Semaphorin 7A plays a critical role in TGF-β1–induced pulmonary fibrosis

Semaphorin (SEMA) 7A regulates neuronal and immune function. In these studies, we tested the hypothesis that SEMA 7A is also a critical regulator of tissue remodeling. These studies demonstrate that SEMA 7A and its receptors, plexin C1 and β1 integrins, are stimulated by transforming growth factor (TGF)-β1 in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-β1–induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-β1 stimulated SEMA 7A via a largely Smad 3–independent mechanism and stimulated SEMA 7A receptors, matrix proteins, CCN proteins, fibroblast growth factor 2, interleukin 13 receptor components, proteases, antiprotease, and apoptosis regulators via Smad 2/3–independent and SEMA 7A–dependent mechanisms. SEMA 7A also played an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. TGF-β1 and bleomycin also activated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB)/AKT via SEMA 7A–dependent mechanisms, and PKB/AKT inhibition diminished TGF-β1–induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-β1 and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-β1–induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-β1, highlighting the importance of these findings for other fibrotic stimuli

Quantum Spin Excitations through the metal-to-insulator crossover in YBa2Cu3O6+yY Ba_2 Cu_3 O_{6+y}

We use inelastic neutron scattering to study the temperature dependence of the spin excitations of a detwinned superconducting YBa$_2$Cu$_3$O$_{6.45}$ ($T_c=48$ K). In contrast to earlier work on YBa$_2$Cu$_3$O$_{6.5}$ ($T_c=58$ K), where the prominent features in the magnetic spectra consist of a sharp collective magnetic excitation termed ``resonance'' and a large ($\hbar\omega\approx 15$ meV) superconducting spin gap, we find that the spin excitations in YBa$_2$Cu$_3$O$_{6.45}$ are gapless and have a much broader resonance. Our detailed mapping of magnetic scattering along the $a^\ast$/$b^\ast$-axis directions at different energies reveals that spin excitations are unisotropic and consistent with the ``hourglass''-like dispersion along the $a^\ast$-axis direction near the resonance, but they are isotropic at lower energies. Since a fundamental change in the low-temperature normal state of YBa$_2$Cu$_3$O$_{6+y}$ when superconductivity is suppressed takes place at $y\sim0.5$ with a metal-to-insulator crossover (MIC), where the ground state transforms from a metallic to an insulating-like phase, our results suggest a clear connection between the large change in spin excitations and the MIC. The resonance therefore is a fundamental feature of metallic ground state superconductors and a consequence of high-$T_c$ superconductivity.Comment: 9 pages, 7 figures, accepted by Phys. Rev.

The microstructure network and thermoelectric properties of bulk (Bi,Sb)₂Te₃

We report small-angle neutron scattering studies on the microstructure network in bulk (Bi,Sb)(2)Te-3 synthesized by the melt-spinning (MS) and the spark-plasma-sintering (SPS) process. We find that rough interfaces of multiscale microstructures generated by the MS are responsible for the large reduction of both lattice thermal conductivity and electrical conductivity. Our study also finds that subsequent SPS forms a microstructure network of similar to 10 nm thick lamellae and smooth interfaces between them. This nanoscale microstructure network with smooth interfaces increases electrical conductivity while keeping a low thermal conductivity, making it an ideal microstructure for high thermoelectric efficiency

Highest weight modules over quantum queer Lie superalgebra U_q(q(n))

In this paper, we investigate the structure of highest weight modules over the quantum queer superalgebra $U_q(q(n))$. The key ingredients are the triangular decomposition of $U_q(q(n))$ and the classification of finite dimensional irreducible modules over quantum Clifford superalgebras. The main results we prove are the classical limit theorem and the complete reducibility theorem for $U_q(q(n))$-modules in the category $O_q^{\geq 0}$.Comment: Definition 1.5 and Definition 6.1 are changed, and a remark is added in the new versio

Clinical implementation of whole-genome array CGH as a first-tier test in 5080 pre and postnatal cases

<p>Abstract</p> <p>Background</p> <p>Array comparative genomic hybridization (CGH) is currently the most powerful method for detecting chromosomal alterations in pre and postnatal clinical cases. In this study, we developed a BAC based array CGH analysis platform for detecting whole genome DNA copy number changes including specific micro deletion and duplication chromosomal disorders. Additionally, we report our experience with the clinical implementation of our array CGH analysis platform. Array CGH was performed on 5080 pre and postnatal clinical samples from patients referred with a variety of clinical phenotypes.</p> <p>Results</p> <p>A total of 4073 prenatal cases (4033 amniotic fluid and 40 chorionic villi specimens) and 1007 postnatal cases (407 peripheral blood and 600 cord blood) were studied with complete concordance between array CGH, karyotype and fluorescence <it>in situ </it>hybridization results. Among 75 positive prenatal cases with DNA copy number variations, 60 had an aneuploidy, seven had a deletion, and eight had a duplication. Among 39 positive postnatal cases samples, five had an aneuploidy, 23 had a deletion, and 11 had a duplication.</p> <p>Conclusions</p> <p>This study demonstrates the utility of using our newly developed whole-genome array CGH as first-tier test in 5080 pre and postnatal cases. Array CGH has increased the ability to detect segmental deletion and duplication in patients with variable clinical features and is becoming a more powerful tool in pre and postnatal diagnostics.</p

Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish

Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands

5-HT and 5-HT receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT receptor ligand culminating in the identification of several dual 5-HT and 5-HT receptor ligands. Compound , a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin

Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim

Background: A common approach to cancer therapy in clinical practice is the combination of several drugs to boost the anticancer activity of available drugs while suppressing their unwanted side effects. In this regard, we examined the efficacy of combination treatment with the widely-used genotoxic drug doxorubicin and the mitochondriotoxic Hsp90 inhibitor gamitrinib to exploit disparate stress signaling pathways for cancer therapy.Methods: The cytotoxicity of the drugs as single agents or in combination against several cancer cell types was analyzed by MTT assay and the synergism of the drug combination was evaluated by calculating the combination index. To understand the molecular mechanism of the drug synergism, stress signaling pathways were analyzed after drug combination. Two xenograft models with breast and prostate cancer cells were used to evaluate anticancer activity of the drug combination in vivo. Cardiotoxicity was assessed by tissue histology and serum creatine phosphokinase concentration.Results: Gamitrinib sensitized various human cancer cells to doxorubicin treatment, and combination treatment with the two drugs synergistically increased apoptosis. The cytotoxicity of the drug combination involved activation and mitochondrial accumulation of the proapoptotic Bcl-2 family member Bim. Activation of Bim was associated with increased expression of the proapoptotic transcription factor C/EBP-homologous protein and enhanced activation of the stress kinase c-Jun N-terminal kinase. Combined drug treatment with doxorubicin and gamitrinib dramatically reduced in vivo tumor growth in prostate and breast xenograft models without increasing cardiotoxicity.Conclusions: The drug combination showed synergistic anticancer activities toward various cancer cells without aggravating the cardiotoxic side effects of doxorubicin, suggesting that the full therapeutic potential of doxorubicin can be unleashed through combination with gamitrinib.open

ChREBP Regulates Fructose-induced Glucose Production Independently of Insulin Signaling

Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6-phosphatase (G6pc) that was associated with the effects of fructose administration. We found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic glucose-6-phosphate levels to complete a homeostatic loop. Moreover, fructose activated ChREBP and induced G6pc in the absence of Foxo1a, indicating that carbohydrate-induced activation of ChREBP and G6PC dominates over the suppressive effects of insulin to enhance glucose production. This ChREBP/G6PC signaling axis is conserved in humans. Together, these findings support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance

Observation of the in-plane magnetic field-induced phase transitions in FeSe

We investigate the thermodynamic properties of FeSe under the in-plane magnetic fields using torque magnetometry, specific heat, magnetocaloric measurements. Below the upper critical field Hc2, we observed the field-induced anomalies at H1 ~ 15 T and H2 ~ 22 T near H//ab and below a characteristic temperature T* ~ 2 K. The transition magnetic fields H1 and H2 exhibit negligible dependence on both temperature and field orientation. This contrasts with the strong temperature and angle dependence of Hc2, suggesting that these anomalies are attributed to the field-induced phase transitions, originating from the inherent spin-density-wave instability of quasiparticles near the superconducting gap minima or possible Flude-Ferrell-Larkin-Ovchinnikov state in the highly spin-polarized Fermi surfaces. Our observations imply that FeSe, an atypical multiband superconductor with extremely small Fermi energies, represents a unique model system for stabilizing unusual superconducting orders beyond the Pauli limit.Comment: 8 pages, 4 figures, submitte