of comparable magnitude in both systems, but only the amorphous sample shows ultrafast demagnetization caused by the spin-lattice depolarization of the THz-induced ultrafast spin current. Quantitative modeling shows that such spin-lattice scattering events occur on similar time scales than the conventional spin conserving electronic scattering (∼30 fs). This is significantly faster than optical laser-induced demagnetization. THz conductivity measurements point towards the influence of lattice disorder in amorphous CoFeB as the driving force for enhanced spin-lattice scattering.

Correlation-Driven Insulator-Metal Transition in Near-Ideal Vanadium Dioxide Films.

We use polarization- and temperature-dependent x-ray absorption spectroscopy, in combination with photoelectron microscopy, x-ray diffraction, and electronic transport measurements, to study the driving force behind the insulator-metal transition in VO_{2}. We show that both the collapse of the insulating gap and the concomitant change in crystal symmetry in homogeneously strained single-crystalline VO_{2} films are preceded by the purely electronic softening of Coulomb correlations within V-V singlet dimers. This process starts 7 K (±0.3 K) below the transition temperature, as conventionally defined by electronic transport and x-ray diffraction measurements, and sets the energy scale for driving the near-room-temperature insulator-metal transition in this technologically promising material.

DNA vaccine against visceral leishmaniasis: a promising approach for prevention and control.

The visceral leishmaniasis (VL) caused by Leishmania donovani parasite severely affects large populations in tropical and subtropical regions of the world. The arsenal of drugs available is limited, and resistance is common in clinical field isolates. Therefore, vaccines could be an important alternative for prevention against VL. Recently, some investigators advocated the protective efficacy of DNA vaccines, which induces the T cell-based immunity against VL. The vaccine antigens are selected as conserved in various Leishmania species and provide a viable strategy for DNA vaccine development. Our understanding for DNA vaccine development against VL is not enough and much technological advancement is required. Improved formulations and methods of delivery are required, which increase the uptake of DNA vaccine by cells; optimization of vaccine vectors/encoded antigens to augment and direct the host immune response in VL. Despite the many genes identified as vaccine candidates, the disappointing potency of the DNA vaccines in VL underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the design, strategy, safety issues, varied candidates, progress and challenges that play a role in their ability against VL.

Field Effect and Strongly Localized Carriers in the Metal-Insulator Transition Material VO(2).

The intrinsic field effect, the change in surface conductance with an applied transverse electric field, of prototypal strongly correlated VO(2) has remained elusive. Here we report its measurement enabled by epitaxial VO(2) and atomic layer deposited high-κ dielectrics. Oxygen migration, joule heating, and the linked field-induced phase transition are precluded. The field effect can be understood in terms of field-induced carriers with densities up to ∼5×10(13) cm(-2) which are trongly localized, as shown by their low, thermally activated mobility (∼1×10(-3) cm(2)/V s at 300 K). These carriers show behavior consistent with that of Holstein polarons and strongly impact the (opto)electronics of VO(2).

Immunostimulatory potential and proteome profiling of Leishmania donovani soluble exogenous antigens.

Isolation of the soluble exogenous antigens (SEAgs), its immune response study and proteome profiling is an essential prerequisite for understanding the molecular pathogenesis of Leishmania donovani. The immunostimulatory potential of L. donovani SEAgs, purified from culture of L. donovani clinical isolate, was evaluated for their ability to induce cellular responses in treated/cured hamsters. SEAgs induced significant proliferative responses in lymphocytes (SI 5.6 ± 2.3; P < 0.01) isolated from cured hamster. In addition, significant NO production in response to SEAgs was also noticed in macrophages of hamsters, mouse and human cell lines (J774A-1 and THP1). Western blot analyses with antibodies against proteophosphoglycan (PPG; surface-expressed and secreted molecule) of L. donovani revealed that PPG molecules are also present in L. donovani SEAgs. Mass spectrometry (MS)-based proteome analysis of 12 protein bands of SEAgs through MALDI-TOF/TOF endorsed the identification of some Th1-stimulatory immunogenic proteins. These immunogenic proteins may offer increased hope for the discovery of new promising vaccine candidates against visceral leishmaniasis (VL). The overall results suggest that immunostimulatory molecules are present in the SEAgs, which may be further exploited, for developing a subunit vaccine against VL a fatal human disease.

Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents.

AIM: To test the impact of cholecystokinin (CCK) plus either amylin or a glucagon-like peptide-1 receptor (GLP-1R) agonist on metabolic variables in diet-induced obese (DIO) rodents. METHODS: A stabilized acetylated version of CCK-8 (Ac-Y*-CCK-8), selective CCK1 receptor (CCK1R) or CCK2 receptor (CCK2R) agonists, amylin or the GLP-1R agonist and exenatide analogue AC3174 were administered in select combinations via continuous subcutaneous infusion to DIO rats for 14 days, or Lep(ob) /Lep(ob) mice for 28 days, and metabolic variables were assessed. RESULTS: Combined administration of Ac-Y*-CCK-8 with either amylin or AC3174 induced greater than additive weight loss in DIO rats, with the overall magnitude of effect being greater with AC3174 + Ac-Y*-CCK-8 treatment. Co-infusion of AC3174 with a specific CCK1R agonist, but not a CCK2R agonist, recapitulated the weight loss mediated by AC3174 + Ac-Y*-CCK-8 in DIO rats, suggesting that synergy is mediated by CCK1R activation. In a 4 × 4 full-factorial response surface methodology study in DIO rats, a synergistic interaction between AC3174 and the CCK1R-selective agonist on body weight and food intake was noted. Co-administration of AC3174 and the CCK1R-selective agonist to obese diabetic Lep(ob) /Lep(ob) mice elicited a significantly greater reduction in percentage of glycated haemoglobin and food intake relative to the sum effects of monotherapy groups. CONCLUSIONS: The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.

Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA.

BACKGROUND: We characterized the incidence of central nervous system (CNS) metastases after treatment with trastuzumab emtansine (T-DM1) versus capecitabine-lapatinib (XL), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study. PATIENTS AND METHODS: In EMILIA, patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with trastuzumab and a taxane were randomized to T-DM1 or XL until disease progression. Patients with treated, asymptomatic CNS metastases at baseline and patients developing postbaseline CNS metastases were identified retrospectively by independent review; exploratory analyses were carried out. RESULTS: Among 991 randomized patients (T-DM1 = 495; XL = 496), 95 (T-DM1 = 45; XL = 50) had CNS metastases at baseline. CNS progression occurred in 9 of 450 (2.0%) and 3 of 446 (0.7%) patients without CNS metastases at baseline in the T-DM1 and XL arms, respectively, and in 10 of 45 (22.2%) and 8 of 50 (16.0%) patients with CNS metastases at baseline. Among patients with CNS metastases at baseline, a significant improvement in overall survival (OS) was observed in the T-DM1 arm compared with the XL arm [hazard ratio (HR) = 0.38; P = 0.008; median, 26.8 versus 12.9 months]. Progression-free survival by independent review was similar in the two treatment arms (HR = 1.00; P = 1.000; median, 5.9 versus 5.7 months). Multivariate analyses demonstrated similar results. Grade ≥3 adverse events were reported in 48.8% and 63.3% of patients with CNS metastases at baseline administered T-DM1 and XL, respectively; no new safety signals were observed. CONCLUSION: In this retrospective, exploratory analysis, the rate of CNS progression in patients with HER2-positive advanced breast cancer was similar for T-DM1 and for XL, and higher overall in patients with CNS metastases at baseline compared with those without CNS metastases at baseline. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved OS compared with XL.

Experimental evolution of female traits under different levels of intersexual conflict in Drosophila melanogaster.

A number of studies have documented the evolution of female resistance to mate-harm in response to the alteration of intersexual conflict in the populations. However, the life-history consequence of such evolution is still a subject of debate. In this study, we subjected replicate populations of Drosophila melanogaster to different levels of sexual conflict (generated by altering the operational sex ratio) for over 45 generations. Our results suggest that females from populations experiencing higher level of intersexual conflict evolved increased resistance to mate-harm, in terms of both longevity and progeny production. Females from the populations with low conflict were significantly heavier at eclosion and were more susceptible to mate-harm in terms of progeny production under continuous exposure to the males. However, these females produced more progeny upon single mating and had significantly higher longevity in absence of any male exposure-a potential evidence of trade-offs between resistance-related traits and other life-history traits, such as fecundity and longevity. We also report tentative evidence, suggesting an increased male cost of interacting with more resistant females.

Apoptosis-like programmed cell death induces antisense ribosomal RNA (rRNA) fragmentation and rRNA degradation in Leishmania.

Few natural antisense (as) RNAs have been reported as yet in the unicellular protozoan Leishmania. Here, we describe that Leishmania produces natural asRNAs complementary to all ribosomal RNA (rRNA) species. Interestingly, we show that drug-induced apoptosis-like programmed cell death triggers fragmentation of asRNA complementary to the large subunit gamma (LSU-γ) rRNA, one of the six 28S rRNA processed fragments in Leishmania. Heat and oxidative stress also induce fragmentation of asrRNA, but to a lesser extent. Extensive asrRNA cleavage correlates with rRNA breakdown and translation inhibition. Indeed, overexpression of asLSU-γ rRNA accelerates rRNA degradation upon induction of apoptosis. In addition, we provide mechanistic insight into the regulation of apoptosis-induced asrRNA fragmentation by a 67 kDa ATP-dependent RNA helicase of the DEAD-box subfamily. This helicase binds both sense (s)LSU-γ and asLSU-γ rRNAs, and appears to have a key role in protecting rRNA from degradation by preventing asrRNA cleavage and thus cell death. Remarkably, the asrRNA fragmentation process operates not only in trypanosomatid protozoa but also in mammals. Our findings uncover a novel mechanism of regulation involving asrRNA fragmentation and rRNA breakdown, that is triggered by apoptosis and conditions of reduced translation under stress, and seems to be evolutionary conserved.

SABRE-B: an evaluation of paclitaxel and bevacizumab with or without sunitinib as first-line treatment of metastatic breast cancer.

BACKGROUND: The vascular endothelial growth factor (VEGF) pathway can be targeted through VEGF neutralization or VEGF receptor (VEGFR) blockade using tyrosine kinase inhibition. Because laboratory models suggest that combining these approaches might be synergistic, we sought to evaluate the feasibility and efficacy of combining sunitinib with paclitaxel + bevacizumab (PB). METHODS: Patients with human epidermal growth factor receptor 2 (HER2)-negative, metastatic breast cancer receiving first-line chemotherapy were randomized to PB or PB with sunitinib (PBS), with planned escalation of the sunitinib dose. RESULTS: Forty-six patients were randomized to PB or PBS with sunitinib dosed at 25 mg p.o. daily. Patients receiving PBS encountered substantial toxicity that precluded adequate treatment. The percentage of patients with grade ≥3 adverse events was greater in the PBS arm than the PB arm (83% versus 57%), and sunitinib dosing was modified in 78% of patients, most often due to neutropenia, febrile neutropenia, and fatigue. In addition, 44% of patients had sunitinib dose reduction to 12.5 mg, and 39% required discontinuation. Patients receiving PBS had more bevacizumab treatment interruptions and discontinuations because of toxicity. Median treatment duration was longer in the PB arm compared with the PBS arm (14.1 versus 11.1 weeks), reflecting early treatment discontinuation of PBS. Because of poor tolerability of the addition of sunitinib to PB, the planned sunitinib dose escalation was halted and the study accrual was terminated. CONCLUSION: Adding sunitinib to standard doses of bevacizumab plus paclitaxel for metastatic breast cancer is not feasible. Different strategies will be required to evaluate whether there is additional clinical benefit to combining VEGF/VEGFR-targeted agents.

Proteophosphoglycan is differentially expressed in sodium stibogluconate-sensitive and resistant Indian clinical isolates of Leishmania donovani.

Leishmania produce several types of mucin-like glycoproteins called proteophosphoglycans (PPGs) some of which are secreted while others are found on the surface of promastigotes and amastigotes. These proteins are thought to be important in the transmission, invasion and subsequent intracellular survival of parasites. The structure and function of PPGs are species and stage-specific in the case of L. major and L. mexicana, but no such information has hitherto been available for L. donovani. This study presents, for the first time, an initial characterization (localization) of PPG in sodium stibogluconate (SSG)-resistant and sensitive clinical isolates of L. donovani from Bihar (India) by confocal microscopy, flow cytometry and Western blotting using antibodies to L. major PPG. Confocal microscopy analysis revealed that both promastigotes and amastigotes possess PPG on their cell membrane and flagellar pocket membrane but its expression was variable in different isolates. The quantitative analysis by FACS and Western blotting showed that the expression and intensity of PPG bands was higher in SSG-resistant isolates. This study suggests the possibilities of involvement of PPG in drug-resistant mechanisms and of using PPG abundance as a marker for identifying drug-resistant clinical isolates in Indian kala azar.

In vitro and in vivo leishmanicidal activity of Dysoxylum binectariferum and its fractions against Leishmania donovani.

The leishmanicidal effect of crude ethanolic extract of stem bark of Dysoxylum binectariferum and its fractions has been investigated against Leishmania donovani, the causative agent of visceral leishmaniasis. Ethanolic extract was lethal to promastigotes as well as amastigote forms in macrophage system at the concentration of 100 microg/ml. Chloroform fraction significantly inhibited promastigote multiplication and was also active against amastigotes in infected J774A.1 macrophages at 100 microg/ml. Hexane fraction was moderately active and the other fractions were inactive against both the forms. When tested in vivo in hamsters, ethanolic extract was toxic at 500 mg/kg whereas exhibited marginal activity (67.7+/-5.3%) at 250 mg/kg x 5, p.o. on day 7 post treatment (p.t.) which increases slightly (69+/-4.7) by day 30 p.t. Chloroform and n-hexane fractions exhibited 64.3+/-4% and 47.8+/-4.6% parasite inhibition at the dose of 100 mg/kg x 5 p.o., respectively. The pure compound, rohitukine, obtained from chloroform fraction showed weaker in vitro activity and was ineffective in infected hamsters. The lead potential of this plant need further investigations.

Synthesis and biological activity of GnRH antagonists modified at position 3 with 3-(2-methoxy-5-pyridyl)-alanine.

Degarelix is a potent very long-acting GnRH antagonist after subcutaneous administration. In this paper, we describe the synthesis of two analogs of degarelix incorporating racemic 3-(2-methoxy-5-pyridyl)-alanine (2-OMe-5Pal, 5) at position 3. The two diastereomers were separated by reverse-phase high-performance liquid chromatography (RP-HPLC) and the absolute stereochemistry at position 3 in the peptides was determined by enzymatic digestion with proteinase K. These analogs were tested in vitro for their ability to antagonize the GnRH receptor and in vivo for duration of action in a castrated male rat assay. Analog 7 with D2-OMe-5Pal was potent in vitro (IC50 = 5.22 nM); however, analog 8 with L2-OMe-5Pal at position 3 in degarelix lost potency as an antagonist of the human GnRH receptor (IC50 = 36.95 nM). Both the analogs were found to be short-acting in vivo.

Liquid crystal alignment on carbonaceous surfaces with orientational order.

We used near-edge x-ray absorption fine structure (NEXAFS) spectroscopy to link the orientational bond order at three carbonaceous surfaces-rubbed polyimide, ion beam-irradiated polyimide, and ion beam-irradiated diamondlike carbon films-with the direction of liquid crystal (LC) alignment on these surfaces. We show that, in general, LC alignment can be created on any carbonaceous substrate by inducing orientational order at its surface. Our results form the scientific basis for LC alignment layers consisting of amorphous carbon films in which orientational order near the surface is induced by a directional low-energy ion beam.

Self-assembling, cystine-derived, fused nanotubes based on spirane architecture: design, synthesis, and crystal structure of cystinospiranes.

A novel family of cystine-based spirobicyclic peptides (cystinospiranes) has been synthesized by a single-step procedure involving condensation of pentaerythritol-derived tetrachloride with either the simple L-cystine dimethyl ester or its C,C'-extended bispeptides leading to a variety of 19-membered spirobicyclic peptides or its N,N'-extended bispeptides affording the ring-expanded 25-membered cystinospiranes. The design is flexible with respect to the ring size that can be adjusted depending upon the length of the N,N'-extended cystine bispeptide, and the choice of an amino acid, as illustrated here with the preparation of a large number of cystinospiranes containing a wide variety of amino acids. X-ray crystal structure of the parent spirane (5a) revealed nanotube formation by vertical stacking of relatively flat spirobicyclic molecules through contiguous NH- - -O==C hydrogen bonding. The fused pair of parallel nanotubes is open-ended, hollow, and extends to infinity. Crystallographic parameters are the following: C(33)H(52)N(4)O(16)S(4), space group C2, a = 42.181(3) A, b = 5.1165(7) A, c = 11.8687(9) A, beta = 106.23(1) degrees.

Atomic-beam alignment of inorganic materials for liquid-crystal displays.

The technique used to align liquid crystals-rubbing the surface of a substrate on which a liquid crystal is subsequently deposited-has been perfected by the multibillion-dollar liquid-crystal display industry. However, it is widely recognized that a non-contact alignment technique would be highly desirable for future generations of large, high-resolution liquid-crystal displays. A number of alternative alignment techniques have been reported, but none of these have so far been implemented in large-scale manufacturing. Here, we report a non-contact alignment process, which uses low-energy ion beams impinging at a glancing angle on amorphous inorganic films, such as diamond-like carbon. Using this approach, we have produced both laptop and desktop displays in pilot-line manufacturing, and found that displays of higher quality and reliability could be made at a lower cost than the rubbing technique. The mechanism of alignment is explained by adopting a random network model of atomic arrangement in the inorganic films. Order is induced by exposure to an ion beam because unfavourably oriented rings of atoms are selectively destroyed. The planes of the remaining rings are predominantly parallel to the direction of the ion beam.

Study by synchrotron radiation of the structure of a working catalyst at high temperatures and pressures.

A relation among activity, composition, and structure was determined for a working catalyst by means of a stainless-steel reactor cell of novel design that permitted operation at temperatures and pressures similar to those in industrial reactors. Molybdenum K-edge x-ray absorption spectra were used to probe the structural environment of molybdenum in CoMoS/[unknown]-alumina catalysts while hydro-desulfurization of benzothiophene was proceeding at high temperature and pressure. For catalyst samples with different contents of cobalt, radial structure functions obtained from extended x-ray absorption fine structure data presented the same features as those obtained from the spectra of MoS(2)/[unknown]-alumina reference samples. Moreover, Mo-S and Mo-Mo coordination numbers were maximum for the sample with an atomic ratio of Co to (Co + Mo) of 0.33; this sample was also the most active catalyst tested.