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Complaints of fatigue following acquired brain injury (ABI) are often associated with depression. However, the nature of this relationship is unclear; furthermore, research among young people with ABI is limited. The objective of this cross-sectional study was (1) to investigate levels of depression in young outpatients with ABI (15-30 years old) and (2) to determine how different dimensions of fatigue relate to depression. Five dimensions of fatigue were assessed with the Multidimensional Fatigue Inventory (MFI-20), and depression was assessed with the Major Depression Inventory (MDI). Mann-Whitney U-tests and multiple regression analyses were conducted. The ABI group (n = 105), on average 23.7 years old (SD = 4.2) and 31 months post-injury (SD = 61), had elevated levels of fatigue and depression compared to a convenience sample of 160 healthy controls, all p's < .001. In multivariate analyses, the predominantly mental dimensions of fatigue, General Fatigue, Mental Fatigue, and Reduced Motivation, were independently associated with MDI, all p's < .01, while the physical dimensions, Physical Fatigue and Reduced Activity, were not. Distinctions within the concept of fatigue may be important in relation to depression, and future research could benefit from adopting a multidimensional approach in the development of more targeted and effective treatments of fatigue and depression following ABI. [ABSTRACT FROM AUTHOR]

Purpose: The prevalence of follow-on and compounded products of glucagon-like peptide-1 analogs is increasing. We assessed glucagon-like peptide-1 analogs semaglutide and liraglutide for purity, potential immunogenicity, and expected stability, by comparing a representative selection of commercially available follow-on drug substances (DSs) and drug products (DPs) with their corresponding originators.Tests included several chromatography methods coupled with ultraviolet and mass spectrometry detectors, inductively coupled plasma optical emission spectroscopy, inductively coupled plasma mass spectrometry, nuclear magnetic resonance, dissolution analyses, in silico peptide/major histocompatibility complex II-binding prediction, and fibrillation assays.Overall, 16 injectable semaglutide, 8 oral semaglutide, and 2 injectable liraglutide follow-on products were analyzed alongside originator products. Compared with originator, follow-on injectable semaglutide DSs and DPs had new impurities and impurity patterns, including high molecular weight proteins, trace metals, anions, counterions, and residual solvents. Analyses showed that several commercialized follow-on oral semaglutide DPs had a markedly lower quantity of semaglutide than the label claim, while dissolution tests indicated different semaglutide and sodium N-(8-[2-hydroxybenzoyl] amino)caprylate (SNAC) release profiles, which may reduce bioavailability. Neoepitopes were identified in DS and DP semaglutide follow-ons, indicating potential immunogenicity. Fibrillation assays showed increased fibrillation tendency and reduced physical stability in liraglutide follow-on DP samples compared with originator.This study highlights that differences in the manufacturing processes of follow-on semaglutide and liraglutide (vs those used for originators) can result in several changes to the DSs and DPs. The impact of these changes on efficacy and safety outcomes remains unknown and should be investigated by clinical studies.Methods: The prevalence of follow-on and compounded products of glucagon-like peptide-1 analogs is increasing. We assessed glucagon-like peptide-1 analogs semaglutide and liraglutide for purity, potential immunogenicity, and expected stability, by comparing a representative selection of commercially available follow-on drug substances (DSs) and drug products (DPs) with their corresponding originators.Tests included several chromatography methods coupled with ultraviolet and mass spectrometry detectors, inductively coupled plasma optical emission spectroscopy, inductively coupled plasma mass spectrometry, nuclear magnetic resonance, dissolution analyses, in silico peptide/major histocompatibility complex II-binding prediction, and fibrillation assays.Overall, 16 injectable semaglutide, 8 oral semaglutide, and 2 injectable liraglutide follow-on products were analyzed alongside originator products. Compared with originator, follow-on injectable semaglutide DSs and DPs had new impurities and impurity patterns, including high molecular weight proteins, trace metals, anions, counterions, and residual solvents. Analyses showed that several commercialized follow-on oral semaglutide DPs had a markedly lower quantity of semaglutide than the label claim, while dissolution tests indicated different semaglutide and sodium N-(8-[2-hydroxybenzoyl] amino)caprylate (SNAC) release profiles, which may reduce bioavailability. Neoepitopes were identified in DS and DP semaglutide follow-ons, indicating potential immunogenicity. Fibrillation assays showed increased fibrillation tendency and reduced physical stability in liraglutide follow-on DP samples compared with originator.This study highlights that differences in the manufacturing processes of follow-on semaglutide and liraglutide (vs those used for originators) can result in several changes to the DSs and DPs. The impact of these changes on efficacy and safety outcomes remains unknown and should be investigated by clinical studies.Results: The prevalence of follow-on and compounded products of glucagon-like peptide-1 analogs is increasing. We assessed glucagon-like peptide-1 analogs semaglutide and liraglutide for purity, potential immunogenicity, and expected stability, by comparing a representative selection of commercially available follow-on drug substances (DSs) and drug products (DPs) with their corresponding originators.Tests included several chromatography methods coupled with ultraviolet and mass spectrometry detectors, inductively coupled plasma optical emission spectroscopy, inductively coupled plasma mass spectrometry, nuclear magnetic resonance, dissolution analyses, in silico peptide/major histocompatibility complex II-binding prediction, and fibrillation assays.Overall, 16 injectable semaglutide, 8 oral semaglutide, and 2 injectable liraglutide follow-on products were analyzed alongside originator products. Compared with originator, follow-on injectable semaglutide DSs and DPs had new impurities and impurity patterns, including high molecular weight proteins, trace metals, anions, counterions, and residual solvents. Analyses showed that several commercialized follow-on oral semaglutide DPs had a markedly lower quantity of semaglutide than the label claim, while dissolution tests indicated different semaglutide and sodium N-(8-[2-hydroxybenzoyl] amino)caprylate (SNAC) release profiles, which may reduce bioavailability. Neoepitopes were identified in DS and DP semaglutide follow-ons, indicating potential immunogenicity. Fibrillation assays showed increased fibrillation tendency and reduced physical stability in liraglutide follow-on DP samples compared with originator.This study highlights that differences in the manufacturing processes of follow-on semaglutide and liraglutide (vs those used for originators) can result in several changes to the DSs and DPs. The impact of these changes on efficacy and safety outcomes remains unknown and should be investigated by clinical studies.Conclusion: The prevalence of follow-on and compounded products of glucagon-like peptide-1 analogs is increasing. We assessed glucagon-like peptide-1 analogs semaglutide and liraglutide for purity, potential immunogenicity, and expected stability, by comparing a representative selection of commercially available follow-on drug substances (DSs) and drug products (DPs) with their corresponding originators.Tests included several chromatography methods coupled with ultraviolet and mass spectrometry detectors, inductively coupled plasma optical emission spectroscopy, inductively coupled plasma mass spectrometry, nuclear magnetic resonance, dissolution analyses, in silico peptide/major histocompatibility complex II-binding prediction, and fibrillation assays.Overall, 16 injectable semaglutide, 8 oral semaglutide, and 2 injectable liraglutide follow-on products were analyzed alongside originator products. Compared with originator, follow-on injectable semaglutide DSs and DPs had new impurities and impurity patterns, including high molecular weight proteins, trace metals, anions, counterions, and residual solvents. Analyses showed that several commercialized follow-on oral semaglutide DPs had a markedly lower quantity of semaglutide than the label claim, while dissolution tests indicated different semaglutide and sodium N-(8-[2-hydroxybenzoyl] amino)caprylate (SNAC) release profiles, which may reduce bioavailability. Neoepitopes were identified in DS and DP semaglutide follow-ons, indicating potential immunogenicity. Fibrillation assays showed increased fibrillation tendency and reduced physical stability in liraglutide follow-on DP samples compared with originator.This study highlights that differences in the manufacturing processes of follow-on semaglutide and liraglutide (vs those used for originators) can result in several changes to the DSs and DPs. The impact of these changes on efficacy and safety outcomes remains unknown and should be investigated by clinical studies. [ABSTRACT FROM AUTHOR]

Working memory impairment is common in patients in the chronic phase after acquired brain injury (ABI), and there is a need to develop efficacious rehabilitation methods. This trial explored the effects of two different computer-based cognitive rehabilitation (CBCR) programmes on working memory in the chronic phase after ABI, as well as the role of continuous support versus no support from a health professional on the efficacy of CBCR. A total of 72 patients were randomized into four different groups for a 12-week intervention: Two groups trained with the CBCR-programmes 'Cogmed' and 'Brain+ Health,' respectively, and one group completed active-control training. All three groups received continuous support from a health professional. The last group trained with the CBCR programme 'Brain+ Health' but received no support. Before and after the intervention, patients were tested with a neuropsychological battery of working memory, attention and executive functions. Both CBCR-programmes improved working memory when administered with support from a health professional. The programmes improved different sub-components of working memory, possibly because of their individual content and design. None of the CBCR-programmes were more efficacious than sham-training with support. CBCR without support did not improve working memory in patients. [ABSTRACT FROM AUTHOR]

Background: Cognitive decline in Parkinson's disease (PD) has become increasingly recognized in recent years, and there is a need to identify methods for cognitive rehabilitation in PD patients. Objective: The aim of this study was to explore the feasibility and effects of 2 different computer-based cognitive rehabilitation (CBCR) interventions on attention, executive functions, and quality of life (QoL) in PD patients. Methods: Thirty nondemented PD patients were randomly assigned to one of 3 groups: one passive control group and 2 intervention groups with 2 different CBCR programmes. The intervention period was 8 weeks with follow-up visits in clinic every second week. Before and after the intervention period, patients were tested with a neuropsychological battery of attention, executive functions, and QoL. Results: Twenty-four patients completed the study. Patients in one of the CBCR groups experienced a significant within-group increase on the primary measures of attention, executive functions, and QoL. However, this effect was not significant between groups. No significant differences were observed for the other CBCR group or the control group. Conclusions: CBCR is a feasible intervention for cognitive rehabilitation in nondemented PD patients. The effects of training were modest and should be further explored in larger clinical trials. Some CBCR programmes might be more effective than others for PD patients. The protocol for this study was published prospectively at ClinicalTrials.gov on September 18, 2017 with ID: NCT03285347. [ABSTRACT FROM AUTHOR]

Highlights • A mouse model for weak, single mild traumatic brain injury (minimal TBI) is used. • Minimal TBI results in transient deficits in long-term memory reconsolidation. • Minimal TBI causes relapse to less effective search strategies in the water maze. • Minimal TBI leads to a transient increase in freezing during fear conditioning. • A transient rise in hippocampal GFAP after minimal TBI indicates astrogliosis. Abstract Mild traumatic brain injury (mTBI) can lead to diffuse neurophysical damage as well as cognitive and affective alterations. The nature and extent of behavioral changes after mTBI are still poorly understood and how strong an impact force has to be to cause long-term behavioral changes is not yet known. Here, we examined spatial learning acquisition, retention and reversal in a Morris water maze, and assessed search strategies during task performance after a single, mild, closed-skull traumatic impact referred to as "minimal" TBI. Additionally, we investigated changes in conditioned learning in a contextual fear-conditioning paradigm. Results show transient deficits in spatial memory retention, which, although limited, are indicative of deficits in long-term memory reconsolidation. Interestingly, minimal TBI causes animals to relapse to less effective search strategies, affecting performance after a retention pause. Apart from cognitive deficits, results yielded a sub-acute, transient increase in freezing response after fear conditioning, with no increase in baseline behavior, an indication of a stronger affective reaction to aversive stimuli after minimal TBI or greater susceptibility to stress. Furthermore, western blot analysis showed a short-term increase in hippocampal GFAP expression, most likely indicating astrogliosis, which is typically related to injuries of the central nervous system. Our findings provide evidence that even a very mild impact to the skull can have detectable consequences on the molecular, cognitive and affective-like level. However, these effects seemed to be very transient and reversible. [ABSTRACT FROM AUTHOR]

Highlights • New application of broiler weight forecasting using environmental conditions. • Data driven dynamic neural network models are used for forecasting. • Model is configured using mutual information based input variable selection. • Environmental conditions are significant for broiler weight forecasting. • Mean broiler weight forecasting standard error of 66.8 g. Abstract The global demand for poultry meat is predicted to increase by 18% between 2015–17 and 2027, which motivates the need for better tools for production monitoring, planning and optimization. This paper presents the first results on broiler (chicken for meat production) weight forecasting intended for production planning and monitoring using environmental broiler house conditions – such as heating, ventilation, and temperature. We investigate the dynamic impact of environmental conditions on broiler growth, which is known to be highly significant but unexplored in scientific literature. The forecasting is carried out using ensemble dynamic neural network models trained on past production data with mutual information based input variable selection. To investigate the potential of the proposed method, an extensive case study on almost 3.5 years of industrial farm scale production data from a state-of-the-art broiler house is carried out. The dynamic impact of environmental conditions on broiler growth is found to be significant and useful broiler weight forecasts are obtained – effectively providing a foundation for future research on optimization of broiler production. [ABSTRACT FROM AUTHOR]

Therapeutic effects of PSD-95 inhibition have been demonstrated in numerous studies of stroke; however only few studies have assessed the effects of PSD-95 inhibitors in traumatic brain injury (TBI). As the pathophysiology of TBI partially overlaps with that of stroke, PSD-95 inhibition may also be an effective therapeutic strategy in TBI. The objectives of the present study were to assess the effects of a dimeric inhibitor of PSD-95, UCCB01-144, on excitotoxic cell death in vitro and outcome after experimental TBI in rats in vivo. In addition, the pharmacokinetic parameters of UCCB01-144 were investigated in order to assess uptake of the drug into the central nervous system of rats. After a controlled cortical impact rats were randomized to receive a single injection of either saline or two different doses of UCCB01-144 (10 or 20 mg/kg IV) immediately after injury. Spatial learning and memory were assessed in a water maze at 2 weeks post-trauma, and at 4 weeks lesion volumes were estimated. Overall, UCCB01-144 did not protect against NMDA-toxicity in neuronal cultures or experimental TBI in rats. Important factors that should be investigated further in future studies assessing the effects of PSD-95 inhibitors in TBI are discussed. [ABSTRACT FROM AUTHOR]

Background Pronouns have been shown to be impaired in agrammatic production but not all types of pronouns are equally affected. For instance, clitic pronouns are more impaired than non-clitic ones. A usage-based theory of grammatical status suggests a reclassification of pronouns into grammatical and lexical and predicts that grammatical pronouns are more impaired in agrammatic production. Besides, the reorganization of elementary functions (REF) model, which describes the underlying neurocognitive processes of post-injury recovery, explores the variability across individuals with agrammatism. Aims The current study hypothesizes that those pronouns that by the usage-based theory of grammatical status are grammatical are more affected than the lexical ones in agrammatic speech. In addition to this, the REF-model predicts that individuals with agrammatism will either build up unique strategies to cope with the deficit or they will rely more on fixed expressions. Method & Procedures : Spontaneous speech data collected from six French speaking individuals with agrammatism and nine non-injured controls in three different contexts (autobiography, narrative speech and descriptive speech) was used to test the hypothesis. We categorized 137 French pronouns into lexical and grammatical and calculated a grammatical pronoun index (GPI) for the groups and the individual speakers with agrammatism. We also conducted a qualitative analysis to look for adaptive strategies. Results Four individuals with agrammatism out of six produced significantly fewer grammatical pronouns than the non-injured group in the autobiography task. The two individuals with agrammatism who did not significantly differ from the control group were more fluent than the other four. The exclusion of pronouns containing fixed expressions did not result in drastic changes. The pronoun-verb analysis showed that there is no consistent connection between subject pronoun production and verb finiteness. Conclusions Grammatical pronoun production is indeed more severely impaired in agrammatic production. Moreover, the impairment pattern varies across individuals with agrammatism. Variability is observed both across participants with agrammatism and across tasks, which may indicate the use of unique adaptive strategies, as predicted by the REF-model. [ABSTRACT FROM AUTHOR]

Pharmacological inhibition of PSD-95 is a promising therapeutic strategy in the treatment of stroke, and positive effects of monomeric and dimeric PSD-95 inhibitors have been reported in numerous studies. However, whether therapeutic effects will generalize to other types of acute brain injury such as traumatic brain injury (TBI), which has pathophysiological mechanisms in common with stroke, is currently uncertain. We have previously found a lack of neuroprotective effects of dimeric PSD-95 inhibitors in the controlled cortical impact model of TBI in rats. However, as no single animal model is currently able to mimic the complex and heterogeneous pathophysiology of TBI, it is necessary to assess treatment effects across a range of models. In this preliminary study we investigated the neuroprotective abilities of the dimeric PSD-95 inhibitor UCCB01-144 after fimbria-fornix (FF) transection in rats. UCCB01-144 or saline was injected into the lateral tail vein of rats immediately after sham surgery or FF-transection, and effects on spatial delayed alternation in a T-maze were assessed over a 28-day period. Task acquisition was significantly impaired in FF-transected animals, but there were no significant effects of UCCB01-144 on spatial delayed alternation after FF-transection or sham surgery, although decelerated learning curves were seen after treatment with UCCB01-144 in FF-transected animals. The results of the present study are consistent with previous research showing a lack of neuroprotective effects of PSD-95 inhibition in experimental models of TBI. [ABSTRACT FROM AUTHOR]

PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury ( TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD-95, UCCB01-147, on histopathology and long-term cognitive outcome after controlled cortical impact ( CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01-147 (10 mg/kg), the non-competitive NMDAR-receptor antagonist MK-801 (1 mg/kg) or saline immediately after injury. At 2 and 4 weeks post-trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801 provided robust neuroprotection against NMDA-induced toxicity in cultured cortical neurons, UCCB01-147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects of PSD-95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration. [ABSTRACT FROM AUTHOR]

Abstract: Serotonergic agonists may act neuroprotectively against brain injury. This study addressed the therapeutic potential of 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT), a selective 5-HT1A/7 receptor agonist, after mechanical brain injury, and evaluated its effects in terms of acquisition of an allocentric place learning task in a water maze. Rats were divided into 6 experimental groups, three of which were subjected to bilateral transection of fimbria-fornix (FF), while three groups were given control surgery (Sham). After surgery, within both the lesioned, and sham-operated animals, respectively, one group was administered a single dose of saline, one group was given a single dose (0.5mg/kg/b.w.) of 8-OH-DPAT, and one group was treated with daily administration of 8-OH-DPAT (0.5mg/kg/b.w.) for eight days. The acquisition of the water maze based place learning task started on the 8th day post-surgery and continued for 20days. The results show that the lesioned group subjected to repeated administration of 8-OH-DPAT demonstrated a significantly improved acquisition of the place learning task compared to the vehicle injected lesion group. In contrast, the lesioned group treated with a single administration displayed impaired performance compared to the baseline lesion group. There were no significant effects of the 8-OH-DPAT administration in the sham control groups. We conclude that only the repeated stimulation of the 5-HT1A/7 system was associated with beneficial, recovery enhancing effects. [Copyright &y& Elsevier]

Abstract: Excessive N-Methyl-d-aspartate receptor (NMDAR)-dependent production of nitric oxide (NO) is involved in the development and maintenance of chronic pain states, and is mediated by postsynaptic density protein-95 (PSD-95). By binding to both the NMDAR and neuronal NO synthase (nNOS), PSD-95 mediates a specific coupling between NMDAR activation and NO production. NMDAR antagonism shows anti-nociceptive action in humans and animal models of chronic pain but is associated with severe disturbances of cognitive and motor functions. An alternative approach to modulate the NMDAR-related activity is to perturb the NMDAR/PSD-95/nNOS complex by targeting PSD-95, thereby decreasing NO production without interfering with the NMDAR ion channel function. Here, we compared the effects of a dimeric PSD-95 inhibitor, UCCB01-125, and the NMDAR antagonist, MK-801, on mechanical hypersensitivity in the complete Freund''s adjuvant (CFA) model of inflammatory pain. To examine side-effect profiles we also compared the effects of UCCB01-125 and MK-801 in tests of attention, long-term memory, and motor performance. When administered concurrently with CFA, both MK-801 and UCCB01-125 prevented the development of CFA-induced mechanical hypersensitivity 1 and 24 h after treatment. Moreover, UCCB01-125 was found to reverse CFA-induced hypersensitivity when administered 24 h after CFA treatment, an effect lasting for at least 3 days. At the dose reducing hypersensitivity, MK-801 disrupted attention, long-term memory, and motor performance. By contrast, even high doses of UCCB01-125 were devoid of side-effects in these tests. The data suggest that PSD-95 inhibition is a feasible strategy to prevent both development and maintenance of chronic inflammatory pain, while avoiding NMDAR antagonism-related side-effects. [Copyright &y& Elsevier]

Abstract: This study presents an in vivo investigation of the arylpropylsulfonamide α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive modulator (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD). The pharmacokinetics of the drug were examined in male C57BL/6J mice and the drug concentration in blood plasma determined after subcutaneous injection of 1mg/kg b.w. This analysis revealed a rapid increase of the plasma concentration, peaking within 30min after administration with a T 1/2 of approximately 30min and a peak plasma concentration of about 2μM. Analysis of brain tissue homogenates also indicated blood–brain barrier permeability of the compound. Cognitive enhancing effects of the drug were then studied on place learning in male C57BL/6J mice in a water maze. In order to elucidate the potential positive effects of PIMSD on spatial learning the muscarinergic antagonist scopolamine was utilized, which is known to impair spatial learning ability. The mice were divided into four groups and subjected to two sequential subcutaneous injections administered 25min prior to behavioural testing: (1) vehicle/vehicle; (2) PIMSD/vehicle; (3) scopolamine/vehicle; (4) PIMSD/scopolamine. PIMSD at a dose of 3mg/kg b.w. was able to partially reverse the impairment given by 0.5mg/kg b.w. scopolamine. These results suggest that arylpropylsulfonamides such as PIMSD may have a therapeutic use in the enhancement of cognitive function and support the hypothesis that AMPA receptor potentiation is one mechanism that can be targeted for diseases of cognitive impairment. [Copyright &y& Elsevier]

Colorimetric sensing technology for the detection of explosives, drugs, and their precursor chemicals is an important and effective approach. In this work, we use various machine learning models to detect these substances from colorimetric sensing experiments conducted in controlled environments. The detection experiments based on the response of a colorimetric chip containing 26 chemo-responsive dyes indicate that homemade explosives (HMEs) such as hexamethylene triperoxide diamine (HMTD), triacetone triperoxide (TATP), and methyl ethyl ketone peroxide (MEKP) used in improvised explosives devices are detected with true positive rate (TPR) of 70-75%, 73-90% and 60-82% respectively. Time series classifiers such as Convolutional Neural Networks (CNN) are explored, and the results indicate that improvements can be achieved with the use of kinetics of the chemical responses. The use of CNNs is limited, however, to scenarios where a large number of measurements, typically in the range of a few hundred, of each analyte are available. Feature selection of important dyes using the Group Lasso (GPLASSO) algorithm indicated that certain dyes are more important in discrimination of an analyte from ambient air. This information could be used for optimizing the colorimetric sensor and extend the detection to more analytes.

Biologics such as peptides and proteins possess a number of attractive attributes that make them particularly valuable as therapeutics, including their high activity, high specificity, and low toxicity. However, one of the key challenges associated with this class of drugs is their propensity to aggregate. Given the safety and immunogenicity concerns related to polypeptide aggregates, it is particularly important to sensitively detect aggregates in therapeutic drug formulations as part of the quality control process. Here, we report the development of conformation-specific antibodies that recognize polypeptide aggregates composed of a GLP-1 receptor agonist (liraglutide) and their integration into a sensitive immunoassay for detecting liraglutide amyloid fibrils. We sorted single-chain antibody libraries against liraglutide fibrils using yeast surface display and magnetic-activated cell sorting, and identified several antibodies with high conformational specificity. Interestingly, these antibodies cross-react with amyloid fibrils formed by several other polypeptides, revealing that they recognize molecular features common to different types of fibrils. Moreover, we find that our immunoassay using these antibodies is >50-fold more sensitive than the conventional method for detecting liraglutide aggregation (Thioflavin T fluorescence). We expect that our systematic approach for generating a sensitive, aggregate-specific immunoassay can be readily extended to other biologics to improve the quality and safety of formulated drug products., (© 2020 Wiley Periodicals LLC.)

The left inferior frontal gyrus (IFG) is a key region for language comprehension and production. Previous studies point to a preferential involvement of left anterior IFG (aIFG) in lexical and semantic processes, while the posterior IFG (pIFG) has been implicated in supporting syntactic and phonological processes. Here we used focal neuronavigated transcranial magnetic stimulation (TMS) to probe the functional involvement of left IFG in lexical and grammatical processing at the sentence level. We applied 10 Hz TMS effective or sham bursts to left aIFG and pIFG, while healthy volunteers performed an adjective-noun production task contrasting grammatical and lexical determiners. For each trial, we measured the time from the stimulus onset to the moment of articulation (response time) and the time from articulation onset to the end of articulation (duration). Focal TMS of IFG generally delayed response times. The TMS-induced delay in response times was relatively stronger for the grammatical condition compared to the lexical condition, when TMS targeted aIFG. Articulation of the determiner was generally shorter in trials presenting grammatical determiners relative to lexical determiners. The shorter articulation time for grammar determiners was facilitated by effective TMS to pIFG. Together, the effects of TMS on task performance provide novel evidence for a joint involvement of anterior and posterior parts of left IFG in implementing grammatical determiners during language production, suggesting an involvement of aIFG in the initiation and pIFG in the production of grammatically appropriate verbal responses at the sentence level., (Copyright © 2020 Ishkhanyan, Michel Lange, Boye, Mogensen, Karabanov, Hartwigsen and Siebner.)

Sensitive detection of protein aggregates is important for evaluating the quality of biopharmaceuticals and detecting misfolded proteins in several neurodegenerative diseases. However, it is challenging to detect extremely low concentrations (<10 ppm) of aggregated protein in the presence of high concentrations of soluble protein. Glucagon, a peptide hormone used in the treatment of extreme hypoglycemia, is aggregation-prone and forms amyloid fibrils. Detection of glucagon fibrils using conformation-specific antibodies is an attractive approach for identifying such aggregates during process and formulation development. Therefore, we have used yeast surface display and magnetic-activated cell sorting to sort single-chain antibody libraries to identify antibody variants with high conformational specificity for glucagon fibrils. Notably, we find several high-affinity antibodies that display excellent selectivity for glucagon fibrils, and we have integrated these antibodies into a sensitive immunoassay. Surprisingly, the sensitivity of our assay-which involves direct (nonantibody mediated) glucagon immobilization in microtiter plates-can be significantly enhanced by pretreating the microtiter plates with various types of globular proteins before glucagon immobilization. Moreover, increased total concentrations of glucagon peptide also significantly improve the sensitivity of our assay, which appears to be due to the strong seeding activity of immobilized fibrils at high glucagon concentrations. Our final assay is highly sensitive (fibril detection limit of ~0.5-1 ppm) and is >20 times more sensitive than detection using a conventional, amyloid-specific fluorescent dye (Thioflavin T). We expect that this type of sensitive immunoassay can be readily integrated into the drug development process to improve the generation of safe and potent peptide therapeutics., (© 2019 Wiley Periodicals, Inc.)

Objectives: To identify studies concerning the effects of computer based cognitive rehabilitation (CBCR) on visuospatial neglect (VN) after stroke to summarize the current state of knowledge in this research field and make recommendations for future research., Methods: Four electronic databases were systematically searched. Authors of relevant studies were contacted to detect unpublished data or articles not found by searching databases. Data was extracted from included studies using predefined coding schemes and characteristics and results of individual studies were summarized qualitatively., Selection Criteria: Studies were included if at least 50% of the included patients had a stroke, if the studies explored the effects of CBCR as a primary intervention for rehabilitation of VN and if they included neuropsychological outcome measures for the presence of VN., Results: Seven studies were included. Six of the seven studies suggested positive effects of CBCR on VN after stroke. However, the study that did not find these effects was also the study with the strongest methodological quality. All included studies consisted of small samples, varied greatly in design and had various methodological limitations., Conclusion: Because the existing literature is very sparse and studies have various methodological limitations, it is currently not possible to either support or reject the effects of CBCR on VN after stroke. Future studies should aim to compare CBCR with active and passive control conditions and include larger samples in randomized and blinded designs.

The interaction between working memory and language processing is widely discussed in cognitive research. However, those studies often explore the relationship between language comprehension and working memory (WM). The role of WM is rarely considered in language production, despite some evidence suggesting a relationship between the two cognitive systems. This study attempts to fill that gap by using a complex span task during language production. We make our predictions based on the reorganization of elementary functions neurocognitive model, a usage based theory about grammatical status, and language production models. In accordance with these theories, we expect an overlap between language production and WM at one or more levels of language planning. Our results show that WM is involved at the phonological encoding level of language production and that adding WM load facilitates language production, which leads us to suggest that an extra task-specific storage is being created while the task is performed.

In the present communication, phenomenal consciousness, access consciousness and the closely related concept of working memory are presented in the context of a neurocognitive model-the REF (reorganization of elementary functions) framework. The REF framework is based on connectionist networks within which the 'units' are advanced processing modules called elementary functions (EFs). In this framework, the focus is on dynamically changeable 'strategies'-based on reorganizations of the connectivity between EFs-rather than on the more traditional 'cognitive functions'. The background for the REF framework and especially how the neural correlate of consciousness is understood within these models is summarized. According to the REF framework, phenomenal consciousness cannot 'overflow' availability of information for action. Phenomenal consciousness may, however, overflow working memory because working memory in the present context is seen as a surface phenomenon reflecting underlying dynamic strategies-influenced by both experience and situational factors.This article is part of the theme issue 'Perceptual consciousness and cognitive access'., (© 2018 The Author(s).)

In the present paper it is argued that the "neural correlate of consciousness" (NCC) does not appear to be a separate "module" - but an aspect of information processing within the neural substrate of various cognitive processes. Consequently, NCC can only be addressed adequately within frameworks that model the general relationship between neural processes and mental states - and take into account the dynamic connectivity of the brain. We presently offer the REFGEN (general reorganization of elementary functions) model as such a framework. This model builds upon and expands the REF (reorganization of elementary functions) and REFCON (of elementary functions and consciousness) models. All three models integrate the relationship between the neural and mental layers of description via the construction of an intermediate level dealing with computational states. The importance of experience based organization of neural and cognitive processes is stressed. The models assume that the mechanisms of consciousness are in principle the same as the basic mechanisms of all aspects of cognition - when information is processed to a sufficiently "high level" it becomes available to conscious experience. The NCC is within the REFGEN model seen as aspects of the dynamic and experience driven reorganizations of the synaptic connectivity between the neurocognitive "building blocks" of the model - the elementary functions.

The focus of the present article is the home and family environment of patients suffering acquired brain injury. In order to obtain the optimal outcome of posttraumatic cognitive rehabilitation it is important (a) to obtain a sufficient intensity of rehabilitative training, (b) to achieve the maximum degree of generalization from formalized training to the daily environment of the patient, and (c) to obtain the best possible utilization of "cognitive reserves" in the form of cognitive abilities and "strategies" acquired pretraumatically. Supplementing the institution-based cognitive training with (potentially computer-based) home-based training these three goals may more easily be met. Home-based training supports a higher intensity of training. Training in the home environment also allows better utilization of cognitive strategies acquired pretraumatically and more direct transfer of training results from formalized training to activities of daily living of the patient.

Acquired brain injury (ABI) severely affects both the injured patient and her/his family. This fact alone calls for a therapeutic approach addressing not only the individual victim of ABI but also her/his family. Additionally, the optimal outcome of posttraumatic cognitive rehabilitation may be best obtained by supplementing the institution-based cognitive training with home-based training. Moving cognitive training and other therapeutic interventions into the home environment does, however, constitute an additional challenge to the family structure and psychological wellbeing of all family members. We presently argue in favour of an increased utilization of family-based intervention programs for the families of brain injured patients - in general and especially in case of utilization of home-based rehabilitative training.

Studies have shown that exercise can positively influence cognitive performance after brain injury. This study investigated the effects of different exercise regimens on allocentric place learning after fimbria‑fornix (FF) transection. One hundred and sixteen pre‑shaped rats were subjected either to a mechanical transection of the FF or control sham surgery and divided into following groups: i) no exercise (NE), ii) voluntary exercise in a running wheel (RW), iii) forced swimming exercise administered as interval training of short (3x5 min) duration (FS‑SI), iv) forced swimming exercise administered as interval training of long (3x15 min) duration (FS‑LI), v) forced swimming exercise administered as one session of short (5 min) duration (FS‑SS), and vi) forced swimming exercise administered as one session of long (15 min) duration (FS‑LS). The exercise was initiated 21 days post‑surgery. Subsequently, all animals were administered 28 acquisition sessions in an 8‑arm radial maze. Both sham operated and lesioned animals showed a significant learning response, however, the lesion induced a marked and lasting impairment, which was not alleviated neither by voluntary nor forced (spaced or one‑session only) exercise regimens. Exercise regimens had no effect on the place learning of control sham animals. We conclude that the lesion location as well as factors related to the exercise‑ and cognitive testing protocols can profoundly influence the potential of exercise as a general recovery‑promoting method.

The postoperative well-being of Wistar rats subjected to fimbria-fornix transections was assessed using a functional observational battery (FOB), including observations of relative body weight change, general condition, fur quality, body posture and movement, appetite, and pica behavior. Fimbria-fornix transected animals (FF), sham-operated animals (Sham), and two non-operated control groups with and without administration of buprenorphine (+BUP and -BUP, respectively) were observed twice daily for seven days after surgery. Buprenorphine (0.4 mg/kg) mixed in a nut paste for voluntary ingestion was supplied twice daily for 84 h to all groups except the -BUP control group starting on the day of surgery. Body weight was slightly decreased postoperatively in both surgical groups (FF and Sham) compared to control groups. The +BUP control group lost weight starting at day four after discontinuation of buprenorphine. Furthermore, the FF group exhibited significantly reduced general condition one day after surgery, with significantly affected body posture and movement for two days after surgery. In addition, mild pica behavior was observed in the FF group during the first postsurgical day. In conclusion, the FOB implemented in the present study appears to be a sensitive and accurate protocol for assessing animal well-being in the experimental setup applied. It is apparent that the FF transection is an invasive procedure that causes mildly adverse postoperative effects on the rats' well-being. We therefore recommend that this FOB is applied as a routine welfare monitoring protocol in experiments using mechanical central nervous system injury models, such as FF transection., (Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Concerns that raisins may be contaminated by fumonisins stem from the persistent occurrence of Aspergillus niger spores on raisins and the recent discovery of fumonisin production by A. niger on grapes, which leads to the widespread occurrence of fumonisin B(2) in wine. This study presents an LC-MS/MS survey of fumonisins in retail raisins. In 10 of 21 brands collected in Denmark, Germany, and The Netherlands, fumonisins B(2) and B(4) were detected at levels up to 13 and 1.3 μg/kg, respectively. Only fumonisin B(2) has been detected in wine, so the presence of fumonisin B(4) in raisins suggests that the fumonisins are produced mainly during the drying process concomitant with the decreasing water activity. Analysis of multiple packages from one manufacturer showed a 3-fold package-to-package variation, suggesting that a few raisins per package are contaminated.

The recent discovery of fumonisin production in Aspergillus niger, raises concerns about the presence of these mycotoxins in grapes and raisins as well as other commodities where A. niger is a frequent contaminant. Here we investigate the potential production of fumonisins in A. niger cultured on grapes and raisins. Sixty-six A. niger, 4 A. tubingensis, and 16 A. acidus strains isolated from raisins were tested for fumonisin production on laboratory media. Neither A. tubingensis nor A. acidus strains produced fumonisins, but 77% of A. niger strains did. None of the strains produced ochratoxin A. Ten selected fumonisin producing A. niger strains were further able to produce fumonisin B(2) and fumonisin B(4) on grapes in the range 171-7841 microg fumonisin B(2)/kg and 14-1157 microg fumonisin B(4)/kg. Four selected strains were able to produce fumonisin B(2) (5-6476 microg/kg) and fumonisin B(4) (12-672 microg/kg) on raisins.