On the developmental origins of human material culture

Material culture – tools, technology, and instrumental skills – has allowed humans to live in almost every habitat on earth. This thesis investigates the developmental roots of human material culture by examining basic tool-use skills and cultural learning abilities in young children. The introduction presents the concepts of the Zone of Latent Solutions (Tennie, Call, & Tomasello, 2009), cumulative culture, and Vygotsky’s (1978) theories as the theoretical background for the following five experiments. Chapter 2 identifies a list of tool-use behaviours that children can invent individually and thus represent an ontogenetic and phylogenetic basis of human tool culture. Chapter 3 extends this list by several behaviours involving the use of two tools in combination (Associative tool use). Chapter 4 focuses on a cultural behaviour that children can only acquire socially. It uses an adapted version of the spaghetti tower task (Caldwell & Millen, 2008a) to study whether children can copy a material cultural product that they could not have invented on their own and whether they can do so without action information. Chapter 5 uses the same task to investigate whether groups of children can produce a ratchet effect. The discussion summarizes the findings and presents limitations and directions for future research

Antibodies to myelin oligodendrocyte glycoprotein in HIV-1 associated neurocognitive disorder: a cross-sectional cohort study

<p>Abstract</p> <p>Background</p> <p>Neuroinflammation and demyelination have been suggested as mechanisms causing HIV-1 associated neurocognitive disorder (HAND). This cross-sectional cohort study explores the potential role of antibodies to myelin oligodendrocyte glycoprotein (MOG), a putative autoantigen in multiple sclerosis, in the pathogenesis of HAND.</p> <p>Methods</p> <p>IgG antibodies against MOG were measured by ELISA in sera and cerebrospinal fluid (CSF) of 65 HIV-positive patients with HAND (n = 14), cerebral opportunistic infections (HIVOI, n = 25), primary HIV infection (HIVM, n = 5) and asymptomatic patients (HIVasy, n = 21). As control group HIV-negative patients with bacterial or viral CNS infections (OIND, n = 18) and other neurological diseases (OND, n = 22) were included. In a subset of HAND patients MOG antibodies were determined before and during antiviral therapy.</p> <p>Results</p> <p>In serum, significantly higher MOG antibody titers were observed in HAND compared to OND patients. In CSF, significantly higher antibody titers were observed in HAND and HIVOI patients compared to HIVasy and OND patients and in OIND compared to OND patients. CSF anti-MOG antibodies showed a high sensitivity and specificity (85.7% and 76.2%) for discriminating patients with active HAND from asymptomatic HIV patients. MOG immunopositive HAND patients performed significantly worse on the HIV dementia scale and showed higher viral load in CSF. In longitudinally studied HAND patients, sustained antibody response was noted despite successful clearance of viral RNA.</p> <p>Conclusions</p> <p>Persistence of MOG antibodies despite viral clearance in a high percentage of HAND patients suggests ongoing neuroinflammation, possibly preventing recovery from HAND.</p

Patterns of Antibody Binding to Aquaporin-4 Isoforms in Neuromyelitis Optica

Neuromyelitis optica (NMO), a severe demyelinating disease, represents itself with optic neuritis and longitudinally extensive transverse myelitis. Serum NMO-IgG autoantibodies (Abs), a specific finding in NMO patients, target the water channel protein aquaporin-4 (AQP4), which is expressed as a long (M-1) or a short (M-23) isoform.The aim of this study was to analyze serum samples from patients with NMO and controls for the presence and epitope specificity of IgG and IgM anti-AQP4 Abs using an immunofluorescence assay with HEK293 cells expressing M-1 or M-23 human AQP4. We included 56 patients with definite NMO (n = 30) and high risk NMO (n = 26), 101 patients with multiple sclerosis, 27 patients with clinically isolated syndromes (CIS), 30 patients with systemic lupus erythematosus (SLE) or Sjögren's syndrome, 29 patients with other neurological diseases and 47 healthy controls. Serum anti-AQP4 M-23 IgG Abs were specifically detected in 29 NMO patients, 17 patients with high risk NMO and two patients with myelitis due to demyelination (CIS) and SLE. In contrast, IgM anti-AQP4 Abs were not only found in some NMO and high risk patients, but also in controls. The sensitivity of the M-23 AQP4 IgG assay was 97% for NMO and 65% for high risk NMO, with a specificity of 100% compared to the controls. Sensitivity with M-1 AQP4 transfected cells was lower for NMO (70%) and high risk NMO (39%). The conformational epitopes of M-23 AQP4 are the primary targets of NMO-IgG Abs, whereas M-1 AQP4 Abs are developed with increasing disease duration and number of relapses.Our results confirm M-23 AQP4-IgG Abs as reliable biomarkers in patients with NMO and high risk syndromes. M-1 and M-23 AQP4-IgG Abs are significantly associated with a higher number of relapses and longer disease duration

Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

<p>Abstract</p> <p>Background</p> <p>Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved.</p> <p>Results</p> <p>We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels.</p> <p>Conclusions</p> <p>We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.</p

Differential binding of autoantibodies to MOG isoforms in inflammatory demyelinating diseases

Objective: To analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases. Methods: Retrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA. Results: The strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA. Conclusions: The novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG

Validation of plasma biomarker candidates for the prediction of eGFR decline in patients with type 2 diabetes

Objective: The decline of estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes is variable and early interventions would likely be cost effective. We elucidated the contribution of 17 plasma biomarkers to the prediction of eGFR loss on top of clinical risk factors. Research Design and Methods: We studied participants in PROVALID, a prospective multinational cohort study of patients with type 2 diabetes and a follow up of more than 24 months (n = 2560; baseline median eGFR 84 mL/min/1.73m2, UACR 8.1 mg/g). The 17 biomarkers were measured at baseline in 481 samples using Luminex technology and ELISA. The prediction of eGFR decline was evaluated by linear mixed modeling. Results: In univariable analyses nine of the 17 markers showed significant differences in median concentration between the two groups. A linear mixed model for eGFR obtained by variable selection exhibited an adjusted R2 of 62%. A panel of twelve biomarkers was selected by the procedure and accounted for 34% of the total explained variability, of which 32% were due to five markers. Each biomarker’s individual contribution to the prediction of eGFR decline on top of clinical predictors was generally low. When included into the model, baseline eGFR exhibited the largest explained variability of eGFR decline (R2 of 79%) and the contribution of each biomarker dropped below 1%. Conclusions: In this longitudinal study of patients with type 2 diabetes and maintained eGFR at baseline, 12 of the 17 candidate biomarkers were associated with eGFR decline, but their predictive power was low

Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease

Objective To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. Methods Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG-and AQP4-antibodies using live cell-based assays. Results 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). Conclusions 67% of all children presenting with NMO or limited forms tested positive for MOG-or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes

Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome

Objective: To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS). Methods: Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study. Results: Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirtyfive children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p = 1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%. Conclusions: Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course

Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening

Newborn screening (NBS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) revealed a higher birth prevalence and genotypic variability than previously estimated, including numerous novel missense mutations in the ACADM gene. On average, these mutations are associated with milder biochemical phenotypes raising the question about their pathogenic relevance. In this study, we analyzed the impact of 10 ACADM mutations identified in NBS (A27V, Y42H, Y133H, R181C, R223G, D241G, K304E, R309K, I331T and R388S) on conformation, stability and enzyme kinetics of the corresponding proteins. Partial to total rescue of aggregation by co-overexpression of GroESL indicated protein misfolding. This was confirmed by accelerated thermal unfolding in all variants, as well as decreased proteolytic stability and accelerated thermal inactivation in most variants. Catalytic function varied from high residual activity to markedly decreased activity or substrate affinity. Mutations mapping to the β-domain of the protein predisposed to severe destabilization. In silico structural analyses of the affected amino acid residues revealed involvement in functionally relevant networks. Taken together, our results substantiate the hypothesis of protein misfolding with loss-of-function being the common molecular basis in MCADD. Moreover, considerable structural alterations in all analyzed variants do not support the view that novel mutations found in NBS bear a lower risk of metabolic decompensation than that associated with mutations detected in clinically ascertained patients. Finally, the detailed insight into how ACADM missense mutations induce loss of MCAD function may provide guidance for risk assessment and counseling of patients, and in future may assist delineation of novel pharmacological strategies

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

Genetic variation across the HLA is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the HLA is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with post‐transplant eGFR at different time‐points, out to 5‐years post‐transplantation. We conducted GWAS meta‐analyses across 10,844 donors and recipients from five European ancestry cohorts. We also analysed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with non‐transplant eGFR, on post‐transplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year post‐transplant. 32% of the variability in eGFR at 1‐year post‐transplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR post‐transplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a post‐transplant context. Despite PRS being a significant predictor of eGFR post‐transplant, the effect size of common genetic factors is limited compared to clinical variables