Test for a learned drinking response : support for appetitive preparedness

Seligman, Ives, Ames and Mineka (1970a) have suggested that by the nature of the stimulus-response association in appetitive states a prepared mechanism using mild deprivation cues exists which will activate an appetitional resolution. Pairing of a neutral stimulus with this prepared mechanism results in a conditioned stimulus capable of electing the drinking response. Contrary to this hypothesis, Mowrer (1956) posited that a water deprived state induces an emotional reaction or thirst fear. It is assumed that reduction of this stimulus may be accomplished by means of alleviating the deprived state. A conditioned external stimulus can therefore elicit the drinking response by the mediational stress stimulus. Rates demonstrated increased water intake at zero hours water deprived in the presence of an external stimulus previously paired with an increasing motive state, one-half hour through 23 hours water deprivation. A hi motive state associated cue, 23 hours through 23-1/2 hours water deprived, failed to elicit a greater drinking response in zero hour deprived animals. Intake monitored at quarter hour segments for two hours revealed that lo to hi drive associated stimulus does not effect overall intake but induces differentiation in drinking patterns causing a significant enhancement and then a reduction in intake amounts. These results are in agree with Seligman et al. (1970a) suggesting that elicitation of the prepared mechanism will evoke a drinking response but that water regulation controls do not allow prolonged hyperdipsia

Electrodynamic tape tether performance with varying tether widths at low Earth altitudes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76406/1/AIAA-2001-1141-528.pd

Ion-Exchanged Waveguides in Glass Doped with PbS Quantum Dots

The lowest-loss (≤1 dB/cm) ion-exchanged waveguides in glass doped with PbS quantum dots are presented. Near-field mode profile and refractive index profile using the refracted near-field technique were measured for these waveguides. We demonstrate that the optical properties of this glass unchanged during the ion-exchange process

Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors.

Purpose:To evaluate the safety, recommended phase II dose (RP2D) and efficacy of pexidartinib, a colony stimulating factor receptor 1 (CSF-1R) inhibitor, in combination with weekly paclitaxel in patients with advanced solid tumors. Patients and Methods:In part 1 of this phase Ib study, 24 patients with advanced solid tumors received escalating doses of pexidartinib with weekly paclitaxel (80 mg/m2). Pexidartinib was administered at 600 mg/day in cohort 1. For subsequent cohorts, the dose was increased by ⩽50% using a standard 3+3 design. In part 2, 30 patients with metastatic solid tumors were enrolled to examine safety, tolerability and efficacy of the RP2D. Pharmacokinetics and biomarkers were also assessed. Results:A total of 51 patients reported ≥1 adverse event(s) (AEs) that were at least possibly related to either study drug. Grade 3-4 AEs, including anemia (26%), neutropenia (22%), lymphopenia (19%), fatigue (15%), and hypertension (11%), were recorded in 38 patients (70%). In part 1, no maximum tolerated dose was achieved and 1600 mg/day was determined to be the RP2D. Of 38 patients evaluable for efficacy, 1 (3%) had complete response, 5 (13%) partial response, 13 (34%) stable disease, and 17 (45%) progressive disease. No drug-drug interactions were found. Plasma CSF-1 levels increased 1.6- to 53-fold, and CD14dim/CD16+ monocyte levels decreased by 57-100%. Conclusions:The combination of pexidartinib and paclitaxel was generally well tolerated. RP2D for pexidartinib was 1600 mg/day. Pexidartinib blocked CSF-1R signaling, indicating potential for mitigating macrophage tumor infiltration

Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke

Microglia are the main immune cells of the brain and contribute to common brain diseases. However, it is unclear how microglia influence neuronal activity and survival in the injured brain in vivo. Here we develop a precisely controlled model of brain injury induced by cerebral ischaemia combined with fast in vivo two-photon calcium imaging and selective microglial manipulation. We show that selective elimination of microglia leads to a striking, 60% increase in infarct size, which is reversed by microglial repopulation. Microglia-mediated protection includes reduction of excitotoxic injury, since an absence of microglia leads to dysregulated neuronal calcium responses, calcium overload and increased neuronal death. Furthermore, the incidence of spreading depolarization (SD) is markedly reduced in the absence of microglia. Thus, microglia are involved in changes in neuronal network activity and SD after brain injury in vivo that could have important implications for common brain diseases

ERβ Binds N-CoR in the Presence of Estrogens via an LXXLL-like Motif in the N-CoR C-terminus

Nuclear receptors (NRs) usually bind the corepressors N-CoR and SMRT in the absence of ligand or in the presence of antagonists. Agonist binding leads to corepressor release and recruitment of coactivators. Here, we report that estrogen receptor β (ERβ) binds N-CoR and SMRT in the presence of agonists, but not antagonists, in vitro and in vivo. This ligand preference differs from that of ERα interactions with corepressors, which are inhibited by estradiol, and resembles that of ERβ interactions with coactivators. ERβ /N-CoR interactions involve ERβ AF-2, which also mediates coactivator recognition. Moreover, ERβ recognizes a sequence (PLTIRML) in the N-CoR C-terminus that resembles coactivator LXXLL motifs. Inhibition of histone deacetylase activity specifically potentiates ERβ LBD activity, suggesting that corepressors restrict the activity of AF-2. We conclude that the ER isoforms show completely distinct modes of interaction with a physiologically important corepressor and discuss our results in terms of ER isoform specificity in vivo

Hyaluronic Acid Binding Sperm Selection for assisted reproduction treatment (HABSelect): Study protocol for a multicentre randomised controlled trial

© Published by the BMJ Publishing Group Limited.Introduction The selection of a sperm with good genomic integrity is an important consideration for improving intracytoplasmic sperm injection (ICSI) outcome. Current convention selects sperm by vigour and morphology, but preliminary evidence suggests selection based on hyaluronic acid binding may be beneficial. The aim of the Hyaluronic Acid Binding Sperm Selection (HABSelect) trial is to determine the efficacy of hyaluronic acid (HA)-selection of sperm versus conventionally selected sperm prior to ICSI on live birth rate (LBR). The mechanistic aim is to assess whether and how the chromatin state of HA-selected sperm corresponds with clinical outcomes - clinical pregnancy rate (CPR), LBR and pregnancy loss (PL). Methods and analysis Couples attending UK Centres will be approached, eligibility screening performed and informed consent sought. Randomisation will occur within 24 hours prior to ICSI treatment. Participants will be randomly allocated 1:1 to the intervention arm (physiological intracytoplasmic sperm injection, PICSI) versus the control arm using conventional methods (ICSI). The primary clinical outcome is LBR ≥37 weeks' gestation with the mechanistic study determining LBR's relationship with sperm DNA integrity. Secondary outcomes will determine this for CPR and PL. Only embryologists performing the procedure will be aware of the treatment allocation. Steps will be taken to militate against biases arising from embryologists being non-blinded. Randomisation will use a minimisation algorithm to balance for key prognostic variables. The trial is powered to detect a 5% difference (24-29%: p=0.05) in LBR ≥37 weeks' gestation. Selected residual sperm samples will be tested by one or more assays of DNA integrity. Ethics and dissemination HABSelect is a UK NIHR-EME funded study (reg no 11/14/34; IRAS REF. 13/YH/0162). The trial was designed in partnership with patient and public involvement to help maximise patient benefits. Trial findings will be reported as per CONSORT guidelines and will be made available in lay language via the trial web site (http://www.habselect.org.uk/). Trial registration number ISRCTN99214271; Pre-results