Lin's method for heteroclinic chains involving periodic orbits

We present an extension of the theory known as Lin's method to heteroclinic chains that connect hyperbolic equilibria and hyperbolic periodic orbits. Based on the construction of a so-called Lin orbit, that is, a sequence of continuous partial orbits that only have jumps in a certain prescribed linear subspace, estimates for these jumps are derived. We use the jump estimates to discuss bifurcation equations for homoclinic orbits near heteroclinic cycles between an equilibrium and a periodic orbit (EtoP cycles)

Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

Purpose: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. Methods: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. Results: Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. Conclusion: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease

Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries

BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease. METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data. FINDINGS: 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59·8% (95% CI 50·8–68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7–48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4–34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5–94·0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50·0%, 15·7–84·3) compared with those without HIV (61·0%, 51·6–69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% of children with microbiologically confirmed tuberculosis. INTERPRETATION: MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung; German Center for Infection Research (DZIF)

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

In situ measurements of respiration and mineralisation processes - Interaction between fauna and geochemical fluxes at active interfaces.

The main aim of this thesis was to show the importance of in situ data for achieving a reliable record for the estimation of the interaction between geochemical processes and fauna in the processes of organic carbon degradation and energy utilization. It could be shown that multidisciplinary approaches made the quantitative determination of many single processes within carbon cycling and energy transfer possible. The effect of daily migrating macrofauna for the organic carbon transport and oxygen consumption in the benthic boundary layer could be shown by the use of a profiling lander, a chamber lander and pore water profiles. Calculated on an area basis the oxygen consumption and therefore the carbon oxidation of the animals was 25-fold higher than the turnover rates of the sediment. This study showed three examples of the effects that fauna has on transportation processes at the sediment / water interface and effects that geochemical conditions have on the development of biological systems and adaptations of animals.13

Dielectric spectroscopy on the quasi–one-dimensional organic charge density wave conductor (Fluoranthene)

Frequency-dependent complex conductivity measurements on the organic quasi–one-dimensional CDW system ${\rm (Fa)_2}{\rm PF}_6$ between $10^{-4}\,{\rm Hz}$ and $3\cdot10^9\,{\rm Hz}$ at temperatures ranging from 20 K to 290 K are reported. Below the temperature of the Peierls transition ($T_{\rm P}=182\,{\rm K}$) the real part of the conductivity exhibits two structures, which can be attributed to two modes of the charge density wave (CDW): a temperature-dependent low-frequency relaxational mode of local oscillating deformations and a high-frequency resonant mode of the pinned CDW as a whole. The measurements indicate that the damping of the relaxational mode is dominated by free carriers in the covered temperature range. At low temperatures the dynamics of the CDW in ${\rm(Fa)_2}{\rm PF_6}$ shows features characteristic of the transition into a glass-like state