Connecting the dots: Motor and default mode network crossroads in post-stroke motor learning deficits.

BACKGROUND: Strokes frequently result in long-term motor deficits, imposing significant personal and economic burdens. However, our understanding of the underlying neural mechanisms governing motor learning in stroke survivors remains limited - a fact that poses significant challenges to the development and optimisation of therapeutic strategies. OBJECTIVE: This study investigates the diversity in motor learning aptitude and its associated neurological mechanisms. We hypothesised that stroke patients exhibit compromised overall motor learning capacity, which is associated with altered activity and connectivity patterns in the motor- and default-mode-network in the brain. METHODS: We assessed a cohort of 40 chronic-stage, mildly impaired stroke survivors and 39 age-matched healthy controls using functional Magnetic Resonance Imaging (fMRI) and connectivity analyses. We focused on neural activity and connectivity patterns during an unilateral motor sequence learning task performed with the unimpaired or non-dominant hand. Primary outcome measures included task-induced changes in neural activity and network connectivity. RESULTS: Compared to controls, stroke patients showed significantly reduced motor learning capacity, associated with diminished cerebral lateralization. Task induced activity modulation was reduced in the motor network but increased in the default mode network. The modulated activation strength was associated with an opposing trend in task-induced functional connectivity, with increased connectivity in the motor network and decreased connectivity in the DMN. CONCLUSIONS: Stroke patients demonstrate altered neural activity and connectivity patterns during motor learning with their unaffected hand, potentially contributing to globally impaired motor learning skills. The reduced ability to lateralize cerebral activation, along with the enhanced connectivity between the right and left motor cortices in these patients, may signify maladaptive neural processes that impede motor adaptation, possibly affecting long-term rehabilitation post-stroke. The contrasting pattern of activity modulation and connectivity alteration in the default mode network suggests a nuanced role of this network in post-stroke motor learning. These insights could have significant implications for the development of customised rehabilitation strategies for stroke patients.

Novel lamprey antibody recognizes terminal sulfated galactose epitopes on mammalian glycoproteins.

The terminal galactose residues of N- and O-glycans in animal glycoproteins are often sialylated and/or fucosylated, but sulfation, such as 3-O-sulfated galactose (3-O-SGal), represents an additional, but poorly understood modification. To this end, we have developed a novel sea lamprey variable lymphocyte receptor (VLR) termed O6 to explore 3-O-SGal expression. O6 was engineered as a recombinant murine IgG chimera and its specificity and affinity to the 3-O-SGal epitope was defined using a variety of approaches, including glycan and glycoprotein microarray analyses, isothermal calorimetry, ligand-bound crystal structure, FACS, and immunohistochemistry of human tissue macroarrays. 3-O-SGal is expressed on N-glycans of many plasma and tissue glycoproteins, but recognition by O6 is often masked by sialic acid and thus exposed by treatment with neuraminidase. O6 recognizes many human tissues, consistent with expression of the cognate sulfotransferases (GAL3ST-2 and GAL3ST-3). The availability of O6 for exploring 3-O-SGal expression could lead to new biomarkers for disease and aid in understanding the functional roles of terminal modifications of glycans and relationships between terminal sulfation, sialylation and fucosylation.

Update on Campylobacter vaccine development.

Background: Acute diarrheal disease caused by viral, bacterial and parasitic infections are a major global health problem with substantial mortality and morbidity in children under five years of age in lower and middle income countries. However, a number of these infections also impact large segments of populations in upper income countries, as well as individuals who travel overseas for work, business or pleasure. Campylobacter has been and continues to be a leading cause of disease burden globally across all income countries. Aims: The aim of this review is to describe recent understanding in burden of disease, consider the current landscape of Campylobacter vaccine development, and address the challenges that need to be overcome. Sources: Relevant data from the literature as well as clinical trials described in European and US registries were used to conduct this review. Content: Despite advances in population health, food security, improved sanitation, water quality and the reduction of poverty, Campylobacter infections continue to plague global populations. The emerging recognition of chronic health consequences attributed to this pathogen is changing the potential valuation of preventive interventions. Advancing development of new vaccines is a present opportunity and holds promise.

Human DC-SIGN binds specific human milk glycans.

Human milk glycans (HMGs) are prebiotics, pathogen receptor decoys and regulators of host physiology and immune responses. Mechanistically, human lectins (glycan-binding proteins, hGBP) expressed by dendritic cells (DCs) are of major interest, as these cells directly contact HMGs. To explore such interactions, we screened many C-type lectins and sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed by DCs for glycan binding on microarrays presenting over 200 HMGs. Unexpectedly, DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) showed robust binding to many HMGs, whereas other C-type lectins failed to bind, and Siglec-5 and Siglec-9 showed weak binding to a few glycans. By contrast, most hGBP bound to multiple glycans on other microarrays lacking HMGs. An α-linked fucose residue was characteristic of HMGs bound by DC-SIGN. Binding of DC-SIGN to the simple HMGs 2'-fucosyl-lactose (2'-FL) and 3-fucosyl-lactose (3-FL) was confirmed by flow cytometry to beads conjugated with 2'-FL or 3-FL, as well as the ability of the free glycans to inhibit DC-SIGN binding. 2'-FL had an IC50 of ∼1 mM for DC-SIGN, which is within the physiological concentration of 2'-FL in human milk. These results demonstrate that DC-SIGN among the many hGBP expressed by DCs binds to α-fucosylated HMGs, and suggest that such interactions may be important in influencing immune responses in the developing infant.

Galectins are human milk glycan receptors.

The biological recognition of human milk glycans (HMGs) is poorly understood. Because HMGs are rich in galactose we explored whether they might interact with human galectins, which bind galactose-containing glycans and are highly expressed in epithelial cells and other cell types. We screened a number of human galectins for their binding to HMGs on a shotgun glycan microarray consisting of 247 HMGs derived from human milk, as well as to a defined HMG microarray. Recombinant human galectins (hGal)-1, -3, -4, -7, -8 and -9 bound selectively to glycans, with each galectin recognizing a relatively unique binding motif; by contrast hGal-2 did not recognize HMGs, but did bind to the human blood group A Type 2 determinants on other microarrays. Unlike other galectins, hGal-7 preferentially bound to glycans expressing a terminal Type 1 (Galß1-3GlcNAc) sequence, a motif that had eluded detection on non-HMG glycan microarrays. Interactions with HMGs were confirmed in a solution setting by isothermal titration microcalorimetry and hapten inhibition experiments. These results demonstrate that galectins selectively bind to HMGs and suggest the possibility that galectin-HMG interactions may play a role in infant immunity.

Microbial glycan microarrays define key features of host-microbial interactions.

Genomic approaches continue to provide unprecedented insight into the microbiome, yet host immune interactions with diverse microbiota can be difficult to study. We therefore generated a microbial microarray containing defined antigens isolated from a broad range of microbial flora to examine adaptive and innate immunity. Serological studies with this microarray show that immunoglobulins from multiple mammalian species have unique patterns of reactivity, whereas exposure of animals to distinct microbes induces specific serological recognition. Although adaptive immunity exhibited plasticity toward microbial antigens, immunological tolerance limits reactivity toward self. We discovered that several innate immune galectins show specific recognition of microbes that express self-like antigens, leading to direct killing of a broad range of Gram-negative and Gram-positive microbes. Thus, host protection against microbes seems to represent a balance between adaptive and innate immunity to defend against evolving antigenic determinants while protecting against molecular mimicry.

Allostatic load and work conditions.

Adverse work characteristics and poor social support have been associated with an increased risk for cardiovascular disease and other adverse health outcomes in otherwise apparently healthy adults. We undertook a cross-sectional study to evaluate the relationship between objective health status and work characteristics in industrial workers in Germany. Volunteers (n=324) were recruited from a representative random sample (n=537) of employees of an airplane manufacturing plant. Psychosocial work characteristics were assessed by the 52-item, 13-subscale salutogenetic subjective work analysis (SALSA) questionnaire, which assesses potentially salutogenic and pathogenic conditions. Factor analysis revealed three factors: decision latitude, job demands and social support. Biological health status was determined by the revised allostatic load score with 14 components: body-mass index, waist-to-hip ratio; systolic and diastolic blood pressure; plasma levels of C-reactive protein (CRP), tumor-necrosis factor-alpha, HDL, cholesterol, dehydroepiandrosterone sulfate; glycosylated hemoglobin; urinary cortisol, epinephrine, norepinephrine, and albumin. Score points were given for values in the high-risk quartile (maximum=14). General linear models revealed that older individuals and men had significantly higher allostatic load scores than younger participants or women. Of the SALSA factors, only job demands related significantly to allostatic load. The effect of demands was stronger in older individuals. Post-hoc analysis showed possible positive associations between high job demands and blood pressure or CRP, and between low social support and nocturnal excretion of cortisol or plasma levels of CRP. We conclude that this cross-sectional study on industrial employees found a weak association between a health summary score based on objective medical data and self-reported adverse work characteristics.

Assessment of exhaustion and related risk factors in employees in the manufacturing industry--a cross-sectional study.

OBJECTIVES: Vital exhaustion, a construct overlapping with burnout, is an independent risk factor for adverse health outcomes, including cardiovascular disease. We aimed to assess vital exhaustion in employees in the manufacturing industry and identify work characteristics associated with exhaustion. METHODS: Cross-sectional study. A stratified, representative random sample of employees from a manufacturing plant for airplane parts and assemblies was invited ( n=647), of whom 537 employees (83% accrual) volunteered to participate. Scores obtained by the nine-item Shortened Maastricht Exhaustion Questionnaire were compared with the mental and physical summary scales of the SF-12 General Health Survey and to a list of 20 health complaints. Pathogenic and salutogenic work characteristics were assessed by the self-reported 52-item, 13-subscale SALSA questionnaire. RESULTS: Vital exhaustion correlated with the mental summary score of the SF-12 and the number of health complaints and was positively associated with age. Exhaustion was not associated with gender, position (socio-economic status) or being on a wage (paid per completed item up to a contracted amount) or salary (payment as fixed monthly income). The instrument identified departments with high levels of exhaustion. Of the observed variance in exhaustion, 29% was explained by age, department, and five work characteristics: High levels of exhaustion (score >10) were related to excessive workload or qualitative demands (scoring in the highest quartile; OR(adj) 7.5; 95% CI 2.4-23), to adverse physical work conditions (OR(adj) 6.9; 95% CI 2.2-21), to adverse co-worker behavior (OR(adj) 4.8; 95% CI 1.4-16), to qualification potential (OR(adj) 0.32; 95% CI 0.11-0.97), and to social support by co-workers (OR(adj) 0.34; 95% CI 0.13-0.99), respectively. CONCLUSIONS: The nine-item instrument allows rapid screening of employees for self-reported levels of exhaustion. Besides physical work conditions and workload, absence or presence of social support by co-workers is strongly associated with exhaustion.