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CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aβ) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in participants with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from 18 participants in an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau, and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.

Habitat loss and fragmentation due to accelerated agriculture expansion is a major threat to existing wildlife populations across Asia. The human-wildlife interface mosaic across Asia is varied in terms of juxtaposition and structure, which can strongly influence biodiversity value and impacts on wildlife species. Here we analyzed habitat selection behavior of Asian elephant (Elephas maximus) across three study sites with different agriculture use patterns in Myanmar, a country recognized as a global biodiversity hotspot, including but not limited to, commercial palm oil and sugarcane plantations, and subsistence agriculture. These different agriculture use landscape capture landscape mosaic structure found across Asia. Given elephants exhibit heterogeneous spatial behavior, we fitted individual step selection and resource selection models to gain insight into the diversity of strategies employed at the local (step) and home range (third-order) scale. We used variance partitioning analysis to quantify the explanatory contribution of individual and study sites across both scales. We found that the variation in the resource selection behavior was mainly due to individual differences, and the configuration of agriculture present in an individual’s range was the most influential to its selection behavior. Enhancing understanding of how the level of fragmentation on the landscape relates to agricultural use can serve to help focus conservation efforts. Continued accelerated agriculture expansion is increasing the rate of contact between elephants and humans and, thereby escalating negative human-elephant interactions, often resulting in human and elephant deaths. Gaining a deeper understanding of habitat selection behavior by elephants across the changing landscapes of Asia can help inform management decisions and conservation actions.

The future of successful public health practice requires public health students to be educated within a decolonised curriculum that challenges the historical biases and inequalities that are deeply embedded within global public health and society. In this commentary, we reflect on what it can mean and why it's important to decolonise and diversify a public health curriculum. We describe how we used a student-led approach to begin this process, and share recommendations that are applicable to national and international curricula.

The COVID-19 pandemic provides an opportunity to explore the impact of government mandates on movement restrictions and non-pharmaceutical interventions on a novel infection, and we investigate these strategies in early-stage outbreak dynamics. The rate of disease spread in South Africa varied over time as individuals changed behavior in response to the ongoing pandemic and to changing government policies. Using a system of ordinary differential equations, we model the outbreak in the province of Gauteng, assuming that several parameters vary over time. Analyzing data from the time period before vaccination gives the approximate dates of parameter changes, and those dates are linked to government policies. Unknown parameters are then estimated from available case data and used to assess the impact of each policy. Looking forward in time, possible scenarios give projections involving the implementation of two different vaccines at varying times. Our results quantify the impact of different government policies and demonstrate how vaccinations can alter infection spread.

ABSTRACT: A study was conducted to understand the relationship among dietary branched-chain amino acids (BCAA) on the performance of Ross 344 × 708 male broilers. A total of 2,592 d-old male chicks were randomly placed into 144-floor pens according to a 23 full factorial central composite design (CCD) with 20 treatments (14 treatments and 6 center points). Each treatment consisted of varying digestible Ile:Lys (52 to 75), Val:Lys (64 to 87), and Leu:Lys (110 to 185) ratios. Birds and feed were weighed at 20 and 34 d of age to determine body weight gain (BWG), feed intake, and feed conversion ratio (FCR). At 35 d of age, feather amino acid composition and carcass characteristics were evaluated. Data were analyzed as CCD using the surface response option of JMP v. 15. Body weight gain (1,332 g; P < 0.001; R2 = 0.93) and FCR (1.54; P = 0.002; R2 = 0.88) were optimized at the lowest Leu:Lys ratio (110) with moderate Val:Lys (78 to 79) and Ile:Lys (65 to 66) ratios. Poorer BWG and FCR were observed as Leu:Lys ratio increased while increasing Val:Lys and Ile:Lys ratios alleviated the poor performance. Carcass (71.5%; P = 0.031; R2 = 0.76) and breast yield (26.7%; P < 0.001; R2 = 0.96) were maximized at the highest Leu:Lys ratio. This effect was complemented by increasing Ile:Lys ratio beyond 68. Lower Ile:Lys and Val:Lys ratios were required to maximize carcass and breast yield at the lowest Leu:Lys ratio. However, this strategy yielded less meat than providing a high Leu:Lys ratio diet. Dietary BCAA had little effect on altering the composition of feather protein and amino acid (P > 0.10). These results suggest that optimum BCAA ratios to Lys may vary depending on response criteria and demonstrate the importance of maintaining proper Val and Ile ratios centered on dietary Leu. Live performance can be optimized in diets with low Leu:Lys ratios; however, meat yield can be enhanced by increasing dietary Leu:Lys along with Ile:Lys ratios.

Abstract Background Severe anaemia (haemoglobin

In the Pliocene Model Intercomparison Project Phase 2 (PlioMIP2), coupled climate models have been used to simulate an interglacial climate during the mid-Piacenzian warm period (mPWP; 3.264 to 3.025 Ma). Here, we compare the Atlantic Meridional Overturning Circulation (AMOC), poleward ocean heat transport and sea surface warming in the Atlantic simulated with these models. In PlioMIP2, all models simulate an intensified mid-Pliocene AMOC. However, there is no consistent response in the simulated Atlantic ocean heat transport nor in the depth of the Atlantic overturning cell. The models show a large spread in the simulated AMOC maximum, the Atlantic ocean heat transport and the surface warming in the North Atlantic. Although a few models simulate a surface warming of ∼ 8–12 ∘C in the North Atlantic, similar to the reconstruction from Pliocene Research, Interpretation and Synoptic Mapping (PRISM) version 4, most models appear to underestimate this warming. The large model spread and model–data discrepancies in the PlioMIP2 ensemble do not support the hypothesis that an intensification of the AMOC, together with an increase in northward ocean heat transport, is the dominant mechanism for the mid-Pliocene warm climate over the North Atlantic.

Abstract The composition of extracellular vesicles (EVs) is altered in many pathological conditions, and their molecular content provides essential information on features of parent cells and mechanisms of crosstalk between cells and organs. Metabolic Syndrome (MetS) is a cluster of clinical manifestations including obesity, insulin resistance, dyslipidemia and hypertension that increases the risk of cardiovascular disease and type 2 diabetes mellitus. Here, we investigated the crosstalk between liver and adipocytes by characterizing EVs secreted by primary hepatocytes isolated from Zucker rat model, and studied the effect they have on 3T3‐L1 adipocytes. We found that steatotic hepatocytes secrete EVs with significantly reduced exosomal markers in comparison with their lean counterpart. Moreover, proteomic analysis revealed that those EVs reflect the metabolic state of the parent cell in that the majority of proteins upregulated relate to fat metabolism, fatty acid synthesis, glycolysis, and pentose phosphate pathway. In addition, hepatocytes‐secreted EVs influenced lipolysis and insulin sensitivity in recipient 3T3‐L1 adipocytes. Untargeted metabolomic analysis detected alterations in different adipocyte metabolic pathways in cells treated with hepatic EVs. In summary, our work showed that steatosis has a significant impact in the amount and composition of EVs secreted by hepatocytes. Moreover, our data point to the involvement of hepatic‐EVs in the development of pathologies associated with MetS.

The ability to make measurements of phosphate (PO43–) concentrations at temporal and spatial scales beyond those offered by shipboard observations offers new opportunities for investigations of the marine phosphorus cycle. We here report the first in situ PO43– dataset from an underwater glider (Kongsberg Seaglider) equipped with a PO43– Lab-on-Chip (LoC) analyser. Over 44 days, a 120 km transect was conducted in the northern North Sea during late summer (August and September). Surface depletion of PO43– (

We present a Lagrangian convective transport scheme developed for global chemistry and transport models, which considers the variable residence time that an air parcel spends in convection. This is particularly important for accurately simulating the tropospheric chemistry of short-lived species, e.g., for determining the time available for heterogeneous chemical processes on the surface of cloud droplets. In current Lagrangian convective transport schemes air parcels are stochastically redistributed within a fixed time step according to estimated probabilities for convective entrainment as well as the altitude of detrainment. We introduce a new scheme that extends this approach by modeling the variable time that an air parcel spends in convection by estimating vertical updraft velocities. Vertical updraft velocities are obtained by combining convective mass fluxes from meteorological analysis data with a parameterization of convective area fraction profiles. We implement two different parameterizations: a parameterization using an observed constant convective area fraction profile and a parameterization that uses randomly drawn profiles to allow for variability. Our scheme is driven by convective mass fluxes and detrainment rates that originate from an external convective parameterization, which can be obtained from meteorological analysis data or from general circulation models. We study the effect of allowing for a variable time that an air parcel spends in convection by performing simulations in which our scheme is implemented into the trajectory module of the ATLAS chemistry and transport model and is driven by the ECMWF ERA-Interim reanalysis data. In particular, we show that the redistribution of air parcels in our scheme conserves the vertical mass distribution and that the scheme is able to reproduce the convective mass fluxes and detrainment rates of ERA-Interim. We further show that the estimated vertical updraft velocities of our scheme are able to reproduce wind profiler measurements performed in Darwin, Australia, for velocities larger than 0.6 m s−1. SO2 is used as an example to show that there is a significant effect on species mixing ratios when modeling the time spent in convective updrafts compared to a redistribution of air parcels in a fixed time step. Furthermore, we perform long-time global trajectory simulations of radon-222 and compare with aircraft measurements of radon activity.

We describe a new algorithm that automatically delineates the cliff top and toe of a cliffed coastline from a digital elevation model (DEM). The algorithm builds upon existing methods but is specifically designed to resolve very irregular planform coastlines with many bays and capes, such as parts of the coastline of Great Britain. The algorithm automatically and sequentially delineates and smooths shoreline vectors, generates orthogonal transects and elevation profiles with a minimum spacing equal to the DEM resolution, and extracts the position and elevation of the cliff top and toe. Outputs include the non-smoothed raster and smoothed vector coastlines, normals to the coastline (as vector shape files), xyz profiles (as comma-separated-value, CSV, files), and the cliff top and toe (as point shape files). The algorithm also automatically assesses the quality of the profile and omits low-quality profiles (i.e. extraction of cliff top and toe is not possible). The performance of the proposed algorithm is compared with an existing method, which was not specifically designed for very irregular coastlines, and to manually digitized boundaries by numerous professionals. Also, we assess the reproducibility of the results using different DEM resolutions (5, 10 and 50 m), different user-defined parameter sets related to the degree of coastline smoothing, and the threshold used to identify the cliff top and toe. The model output sensitivity is found to be smaller than the manually digitized uncertainty. The code and a manual are publicly available on a GitHub repository.

Abstract High-energy jets recoiling against missing transverse energy (MET) are powerful probes of dark matter at the LHC. Searches based on large MET signatures require a precise control of the $$Z(\nu {\bar{\nu }})+$$ Z ( ν ν ¯ ) + jet background in the signal region. This can be achieved by taking accurate data in control regions dominated by $$Z(\ell ^+\ell ^-)+$$ Z ( ℓ + ℓ - ) + jet, $$W(\ell \nu )+$$ W ( ℓ ν ) + jet and $$\gamma +$$ γ + jet production, and extrapolating to the $$Z(\nu {\bar{\nu }})+$$ Z ( ν ν ¯ ) + jet background by means of precise theoretical predictions. In this context, recent advances in perturbative calculations open the door to significant sensitivity improvements in dark matter searches. In this spirit, we present a combination of state-of-the-art calculations for all relevant $$V+$$ V + jets processes, including throughout NNLO QCD corrections and NLO electroweak corrections supplemented by Sudakov logarithms at two loops. Predictions at parton level are provided together with detailed recommendations for their usage in experimental analyses based on the reweighting of Monte Carlo samples. Particular attention is devoted to the estimate of theoretical uncertainties in the framework of dark matter searches, where subtle aspects such as correlations across different $$V+$$ V + jet processes play a key role. The anticipated theoretical uncertainty in the $$Z(\nu {\bar{\nu }})+$$ Z ( ν ν ¯ ) + jet background is at the few percent level up to the TeV range.

The International Surface Temperature Initiative (ISTI) is striving towards substantively improving our ability to robustly understand historical land surface air temperature change at all scales. A key recently completed first step has been collating all available records into a comprehensive open access, traceable and version-controlled databank. The crucial next step is to maximise the value of the collated data through a robust international framework of benchmarking and assessment for product intercomparison and uncertainty estimation. We focus on uncertainties arising from the presence of inhomogeneities in monthly mean land surface temperature data and the varied methodological choices made by various groups in building homogeneous temperature products. The central facet of the benchmarking process is the creation of global-scale synthetic analogues to the real-world database where both the "true" series and inhomogeneities are known (a luxury the real-world data do not afford us). Hence, algorithmic strengths and weaknesses can be meaningfully quantified and conditional inferences made about the real-world climate system. Here we discuss the necessary framework for developing an international homogenisation benchmarking system on the global scale for monthly mean temperatures. The value of this framework is critically dependent upon the number of groups taking part and so we strongly advocate involvement in the benchmarking exercise from as many data analyst groups as possible to make the best use of this substantial effort.

Climate change is expected to have the greatest impact on the world's economically poor. In the Sahel, a climatically sensitive region where rain-fed agriculture is the primary livelihood, expected decreases in water supply will increase food insecurity. Studies on climate change and the intensification of the water cycle in sub-Saharan Africa are few. This is due in part to poor calibration of modeled evapotranspiration (ET), a key input in continental-scale hydrologic models. In this study, a remote sensing model of transpiration (the primary component of ET), driven by a time series of vegetation indices, was used to substitute transpiration from the Global Land Data Assimilation System realization of the National Centers for Environmental Prediction, Oregon State University, Air Force, and Hydrology Research Laboratory at National Weather Service Land Surface Model (GNOAH) to improve total ET model estimates for monitoring purposes in sub-Saharan Africa. The performance of the hybrid model was compared against GNOAH ET and the remote sensing method using eight eddy flux towers representing major biomes of sub-Saharan Africa. The greatest improvements in model performance were at humid sites with dense vegetation, while performance at semi-arid sites was poor, but better than the models before hybridization. The reduction in errors using the hybrid model can be attributed to the integration of a simple canopy scheme that depends primarily on low bias surface climate reanalysis data and is driven primarily by a time series of vegetation indices.

A buoy based instrument platform (the "O-buoy") was designed, constructed, and field tested for year-round measurement of ozone, bromine monoxide, carbon dioxide, and meteorological variables over Arctic sea ice. The O-buoy operated in an autonomous manner with daily, bi-directional data transmissions using Iridium satellite communication. The O-buoy was equipped with three power sources: primary lithium-ion battery packs, rechargeable lead acid packs, and solar panels that recharge the lead acid packs, and can fully power the O-buoy during summer operation. This system was designed to operate under the harsh conditions present in the Arctic, with minimal direct human interaction, to aid in our understanding of the atmospheric chemistry that occurs in this remote region of the world. The current design requires approximately yearly maintenance limited by the lifetime of the primary power supply. The O-buoy system was field tested in Elson Lagoon, Barrow, Alaska from February to May 2009, and deployed in the Beaufort Sea in October 2009. Here, we describe the design and present preliminary data.

The principal mechanisms that connect carbon fluxes with water relations in savanna ecosystems were studied by using eddy covariance method in a savanna ecosystem at Kruger National Park, South Africa. Since the annual drought and rewetting cycle is a major factor influencing the function of savanna ecosystems, this work focused on the close inter-connection between water relations and carbon fluxes. Data from a nine-month measuring campaign lasting from the early wet season to the late dry season were used. Total ecosystem respiration showed highest values at the onset of the growing season, a slightly lower plateau during the main part of the growing season and a continuous decrease during the transition towards the dry season. The regulation of canopy conductance was changed in two ways: changes due to phenology during the course of the growing season and short-term acclimation to soil water conditions. The most constant parameter was water use efficiency that was influenced by VPD during the day but the VPD response curve of water usage did change only slightly during the course of the growing season and decreased by about 30% during the transition from wet to dry season. The regulation of canopy conductance and photosynthetic capacity were closely related. This observation meets recent leaf-level findings that stomatal closure triggers down-regulation of Rubisco during drought. Our results may show the effects of these processes on the ecosystem scale.

During the Mediterranean Intensive Oxidant Study (MINOS) campaign in August 2001 gas-phase organic compounds were measured using comprehensive two-dimensional gas chromatography (GCxGC) at the Finokalia ground station, Crete. In this paper, C7-C11 aromatic and n-alkane measurements are presented and interpreted. The mean mixing ratios of the hydrocarbons varied from 1±1 pptv (i-propylbenzene) to 43±36 pptv (toluene). The observed mixing ratios showed strong day-to-day variations and generally higher levels during the first half of the campaign. Mean diel profiles showed maxima at local midnight and late morning, and minima in the early morning and evening. Results from analysis using a simplified box model suggest that both the chemical sink (i.e. reaction with OH) and the variability of source strengths were the causes of the observed variations in hydrocarbon mixing ratios. The logarithms of hydrocarbon concentrations were negatively correlated with the OH concentrations integral over a day prior to the hydrocarbon measurements. Slopes of the regression lines derived from these correlations for different compounds are compared with literature rate constants for their reactions with OH. The slopes for most compounds agree reasonably well with the literature rate constants. A sequential reaction model has been applied to the interpretation of the relationship between ethylbenzene and two of its potential products, i.e. acetophenone and benzeneacetaldehyde. The model can explain the good correlation observed between [acetophenone]/[ethylbenzene] and [benzeneacetaldehyde]/[ethylbenzene]. The model results and field measurements suggest that the reactivity of benzeneacetaldehyde may lie between those of acetophenone and ethylbenzene and that the ratio between yields of acetophenone and benzeneacetaldehyde may be up to 28:1. Photochemical ages of trace gases sampled at Finokalia during the campaign are estimated using the sequential reaction model and related data. They lie in the range of about 0.5-2.5 days.

The observation of ultrahigh energy neutrinos (UHEνs) has become a priority in experimental astroparticle physics. UHEνs can be detected with a variety of techniques. In particular, neutrinos can interact in the atmosphere (downward-going ν) or in the Earth crust (Earth-skimming ν), producing air showers that can be observed with arrays of detectors at the ground. With the surface detector array of the Pierre Auger Observatory we can detect these types of cascades. The distinguishing signature for neutrino events is the presence of very inclined showers produced close to the ground (i.e., after having traversed a large amount of atmosphere). In this work we review the procedure and criteria established to search for UHEνs in the data collected with the ground array of the Pierre Auger Observatory. This includes Earth-skimming as well as downward-going neutrinos. No neutrino candidates have been found, which allows us to place competitive limits to the diffuse flux of UHEνs in the EeV range and above.

During the COVID-19 pandemic, parents quickly assumed the role of teachers to support their children's learning at home. Deaf and hard of hearing (DHH) students often rely on additional accommodations to access their education. The authors investigated the perspectives of 40 parents of K--12 DHH students on the use of virtual learning during the pandemic. An electronic survey was distributed through Qualtrics to gain an understanding of the new learning environment of remote instruction. The participants' responses revealed that they felt that challenges occurred in the areas of time management, language access, technology, motivation, and children's ability to function independently. The respondents were almost evenly split between satisfaction and dissatisfaction with their child's overall educational experience during the pandemic. The results indicated that degree of access significantly influenced the children's experiences of education in virtual learning settings.

This paper addresses pre-FFT synchronisation for orthogonal frequency division multiplex (OFDM) under varying multipath conditions. To ensure the most efficient data transmission possible, there should be no constraints on how much of the cyclic prefix (CP) is occupied by intersymbol interference (ISI). Here a solution for timing synchronisation is proposed, that is, robust even when the strongest multipath components are delayed relative to the first arriving paths. In this situation, existing methods perform poorly, whereas the solution proposed uses the derivative of the correlation function and is less sensitive to the channel impulse response. In this paper, synchronisation of a DVB single-frequency network is investigated. A refinement is proposed that uses heuristic rules based on the maxima of the correlation and derivative functions to further reduce the estimate variance. The technique has relevance to broadcast, OFDMA, and WLAN applications, and simulations are presented which compare the method with existing approaches.