Direct measurement of molecular stiffness and damping in confined water layers

We present {\em direct} and {\em linear} measurements of the normal stiffness and damping of a confined, few molecule thick water layer. The measurements were obtained by use of a small amplitude (0.36 $\textrm{\AA}$), off-resonance Atomic Force Microscopy (AFM) technique. We measured stiffness and damping oscillations revealing up to 7 layers separated by 2.56 $\pm$ 0.20 $\textrm{\AA}$. Relaxation times could also be calculated and were found to indicate a significant slow-down of the dynamics of the system as the confining separation was reduced. We found that the dynamics of the system is determined not only by the interfacial pressure, but more significantly by solvation effects which depend on the exact separation of tip and surface. Thus ` solidification\rq seems to not be merely a result of pressure and confinement, but depends strongly on how commensurate the confining cavity is with the molecule size. We were able to model the results by starting from the simple assumption that the relaxation time depends linearly on the film stiffness.Comment: 7 pages, 6 figures, will be submitted to PR

Hydrodynamic supercontinuum

We report the experimental observation of multi-bound-soliton solutions of the nonlinear Schrödinger equation (NLS) in the context of hydrodynamic surface gravity waves. Higher-order N-soliton solutions with N=2, 3 are studied in detail and shown to be

A 52-Week Study of Olanzapine with a Randomized Behavioral Weight Counseling Intervention in Adolescents with Schizophrenia or Bipolar I Disorder

Objectives: To evaluate the 52-week safety/tolerability of oral olanzapine for adolescents with schizophrenia or bipolar mania and compare effectiveness of a standard versus intense behavioral weight intervention in mitigating risk of weight gain. Methods: Patients 13?17 years old with schizophrenia (Brief Psychiatric Rating Scale for Children [BPRS-C] total score >30; item score ≥3 for hallucinations, delusions, or peculiar fantasies) or bipolar I disorder (manic or mixed episode; Young Mania Rating Scale [YMRS] total score ≥15) received open-label olanzapine (2.5?20?mg/day) and were randomized to standard (n?=?102; a single weight counseling session) or intense (n?=?101; weight counseling at each study visit) weight intervention. The primary outcome measure was mean change in body mass index (BMI) from baseline to 52 weeks using mixed-model repeated measures. Symptomatology was also assessed. Results: No statistically significant differences between groups were observed in mean baseline-to-52-week change in BMI (standard: +3.6?kg/m2; intense: +2.8?kg/m2; p?=?0.150) or weight (standard: +12.1?kg; intense: +9.6?kg; p?=?0.148). Percentage of patients at endpoint who had gained ≥15% of their baseline weight was 40% for the standard group and 31% for the intense group (p?=?0.187). Safety/tolerability results were generally consistent with those of previous olanzapine studies in adolescents, with the most notable exception being the finding of a mean decrease in prolactin. On symptomatology measures, patients with schizophrenia had a mean baseline-to-52-week change in BPRS-C of ?32.5 (standard deviation [SD]?=?10.8), and patients with bipolar disorder had a mean change in YMRS of ?16.7 (SD?=?8.9), with clinically and statistically significant improvement starting at 3?4 days for each. Conclusions: Long-term weight gain was high in both groups, with no statistically significant differences between the standard or intense behavioral weight interventions in BMI or weight. Safety, tolerability, and effectiveness findings were generally consistent with the known profile of olanzapine in adolescents.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140324/1/cap.2016.0010.pd

Treatment with an Anti-CD44v10-Specific Antibody Inhibits the Onset of Alopecia Areata in C3H/HeJ Mice

A murine CD44v10-neutralizing antibody has been reported to impair delayed-type hypersensitivity reactions. Because alopecia areata is characterized by a delayed-type hypersensitivity-like T cell mediated immune response, we addressed the question whether an anti-CD44v10-antibody influences the onset of alopecia areata. Therefore, we used the C3H/HeJ mouse model with the induction of alopecia areata in unaffected mice by the grafting of lesional alopecia areata mouse skin. Six grafted mice were injected (intraperitoneally) with anti-CD44v10, six grafted mice with anti-CD44standard, and six with phosphate-buffered saline only. After 11 wk phosphate-buffered saline injected animals on average had developed alopecia areata on 36.8% of their body. The onset of hair loss was slightly delayed and its extent reduced to 17.2% of their body in anti-CD44standard-treated mice. By contrast, five of six anti-CD44v10-treated mice did not show any hair loss and one mouse developed alopecia areata on only 1% of the body. Immunohistochemical examination revealed a marked reduction of perifollicular CD8+ lymphocytes and, to a lesser degree, CD4+ cells as well as a decreased expression of major histocompatibility complex class I on hair follicle epithelium in anti-CD44v10-treated mice as compared with phosphate-buffered saline or anti-CD44 standard-treated mice. Our data show that anti-CD44v10 is able to inhibit the onset of alopecia areata in C3H/HeJ mice. This might be accomplished by an anti-CD44v10-triggered impairment of immune cell homing (e.g., CD8+ T cells), resulting in a decrease of their number in target tissues

Anti-schistosomal intervention targets identified by lifecycle transcriptomic analyses

BACKGROUND: Novel methods to identify anthelmintic drug and vaccine targets are urgently needed, especially for those parasite species currently being controlled by singular, often limited strategies. A clearer understanding of the transcriptional components underpinning helminth development will enable identification of exploitable molecules essential for successful parasite/host interactions. Towards this end, we present a combinatorial, bioinformatics-led approach, employing both statistical and network analyses of transcriptomic data, for identifying new immunoprophylactic and therapeutic lead targets to combat schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: Utilisation of a Schistosoma mansoni oligonucleotide DNA microarray consisting of 37,632 elements enabled gene expression profiling from 15 distinct parasite lifecycle stages, spanning three unique ecological niches. Statistical approaches of data analysis revealed differential expression of 973 gene products that minimally describe the three major characteristics of schistosome development: asexual processes within intermediate snail hosts, sexual maturation within definitive vertebrate hosts and sexual dimorphism amongst adult male and female worms. Furthermore, we identified a group of 338 constitutively expressed schistosome gene products (including 41 transcripts sharing no sequence similarity outside the Platyhelminthes), which are likely to be essential for schistosome lifecycle progression. While highly informative, statistics-led bioinformatics mining of the transcriptional dataset has limitations, including the inability to identify higher order relationships between differentially expressed transcripts and lifecycle stages. Network analysis, coupled to Gene Ontology enrichment investigations, facilitated a re-examination of the dataset and identified 387 clusters (containing 12,132 gene products) displaying novel examples of developmentally regulated classes (including 294 schistosomula and/or adult transcripts with no known sequence similarity outside the Platyhelminthes), which were undetectable by the statistical comparisons. CONCLUSIONS/SIGNIFICANCE: Collectively, statistical and network-based exploratory analyses of transcriptomic datasets have led to a thorough characterisation of schistosome development. Information obtained from these experiments highlighted key transcriptional programs associated with lifecycle progression and identified numerous anti-schistosomal candidate molecules including G-protein coupled receptors, tetraspanins, Dyp-type peroxidases, fucosyltransferases, leishmanolysins and the netrin/netrin receptor complex

Excreted/secreted Schistosoma mansoni venom allergen-like 9 (SmVAL9) modulates host extracellular matrix remodelling gene expression

AbstractThe Schistosoma mansoni venom allergen-like (SmVAL) protein family consists of 29 members, each possessing a conserved α-β-α sandwich tertiary feature called the Sperm-coating protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) domain. While the SmVALs have been found in both excretory/secretory (E/S) products and in intra/sub-tegumental (non-E/S) fractions, the role(s) of this family in host/parasite relationships or schistosome developmental processes remains poorly resolved. In order to begin quantifying SmVAL functional diversity or redundancy, dissecting the specific activity (ies) of individual family members is necessary. Towards this end, we present the characterisation of SmVAL9; a protein previously found enriched in both miracidia/sporocyst larval transformation proteins and in egg secretions. While our study confirms that SmVAL9 is indeed found in soluble egg products and miracidia/sporocyst larval transformation proteins, we find it to be maximally transcribed/translated in miracidia and subsequently down-regulated during in vitro sporocyst development. SmVAL9 localisation within sporocysts appears concentrated in parenchymal cells/vesicles as well as associated with larval germinal cells. Furthermore, we demonstrate that egg-derived SmVAL9 carries an N-linked glycan containing a schistosome-specific difucosyl element and is an immunogenic target during chronic murine schistosomiasis. Finally, we demonstrate that recombinant SmVAL9 affects the expression of extracellular matrix, remodelling matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) gene products in both Biomphalaria glabrata embryonic cell (BgMMP1) and Mus musculus bone marrow-derived macrophage (MmMMP2, MmMMP9, MmMMP12, MmMMP13, MmMMP14, MmMMP28, TIMP1 and TIMP2) in vitro cultures. These findings importantly suggest that excreted/secreted SmVAL9 participates in tissue reorganisation/extracellular matrix remodelling during intra-mammalian egg translocation, miracidia infection and intra-molluscan sporocyst development/migration