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We explored the behavioral flexibility of Commissaris's long-tongued bats through a spatial serial reversal foraging task. Bats kept in captivity for short periods were trained to obtain nectar rewards from two artificial flowers. At any given time, only one of the flowers provided rewards and these reward contingencies reversed in successive blocks of 50 flower visits. All bats detected and responded to reversals by making most of their visits to the currently active flower. As the bats experienced repeated reversals, their preference re-adjusted faster. Although the flower state reversals were theoretically predictable, we did not detect anticipatory behavior, that is, frequency of visits to the alternative flower did not increase within each block as the programmed reversal approached. The net balance of these changes was a progressive improvement in performance in terms of the total proportion of visits allocated to the active flower. The results are compatible with, but do not depend on, the bats displaying an ability to 'learn to learn' and show that the dynamics of allocation of effort between food sources can change flexibly according to circumstances.
\n \n\n \n \nLight enables vision and exerts widespread effects on physiology and behavior, including regulating circadian rhythms, sleep, hormone synthesis, affective state, and cognitive processes. Appropriate lighting in animal facilities may support welfare and ensure that animals enter experiments in an appropriate physiological and behavioral state. Furthermore, proper consideration of light during experimentation is important both when it is explicitly employed as an independent variable and as a general feature of the environment. This Consensus View discusses metrics to use for the quantification of light appropriate for nonhuman mammals and their application to improve animal welfare and the quality of animal research. It provides methods for measuring these metrics, practical guidance for their implementation in husbandry and experimentation, and quantitative guidance on appropriate light exposure for laboratory mammals. The guidance provided has the potential to improve data quality and contribute to reduction and refinement, helping to ensure more ethical animal use.
\n \n\n \n \nTDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as \"TDP-43 proteinopathies\". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ~50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3\u202fmonths of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6\u202fmonths of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3\u202fmonths of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12\u202fmonths of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.
\n \n\n \n \nBACKGROUND: Gender clinic and single-item questionnaire-based data report increased co-occurrence of gender diversity and neurodevelopmental conditions. The nuances of these associations are under-studied. We used a transdiagnostic approach, combining categorical and dimensional characterization of neurodiversity, to further the understanding of its associations with gender diversity in identity and expression in children. METHODS: Data from 291 children (Autism N\u2009=\u2009104, ADHD N\u2009=\u2009104, Autism\u2009+\u2009ADHD N\u2009=\u200917, neurotypical N\u2009=\u200966) aged 4-12\u2009years enrolled in the Province of Ontario Neurodevelopmental Network were analyzed. Gender diversity was measured multi-dimensionally using a well-validated parent-report instrument, the Gender Identity Questionnaire for Children (GIQC). We used gamma regression models to determine the significant correlates of gender diversity among age, puberty, sex-assigned-at-birth, categorical neurodevelopmental diagnoses, and dimensional neurodivergent traits (using the Social Communication Questionnaire and the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scales). Internalizing and externalizing problems were included as covariates. RESULTS: Neither a categorical diagnosis of autism nor ADHD significantly correlated with current GIQC-derived scores. Instead, higher early-childhood dimensional autistic social-communication traits correlated with higher current overall gender incongruence (as defined by GIQC-14 score). This correlation was potentially moderated by sex-assigned-at-birth: greater early-childhood autistic social-communication traits were associated with higher current overall gender incongruence in assigned-males-at-birth, but not assigned-females-at-birth. For fine-grained gender diversity domains, greater autistic restricted-repetitive behavior traits were associated with greater diversity in gender identity across sexes-assigned-at-birth; greater autistic social-communication traits were associated with lower stereotypical male expression across sexes-assigned-at-birth. CONCLUSIONS: Dimensional autistic traits, rather than ADHD traits or categorical neurodevelopmental diagnoses, were associated with gender diversity domains across neurodivergent and neurotypical children. The association between early-childhood autistic social-communication traits and overall current gender diversity was most evident in assigned-males-at-birth. Nuanced interrelationships between neurodivergence and gender diversity should be better understood to clarify developmental links and to offer tailored support for neurodivergent and gender-diverse populations.
\n \n\n \n \nRecent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G\u2009>\u2009A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of \u03b17 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human \u03b17 receptors using fluorescent protein tagged \u03b17 nAChR and F\u00f6rster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-\u03b1-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of \u03b17 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and \u03b17 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and \u03b17, which translates to decreased cell surface and functional expression of \u03b17 nAChR.
\n \n\n \n \nOBJECTIVES: Most lifetime mental health problems (MHP) start before the age of 25. Yet young people-particularly those of minority backgrounds-often do not seek or access professional help. In the UK, young people of Eastern European (EE) backgrounds represent a large minority group; however, little is known about their experiences of MHP and help-seeking. In this study, we aim to understand the help-seeking process from the perspectives of EE young people. DESIGN: We used a qualitative study design with semi-structured individual interviews. The results were analysed using reflexive thematic analysis. METHOD: Twelve young people (18-25\u2009years) of EE backgrounds, living in Oxfordshire, UK, took part. All participants had experienced a severe MHP and were identified in the community. RESULTS: EE young people's experiences of MHP and help-seeking were driven by a sense of being caught between different cultures and simultaneously needing to navigate the potentially contrasting expectations of both cultures. This process was reinforced or tempered by the perceived continuing influence of young people's families, that is, families with more open views about MHP made it easier for young people to navigate through the process of help-seeking. Young people's internalised cultural and familial beliefs about MHP affected their decision-making when experiencing difficulties, their levels of trust in services, and perceived sense of resourcefulness and ability to cope. CONCLUSIONS: Recognising and responding to the cultural tension that young people of EE backgrounds may experience can help us to develop more accessible and inclusive mental health services.
\n \n\n \n \nLearning regularities in the environment is a fundamental of human cognition that is supported by a network of brain regions that include the hippocampus. In two experiments, we assessed the effects of selective bilateral damage to human hippocampal subregion CA3, which was associated with autobiographical episodic amnesia extending\u2009~50\u2009years prior to the damage, on the ability to recognize complex, deterministic event sequences presented either in a spatial or a non-spatial configuration. In contrast to findings from related paradigms, modalities, and homologue species, hippocampal damage did not preclude recognition memory for an event sequence studied and tested at four spatial locations, whereas recognition memory for an event sequence presented at single location was at chance. In two additional experiments, recognition memory for novel single-items was intact, whereas the ability to recognize novel single-items in a different location from that presented at study was at chance. The results are at variance with a general role of the hippocampus in the learning and recognition of complex event sequences based on non-adjacent spatial and temporal dependencies. We discuss the impact of the results on established theoretical accounts of the hippocampal contributions to implicit sequence learning and episodic memory.
\n \n\n \n \nThe Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of \"Pushing the Forefront of Neuromodulation\". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.
\n \n\n \n \nBrain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased \u03b2-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.
\n \n\n \n \nA major subpopulation of midbrain 5-hydroxytryptamine (5-HT) neurons expresses the vesicular glutamate transporter 3 (VGLUT3) and co-releases 5-HT and glutamate, but the function of this co-release is unclear. Given the strong links between 5-HT and uncontrollable stress, we used a combination of c-Fos immunohistochemistry and conditional gene knockout mice to test the hypothesis that glutamate co-releasing 5-HT neurons are activated by stress and involved in stress coping. Acute, uncontrollable swim stress increased c-Fos immunoreactivity in neurons co-expressing VGLUT3 and the 5-HT marker tryptophan hydroxylase 2 (TPH2) in the dorsal raphe nucleus (DRN). This effect was localized in the ventral DRN subregion and prevented by the antidepressant fluoxetine. In contrast, a more controllable stressor, acute social defeat, had no effect on c-Fos immunoreactivity in VGLUT3-TPH2 co-expressing neurons in the DRN. To test whether activation of glutamate co-releasing 5-HT neurons was causally linked to stress coping, mice with a specific deletion of VGLUT3 in 5-HT neurons were exposed to acute swim stress. Compared to wildtype controls, the mutant mice showed increased climbing behavior, a measure of active coping. Wildtype mice also showed increased climbing when administered fluoxetine, revealing an interesting parallel between the behavioral effects of genetic loss of VGLUT3 in 5-HT neurons and 5-HT reuptake inhibition. We conclude that 5-HT-glutamate co-releasing neurons are recruited by exposure to uncontrollable stress. Furthermore, natural variation in the balance of 5-HT and glutamate co-released at the 5-HT synapse may impact stress susceptibility.
\n \n\n \n \nA reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer's disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer's disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein \u03b54 allele carriership and the relationship with cognition. Seven hundred participants aged 40-59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3\u2005T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein \u03b54 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dementia family history. Larger volumes of the thalamus (P = 0.016) and posterior thalamus (Pfalse discovery rate = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein \u03b54 allele carriers. We did not find significant volumetric differences in thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without a dementia family history but have little effect on those with a dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein \u03b54 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.
\n \n\n \n \nSpinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is 'burnt out' and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.
\n \n\n \n \nPURPOSE: The delay alternating with nutation for tailored excitation (DANTE)-sampling perfection with application-optimized contrasts (SPACE) sequence facilitates 3D intracranial vessel wall imaging with simultaneous suppression of blood and CSF. However, the achieved image contrast depends closely on the selected sequence parameters, and the clinical use of the sequence is limited in vivo by observed signal variations in the vessel wall, CSF, and blood. This paper introduces a comprehensive DANTE-SPACE simulation framework, with the aim of providing a better understanding of the underlying contrast mechanisms and facilitating improved parameter selection and contrast optimization. METHODS: An extended phase graph formalism was developed for efficient spin ensemble simulation of the DANTE-SPACE sequence. Physiological processes such as pulsatile flow velocity variation, varying flow directions, intravoxel velocity variation, diffusion, and B 1 + $$ {\\mathrm{B}}_1^{+} $$ effects were included in the framework to represent the mechanisms behind the achieved signal levels accurately. RESULTS: Intravoxel velocity variation improved temporal stability and robustness against small velocity changes. Time-varying pulsatile velocity variation affected CSF simulations, introducing periods of near-zero velocity and partial rephasing. Inclusion of diffusion effects was found to substantially reduce the CSF signal. Blood flow trajectory variations had minor effects, but B 1 + $$ {\\mathrm{B}}_1^{+} $$ differences along the trajectory reduced DANTE efficiency in low- B 1 + $$ {\\mathrm{B}}_1^{+} $$ areas. Introducing low-velocity pulsatility of both CSF and vessel wall helped explain the in vivo observed signal heterogeneity in both tissue types. CONCLUSION: The presented simulation framework facilitates a more comprehensive optimization of DANTE-SPACE sequence parameters. Furthermore, the simulation framework helps to explain observed contrasts in acquired data.
\n \n\n \n \nKKT4 is a multi-domain kinetochore protein specific to kinetoplastids, such as Trypanosoma brucei. It lacks significant sequence similarity to known kinetochore proteins in other eukaryotes. Our recent X-ray structure of the C-terminal region of KKT4 shows that it has a tandem BRCT (BRCA1 C\u00a0Terminus) domain fold with a sulfate ion bound in a typical binding site for a phosphorylated serine or threonine. Here we present the 1H, 13C and 15N resonance assignments for the BRCT domain of KKT4 (KKT4463-645) from T. brucei. We show that the BRCT domain can bind phosphate ions in solution using residues involved in sulfate ion binding in the X-ray structure. We have used these assignments to characterise the secondary structure and backbone dynamics of the BRCT domain in solution. Mutating the residues involved in phosphate ion binding in T. brucei KKT4 BRCT\u00a0results in growth defects confirming the importance of the BRCT phosphopeptide-binding activity in vivo. These results may facilitate rational drug design efforts in the future to combat diseases caused by kinetoplastid parasites.
\n \n\n \n \nBACKGROUND: Daydreaming may contribute to the maintenance of grandiose delusions. Repeated, pleasant and vivid daydreams about the content of grandiose delusions may keep the ideas in mind, elaborate the details, and increase the degree of conviction in the delusion. Pleasant daydreams more generally could contribute to elevated mood, which may influence the delusion content. AIMS: We sought to develop a brief questionnaire, suitable for research and clinical practice, to assess daydreaming and test potential associations with grandiosity. METHOD: 798 patients with psychosis (375 with grandiose delusions) and 4518 non-clinical adults (1788 with high grandiosity) were recruited. Participants completed a daydreaming item pool and measures of grandiosity, time spent thinking about the grandiose belief, and grandiose belief conviction. Factor analysis was used to derive the Qualities of Daydreaming Scale (QuOD) and associations were tested using pairwise correlations and structural equation modelling. RESULTS: The questionnaire had three factors: realism, pleasantness, and frequency of daydreams. The measure was invariant across clinical and non-clinical groups. Internal consistency was good (alpha-ordinals: realism=0.86, pleasantness=0.93, frequency=0.82) as was test-retest reliability (intra-class coefficient=0.75). Daydreaming scores were higher in patients with grandiose delusions than in patients without grandiose delusions or in the non-clinical group. Daydreaming was significantly associated with grandiosity, time spent thinking about the grandiose delusion, and grandiose delusion conviction, explaining 19.1, 7.7 and 5.2% of the variance in the clinical group data, respectively. Similar associations were found in the non-clinical group. CONCLUSIONS: The process of daydreaming may be one target in psychological interventions for grandiose delusions.
\n \n\n \n \nWhat drives our curiosity remains an elusive and hotly debated issue, with multiple hypotheses proposed but a cohesive account yet to be established. This review discusses traditional and emergent theories that frame curiosity as a desire to know and a drive to learn, respectively. We adopt a model-based approach that maps the temporal dynamics of various factors underlying curiosity-based exploration, such as uncertainty, information gain, and learning progress. In so doing, we identify the limitations of past theories and posit an integrated account that harnesses their strengths in describing curiosity as a tool for optimal environmental exploration. In our unified account, curiosity serves as a 'common currency' for exploration, which must be balanced with other drives such as safety and hunger to achieve efficient action.
\n \n\n \n \nAdolescence is a timed process with an onset, tempo, and duration. Nevertheless, the temporal dimension, especially the pace of maturation, remains an insufficiently studied aspect of developmental progression. The primary objective is to estimate the precise influence of pubertal maturational tempo on the configuration of associative brain regions. To this end, the connection between maturational stages and the level of hierarchical organization of large-scale brain networks in 12-13-year-old females is analyzed. Skeletal maturity is used as a proxy for pubertal progress. The degree of maturity is defined by the difference between bone age and chronological age. To assess the level of hierarchical organization in the brain, the temporal dynamic of closed eye resting state high-density electroencephalography (EEG) in the alpha frequency range is analyzed. Different levels of hierarchical order are captured by the measured asymmetry in the directionality of information flow between different regions. The calculated EEG-based entropy production of participant groups is then compared with accelerated, average, and decelerated maturity. Results indicate that an average maturational trajectory optimally aligns with cerebral hierarchical order, and both accelerated and decelerated timelines result in diminished cortical organization. This suggests that a \"Goldilocks rule\" of brain development is favoring a particular maturational tempo.
\n \n\n \n \nSpecies distribution modeling is widely used to quantify and predict species-environment relationships. Most past applications and methods in species distribution modeling assume context independent and stationary relationships between patterns of species occurrence and environmental variables. There has been relatively little research investigating context dependence and nonstationarity in species distribution modeling. In this paper we explore spatially varying limiting factors in species-environment relationships using high resolution telemetry data from 14 individual wildcat hybrids distributed across geographical and environmental gradients in Scotland. (1) We proposed that nonstationary limiting factors would be indicated by significant association between statistical measures of variability of predictors and the predictive importance of those variables. (2) We further proposed that most of the limiting factor relationships observed would be related to spatial variation and a lesser amount to mean value of environmental variables within individual study sites. (3) Additionally, we anticipated that when there was a relationship between variation of an environmental factor and its importance as a predictor this relationship would be positive, such that higher variation would be associated with higher importance of the variable as a predictor (following the theory of limiting factors). (4) Conversely, we proposed that when there was a relationship between the mean value of an environmental variable and its importance as a predictor this relationship would be roughly evenly split between positive and negative relationships, given that environmental variables could become limiting either when they are highly abundant or high value, or when they are rare or low value in a particular landscape, depending on the nature of the species-environment relationship for that ecological variable. (5) Finally, we hypothesized that the frequency of supported limiting factor relationships would differ among variable groups, with variables that were directly related to key environmental resources more likely to be limiting than those that would have more indirect impacts on wildcat hybrid habitat selection or foraging. Our results show that assumptions of global, stationary habitat associations are likely not met in many habitat models, requiring explicit consideration of scale and context dependence in a nonstationary modeling paradigm. We found that both the mean value and the standard deviation are strong predictors of whether that variable will be limiting and differentially important as a predictor of occurrence. We confirmed that limiting factors become more limiting when it has higher variability across the sampled data, or when it is rare or not abundant. The frequency of supported limiting factor relationships differed among variable groups, with variables that were directly related to environmental resources likely to be essential for wildcat hybrid ecology more likely to be limiting than those that would have more indirect impacts on wildcat hybrid habitat selection or foraging.
\n \n\n \n \nBACKGROUND: Cognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized. Whether objectively measurable cognitive deficits exist and how long they persist are unclear. METHODS: We invited 800,000 adults in a study in England to complete an online assessment of cognitive function. We estimated a global cognitive score across eight tasks. We hypothesized that participants with persistent symptoms (lasting \u226512 weeks) after infection onset would have objectively measurable global cognitive deficits and that impairments in executive functioning and memory would be observed in such participants, especially in those who reported recent poor memory or difficulty thinking or concentrating (\"brain fog\"). RESULTS: Of the 141,583 participants who started the online cognitive assessment, 112,964 completed it. In a multiple regression analysis, participants who had recovered from Covid-19 in whom symptoms had resolved in less than 4 weeks or at least 12 weeks had similar small deficits in global cognition as compared with those in the no-Covid-19 group, who had not been infected with SARS-CoV-2 or had unconfirmed infection (-0.23 SD [95% confidence interval {CI}, -0.33 to -0.13] and -0.24 SD [95% CI, -0.36 to -0.12], respectively); larger deficits as compared with the no-Covid-19 group were seen in participants with unresolved persistent symptoms (-0.42 SD; 95% CI, -0.53 to -0.31). Larger deficits were seen in participants who had SARS-CoV-2 infection during periods in which the original virus or the B.1.1.7 variant was predominant than in those infected with later variants (e.g., -0.17 SD for the B.1.1.7 variant vs. the B.1.1.529 variant; 95% CI, -0.20 to -0.13) and in participants who had been hospitalized than in those who had not been hospitalized (e.g., intensive care unit admission, -0.35 SD; 95% CI, -0.49 to -0.20). Results of the analyses were similar to those of propensity-score-matching analyses. In a comparison of the group that had unresolved persistent symptoms with the no-Covid-19 group, memory, reasoning, and executive function tasks were associated with the largest deficits (-0.33 to -0.20 SD); these tasks correlated weakly with recent symptoms, including poor memory and brain fog. No adverse events were reported. CONCLUSIONS: Participants with resolved persistent symptoms after Covid-19 had objectively measured cognitive function similar to that in participants with shorter-duration symptoms, although short-duration Covid-19 was still associated with small cognitive deficits after recovery. Longer-term persistence of cognitive deficits and any clinical implications remain uncertain. (Funded by the National Institute for Health and Care Research and others.).
\n \n\n \n \nSimultaneous stoichiometric expression of multiple genes plays a major part in modern research and biotechnology. Traditional methods for incorporating multiple transgenes (or \"gene stacking\") have drawbacks such as long time frames, uneven gene expression, gene silencing, and segregation derived from the use of multiple promoters. 2A self-cleaving peptides have emerged over the last two decades as a functional gene stacking method and have been used in plants for the co-expression of multiple genes under a single promoter. Here we describe design features of multicistronic polyproteins using 2A peptides for co-expression in plant cells and targeting to the endoplasmic reticulum (ER). We designed up to quad-cistronic vectors that could target proteins in tandem to the ER. We also exemplify the incorporation of self-excising intein domains within 2A polypeptides, to remove residue additions. These features could aid in the design of stoichiometric protein co-expression strategies in plants in combination with targeting to different subcellular compartments.
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