Positive allosteric modulation as a potential therapeutic strategy in anti-NMDA receptor encephalitis

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENTAnti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.</jats:p

Effects of an enzyme blend (livestock answer) in diets containing dried distillers grains with solubles on growth performance of nursery and finishing pigs

Two trials were conducted to determine the effects of an enzyme blend (Livestock Answer; Environmental Care and Share, Golden, CO) on growth performance of nursery and wean-to-finish pigs. Livestock Answer contains amylases, cellulases, proteases, lipases, and phytases. In Exp. 1, a total of 180 pigs (PIC TR4 × 1050, initially 12.3 lb and 21 d old) were used in a 28-d trial. Pigs were blocked by weight and allotted at weaning to 1 of 3 enzyme levels (0%, 0.125%, and 0.175%). There were 6 pigs per pen and 10 replications per treatment. Diets were corn-soybean meal based and contained 15% dried distillers grains with solubles (DDGS) during Phase 1 (d 0 to 14) and 25% DDGS during Phase 2 (d 14 to 28). From d 0 to 14, increasing enzyme level improved ADG (quadratic; P = 0.04) and F/G (linear; P = 0.05) and tended to improve (P \u3c 0.07) ADFI and pig weight on d 14. From d 14 to 28, enzyme level had no effect (P \u3e 0.20) on ADG or ADFI but worsened F/G (quadratic; P = 0.04). Pigs fed an enzyme blend for the first 14 d after weaning had improved growth performance. However, over the entire 28-d nursery period, enzyme level had no effect (P \u3e 0.22) on pig performance. In Exp. 2, a total of 224 nursery pigs (PIC TR4 ×1050, initially 13.4 lb and 21 d of age) were blocked by weight and allotted to 1 of 4 treatments. There were 8 pigs per pen and 7 pens per treatment. Livestock Answer was added at 0.125% to either the nursery or finisher stage or both in a 2 × 2 factorial arrangement (with and without in nursery and with and without in finisher). Diets were corn-soybean meal based and contained 15% DDGS from d 0 to 14, 25% DDGS from d 14 to 35, and 30% DDGS from d 35 to d 126. On d 126, pigs were harvested and carcass data were collected. Adding the enzyme to nursery, finishing, and nursery and finishing combined diets containing DDGS did not influence (P \u3e 0.20) ADG, ADFI, F/G, or any of the carcass criteria measured in Exp 2.; Swine Day, Manhattan, KS, November 19, 200

Short-term thermal and electric load forecasting in buildings

Increasing environmental awareness and energy costs encourage the increase of the contribution of renewable energy sources (RES) to the energy supply of buildings. However, the integration of RES and energy storage systems introduces significant challenges for the energy management system (EMS) of complex building energy systems. An energy management strategy based on fixed control rules may fail to efficiently operate such systems. These circumstances raise the need to apply advanced control strategies. A promising approach is model predictive control (MPC), which allows the consideration of the expected dynamic system behavior as well as of forecasts of the loads and of the renewable energy generated. Obviously, the performance of an MPC-based EMS crucially depends on the accuracy of the load forecasts. The goal of this paper is to compare the capabilities of neural networks (NNs) and of the least squares support vector machine (LS-SVM) in forecasting the hourly thermal and electric load of buildings. Two short-term load forecasting algorithms are evaluated which treat every hour of the day separately by an individual forecasting model. Additionally, the algorithms also distinguish between working days, weekends and holidays. In order to adapt to changing load patterns, the algorithms use the sliding window training approach. Both algorithms are tested using the measured thermal and electric load data of a large office building and of a small building which houses a kindergarten. In the tests conducted, in general, the forecasting algorithm based on the LS-SVM shows a better performance than the forecasting algorithm based on NNs. In addition, the LS-SVM involves fewer free parameters to be determined than a NN, which makes the former easier to apply. The results reported further indicate that the accurate forecasting of the load of a small building is the more challenging task compared to the load forecasting of a large office building. Furthermore, using a training window size of more than 20 days does not significantly improve the performance of the algorithms examined

The McDonald Observatory Planet Search: New Long-Period Giant Planets, and Two Interacting Jupiters in the HD 155358 System

We present high-precision radial velocity (RV) observations of four solar-type (F7-G5) stars - HD 79498, HD 155358, HD 197037, and HD 220773 - taken as part of the McDonald Observatory Planet Search Program. For each of these stars, we see evidence of Keplerian motion caused by the presence of one or more gas giant planets in long-period orbits. We derive orbital parameters for each system, and note the properties (composition, activity, etc.) of the host stars. While we have previously announced the two-gas-giant HD 155358 system, we now report a shorter period for planet c. This new period is consistent with the planets being trapped in mutual 2:1 mean-motion resonance. We therefore perform an in-depth stability analysis, placing additional constraints on the orbital parameters of the planets. These results demonstrate the excellent long-term RV stability of the spectrometers on both the Harlan J. Smith 2.7 m telescope and the Hobby-Eberly telescope.Comment: 38 pages, 10 figures, 6 tables. Accepted for publication in Ap

Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation, and Self-Renewal

SummaryHematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation, and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential are variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings point to the molecular basis of HSC control and expansion

Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma : Final results of the MARC-2 trial

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs 25 vs ≤25 kg/m2. A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most

Tectonic collision and uplift of Wallacea triggered the global songbird radiation

Songbirds (oscine passerines) are the most species-rich and cosmopolitan bird group, comprising almost half of global avian diversity. Songbirds originated in Australia, but the evolutionary trajectory from a single species in an isolated continent to worldwide proliferation is poorly understood. Here, we combine the first comprehensive genome-scale DNA sequence data set for songbirds, fossil-based time calibrations, and geologically informed biogeographic reconstructions to provide a well-supported evolutionary hypothesis for the group. We show that songbird diversification began in the Oligocene, but accelerated in the early Miocene, at approximately half the age of most previous estimates. This burst of diversification occurred coincident with extensive island formation in Wallacea, which provided the first dispersal corridor out of Australia, and resulted in independent waves of songbird expansion through Asia to the rest of the globe. Our results reconcile songbird evolution with Earth history and link a major radiation of terrestrial biodiversity to early diversification within an isolated Australian continent