Investigating the interplay between early life stress, acute secondary pathogenesis, and chronic hippocampal impairments in young mice with traumatic brain injury

While Traumatic brain injury (TBI) is the leading cause of disability in children, it is unclear how early life stress (ELS) may act as a determinant of long-term recovery in brain-injured children. A murine model of ELS preceding TBI at postnatal day (P)21 addressed the following: regionally specific acute pathogenesis of the hippocampus after ELS+TBI, are these early changes predictive of hippocampal damage and impairment at adulthood. Males and females were exposed to ELS (P2-9) with the limited bedding nestlet (LBN) model, randomized to TBI or sham, and euthanized at P22 or adulthood. At P22, ELISAs revealed an upregulation of IL1B, IL-6, TNFα, and IFNγ in both sexes after injury. ELS+TBI elevated IL-1B, IL-10, TNFα, and IFNγ in males compared to TBI. Iba-1 and caspase-3 were evaluated in hippocampal subregions. While TBI increased microglial density in both sexes, ELS+TBI increased microglial density in male CA2 and CA3 but only in the CA3 in females compared to TBI. Quantification of caspase-3 revealed apoptosis in males and females after TBI. ELS + TBI increased apoptosis in CA1 and CA3 in males and females compared to TBI. Adulthood learning and memory were assessed with the NOR and Barnes Maze. Compared to TBI, ELS+TBI reduced novelty preference in females and increased path length to target in both sexes. Hippocampal neuron loss after ELS+TBI was evaluated at adulthood. TBI significantly reduced neurons in all subregions; ELS+TBI reduced neurons in the CA1 region in females only. These findings highlight hippocampal vulnerability after ELS+TBI and ELS prior to a TBI may enhance acute pathogenesis in males. Correlation matrices determined hippocampal acute pathogenesis is predictive of neuronal loss at adulthood and is associated with learning and memory impairments. Males and females were assessed for all outcomes. Both sexes showed similar vulnerability to secondary pathogenesis following TBI and adulthood impairments in learning and memory; males showed greater vulnerability to acute pathogenesis and females showed greater vulnerability to adulthood outcomes. These findings may advocate for opportunities to tailor therapies specific to each sex. Thus, developing pre-clinical biomarkers to predict long-term recovery may continue to bolster care management.Psycholog

One species in eight : DNA barcodes from type specimens resolve a taxonomic quagmire

Each holotype specimen provides the only objective link to a particular Linnean binomen. Sequence information from them is increasingly valuable due to the growing usage of DNA barcodes in taxonomy. As type specimens are often old, it may only be possible to recover fragmentary sequence information from them. We tested the efficacy of short sequences from type specimens in the resolution of a challenging taxonomic puzzle: the Elachista dispunctella complex which includes 64 described species with minuscule morphological differences. We applied a multistep procedure to resolve the taxonomy of this species complex. First, we sequenced a large number of newly collected specimens and as many holotypes as possible. Second, we used all >400 bp examine species boundaries. We employed three unsupervised methods (BIN, ABGD, GMYC) with specified criteria on how to handle discordant results and examined diagnostic bases from each delineated putative species (operational taxonomic units, OTUs). Third, we evaluated the morphological characters of each OTU. Finally, we associated short barcodes from types with the delineated OTUs. In this step, we employed various supervised methods, including distance-based, tree-based and character-based. We recovered 658 bp barcode sequences from 194 of 215 fresh specimens and recovered an average of 141bp from 33 of 42 holotypes. We observed strong congruence among all methods and good correspondence with morphology. We demonstrate potential pitfalls with tree-, distance- and character-based approaches when associating sequences of varied length. Our results suggest that sequences as short as 56bp can often provide valuable taxonomic information. The results support significant taxonomic oversplitting of species in the Elachista dispunctella complex.Peer reviewe

'Return to Work' Coordinator Model and Work Participation of Employees: A Natural Intervention Study in Finland

Purpose Employers increasingly use 'return to work' (RTW) coordinators to support work ability and extend working careers, particularly among employees with reduced work ability. We examined whether applying this model was associated with changes in employee sickness absence and disability retirements. Methods We used data from the Finnish Public Sector study from 2009 until 2015. Employees where the model was introduced in 2012 constituted the cases (n = 4120, one municipality) and employees where the model was not in use during the follow-up, represented the controls (n = 5600, two municipalities). We analysed risk of disability retirement in 2013-2015 and risk of sickness absence after (2013-2015) vs. before (2009-2011) intervention by case-control status. Results The incidence of disability retirement after the intervention was lower in cases compared to controls both in the total population (hazard ratio HR = 0.49, 95% CI 0.30-0.79) and in the subgroup of participants with reduced work ability (HR = 0.34, 95% CI 0.12-0.99). The risk of sickness absence increased from pre-intervention to post-intervention period both among cases and controls although the relative increase was greater among cases (RRpost- vs. pre-intervention = 1.26, 95% CI 1.14-1.40) than controls (RRpost- vs. pre-intervention = 1.03, 95% CI 0.97-1.08). In the group of employees with reduced work ability, no difference in sickness absence trends between cases and controls was observed. Conclusions These findings suggest that RTW-coordinator model may increase employee sickness absence, but decrease the risk of disability retirement, i.e., permanent exclusion from the labour market

Delineating Species with DNA Barcodes : A Case of Taxon Dependent Method Performance in Moths

The accelerating loss of biodiversity has created a need for more effective ways to discover species. Novel algorithmic approaches for analyzing sequence data combined with rapidly expanding DNA barcode libraries provide a potential solution. While several analytical methods are available for the delineation of operational taxonomic units (OTUs), few studies have compared their performance. This study compares the performance of one morphology- based and four DNA-based (BIN, parsimony networks, ABGD, GMYC) methods on two groups of gelechioid moths. It examines 92 species of Finnish Gelechiinae and 103 species of Australian Elachistinae which were delineated by traditional taxonomy. The results reveal a striking difference in performance between the two taxa with all four DNA-based methods. OTU counts in the Elachistinae showed a wider range and a relatively low (ca. 65%) OTU match with reference species while OTU counts were more congruent and performance was higher (ca. 90%) in the Gelechiinae. Performance rose when only monophyletic species were compared, but the taxon-dependence remained. None of the DNA-based methods produced a correct match with non-monophyletic species, but singletons were handled well. A simulated test of morphospecies-grouping performed very poorly in revealing taxon diversity in these small, dull-colored moths. Despite the strong performance of analyses based on DNA barcodes, species delineated using single-locus mtDNA data are best viewed as OTUs that require validation by subsequent integrative taxonomic work.Peer reviewe

Improved control strategy of DFIG-based wind turbines using direct torque and direct power control techniques

This paper presents different control strategies for a variable-speed wind energy conversion system (WECS), based on a doubly fed induction generator. Direct Torque Control (DTC) with Space-Vector Modulation is used on the rotor side converter. This control method is known to reduce the fluctuations of the torque and flux at low speeds in contrast to the classical DTC, where the frequency of switching is uncontrollable. The reference for torque is obtained from the maximum power point tracking technique of the wind turbine. For the grid-side converter, a fuzzy direct power control is proposed for the control of the instantaneous active and reactive power. Simulation results of the WECS are presented to compare the performance of the proposed and classical control approaches.Peer reviewedFinal Accepted Versio

APOE epsilon 4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue : a Finnish biobank, autopsy and clinical study

Apolipoprotein E epsilon 4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.Peer reviewe

Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis

Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABAA receptors (GABAARs). The impact of changes in steady state Cl− gradient is relatively straightforward to understand, but how dynamic interplay between Cl− influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl− load on a fast time scale, whereas Cl−extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl− gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABAAR-mediated inhibition, but increasing GABAAR input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl−. Furthermore, if spiking persisted despite the presence of GABAAR input, Cl− accumulation became accelerated because of the large Cl− driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl− and pH regulation. Several model predictions were tested and confirmed by [Cl−]i imaging experiments. Our study has thus uncovered how Cl− regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K− accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention

Current status of clinical outcome measures in inclusion body myositis: a systematised review

OBJECTIVES: Sporadic inclusion body myositis (IBM) is a debilitating idiopathic inflammatory myopathy (IIM) which affects hand function, ambulation, and swallowing. There is no approved pharmacological therapy for IBM, and there is a lack of suitable outcome measure to assess the effect of an intervention. The IBM scientific interest group under IMACS reviewed the previously used outcome measures in IBM clinical studies to lay the path for developing a core set of outcome measures in IBM. METHODS: In this systematised review, we have extracted all outcome measures reported in IBM clinical studies to determine what measures were being used and to assess the need for optimising outcome measures in IBM. RESULTS: We found 13 observational studies, 17 open-label clinical trials, and 15 randomised control trials (RCTs) in IBM. Six-minute walk distance, IBM-functional rating scale (IBM-FRS), quantitative muscle testing, manual muscle testing, maximal voluntary isometric contraction testing, and thigh muscle volume measured by MRI were used as primary outcome measures. Twelve different outcome measures of motor function were used in IBM clinical trials. IBM-FRS was the most used measure of functionality. Swallowing function was reported as a secondary outcome measure in only 3 RCTs. CONCLUSIONS: There are inconsistencies in using outcome measures in clinical studies in IBM. The core set measures developed by the IMACS group for other IIMs are not directly applicable to IBM. As a result, there is an unmet need for an IBM-specific core set of measures to facilitate the evaluation of new potential therapeutics for IBM

SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission

SLC4A10 is a plasma-membrane bound transporter which utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of cerebrospinal fluid. Using next generation sequencing on samples from five unrelated families encompassing ten affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and typically severe intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorders including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioral abnormalities including delayed habituation and alterations in the 2-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggests an important role of SLC4A10 in the production of the cerebrospinal fluid. However, it is notable that despite diverse roles of the cerebrospinal fluid in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel characteristic neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties

GPVI and GPIbα Mediate Staphylococcal Superantigen-Like Protein 5 (SSL5) Induced Platelet Activation and Direct toward Glycans as Potential Inhibitors

Background Staphylococcus aureus (S. aureus) is a common pathogen capable of causing life-threatening infections. Staphylococcal superantigen-like protein 5 (SSL5) has recently been shown to bind to platelet glycoproteins and induce platelet activation. This study investigates further the interaction between SSL5 and platelet glycoproteins. Moreover, using a glycan discovery approach, we aim to identify potential glycans to therapeutically target this interaction and prevent SSL5-induced effects. Methodology/Principal Findings In addition to platelet activation experiments, flow cytometry, immunoprecipitation, surface plasmon resonance and a glycan binding array, were used to identify specific SSL5 binding regions and mediators. We independently confirm SSL5 to interact with platelets via GPIbα and identify the sulphated-tyrosine residues as an important region for SSL5 binding. We also identify the novel direct interaction between SSL5 and the platelet collagen receptor GPVI. Together, these receptors offer one mechanistic explanation for the unique functional influences SSL5 exerts on platelets. A role for specific families of platelet glycans in mediating SSL5-platelet interactions was also discovered and used to identify and demonstrate effectiveness of potential glycan based inhibitors in vitro. Conclusions/Significance These findings further elucidate the functional interactions between SSL5 and platelets, including the novel finding of a role for the GPVI receptor. We demonstrate efficacy of possible glycan-based approaches to inhibit the SSL5-induced platelet activation. Our data warrant further work to prove SSL5-platelet effects in viv