F8 Inversions at Xq28 Causing Hemophilia A Are Associated With Specific Methylation Changes: Implication for Molecular Epigenetic Diagnosis

Diverse DNA structural variations (SVs) in human cancers and several other diseases are well documented. For genomic inversions in particular, the disease causing mechanism may not be clear, especially if the inversion border does not cross a coding sequence. Understanding about the molecular processes of these inverted genomic sequences, in a mainly epigenetic context, may provide additional information regarding sequence-specific regulation of gene expression in human diseases. Herein, we study one such inversion hotspot at Xq28, which leads to the disruption of F8 gene and results in hemophilia A phenotype. To determine the epigenetic consequence of this rearrangement, we evaluated DNA methylation levels of 12 CpG rich regions with the coverage of 550 kb by using bisulfite-pyrosequencing and next-generation sequencing (NGS)-based bisulfite re-sequencing enrichment assay. Our results show that this inversion prone area harbors widespread methylation changes at the studied regions. However, only 5/12 regions showed significant methylation changes, specifically in case of intron 1 inversion (two regions), intron 22 inversion (two regions) and one common region in both inversions. Interestingly, these aberrant methylated regions were found to be overlapping with the inversion proximities. In addition, two CpG sites reached 100% sensitivity and specificity to discriminate wild type from intron 22 and intron 1 inversion samples. While we found age to be an influencing factor on methylation levels at some regions, covariate analysis still confirms the differential methylation induced by inversion, regardless of age. The hemophilia A methylation inversion “HAMI” assay provides an advantage over conventional PCR-based methods, which may not detect novel rare genomic rearrangements. Taken together, we showed that genomic inversions in the F8 (Xq28) region are associated with detectable changes in methylation levels and can be used as an epigenetic diagnostic marker

Western Beringia and beyond - three decades of German-Russian paleoenvironmental research on Siberian permafrost

With first joint fieldwork on Taymyr Peninsula during mid-1990s, a successful cooperation of German, Russian, and further international partners on permafrost and Quaternary palaeoenvironments in Siberia was started and resulted in extensive joint research for 3 decades. Studies of permafrost deposits and ground ice provided insights on past environmental and climatic changes, covering several hundreds of thousands of years into the past. They provide multi-proxy evidence for multiple glacial/interglacial cycles and different periods of past climate change or stability in Arctic land environments. Study objects were natural permafrost exposures along coastal sections, thaw slumps, and river banks, studied mostly during summers, complemented by permafrost cores from land, lake and sea ground drilled mostly in spring. Exposure geometry and stratigraphic horizon thickness have been surveyed using laser tachymetry, other measuring equipment, and drones. Based on multi-proxy analyses, mid- and late Quaternary periods were studied, resulting in >300 scientific papers. The approach includes geomorphic studies, various geochronological analyses, analysis of frozen sediments (for ice, carbon, nitrogen, and carbonate contents, grain-size parameters, magnetic susceptibility, heavy mineral compositions), ground ice (stable water isotopes, major ions) and of numerous fossil bioindicators, to reconstruct the Quaternary paleoenvironmental change. Oldest permafrost horizons were dated from the Batagay mega-thaw-slump (Yana Uplands) to about 650 ky with luminescence dating. Here and elsewhere, records of Eemian and Holocene interglacial periods, and environmental conditions associated with it were targeted. Many sites with late Pleistocene Yedoma Ice Complex have been explored. Lateglacial and Holocene warming induced enormous periglacial landscape changes by widespread permafrost degradation and substantial paleoecological changes. For vast Siberian areas where glacial records are not available, we aim on the establishment of permafrost as paleoclimatic archive, emphasizing peculiarities of permafrost age control and record resolution and stressing the great potential for understanding climate variability on glacial-interglacial timescales in Western Beringia

A review of the scientific knowledge of the seascape off Dronning Maud Land, Antarctica

Despite the exclusion of the Southern Ocean from assessments of progress towards achieving the Convention on Biological Diversity (CBD) Strategic Plan, the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) has taken on the mantle of progressing efforts to achieve it. Within the CBD, Aichi Target 11 represents an agreed commitment to protect 10% of the global coastal and marine environment. Adopting an ethos of presenting the best available scientific evidence to support policy makers, CCAMLR has progressed this by designating two Marine Protected Areas in the Southern Ocean, with three others under consideration. The region of Antarctica known as Dronning Maud Land (DML; 20°W to 40°E) and the Atlantic sector of the Southern Ocean that abuts it conveniently spans one region under consideration for spatial protection. To facilitate both an open and transparent process to provide the vest available scientific evidence for policy makers to formulate management options, we review the body of physical, geochemical and biological knowledge of the marine environment of this region. The level of scientific knowledge throughout the seascape abutting DML is polarized, with a clear lack of data in its eastern part which is presumably related to differing levels of research effort dedicated by national Antarctic programmes in the region. The lack of basic data on fundamental aspects of the physical, geological and biological nature of eastern DML make predictions of future trends difficult to impossible, with implications for the provision of management advice including spatial management. Finally, by highlighting key knowledge gaps across the scientific disciplines our review also serves to provide guidance to future research across this important region.publishedVersio

First results from the L3+C experiment at CERN

The L3+C experiment combines the high-precision spectrometer of the L3 detector at LEP, CERN, with a small air shower array. The momenta of cosmic ray induced muons can be measured from 20 to 2000 GeV/c. During the 1999 data taking period 5 billion muon events were recorded in the spectrometer. From April until mid Summer 2000 an additional 3 billion muon events have been recorded as well as 25 million air shower events. Here the first results on the muon momentum spectrum and charge ratio will be presented

Low but contrasting neutral genetic differentiation shaped by winter temperature in European great tits

Gene flow is usually thought to reduce genetic divergence and impede local adaptation by homogenising gene pools between populations. However, evidence for local adaptation and phenotypic differentiation in highly mobile species, experiencing high levels of gene flow, is emerging. Assessing population genetic structure at different spatial scales is thus a crucial step towards understanding mechanisms underlying intraspecific differentiation and diversification. Here, we studied the population genetic structure of a highly mobile species – the great tit Parus major – at different spatial scales. We analysed 884 individuals from 30 sites across Europe including 10 close-by sites (< 50 km), using 22 microsatellite markers. Overall we found a low but significant genetic differentiation among sites (FST = 0.008). Genetic differentiation was higher, and genetic diversity lower, in south-western Europe. These regional differences were statistically best explained by winter temperature. Overall, our results suggest that great tits form a single patchy metapopulation across Europe, in which genetic differentiation is independent of geographical distance and gene flow may be regulated by environmental factors via movements related to winter severity. This might have important implications for the evolutionary trajectories of sub-populations, especially in the context of climate change, and calls for future investigations of local differences in costs and benefits of philopatry at large scales

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.publishedVersio

Highlights From the Annual Meeting of the American Epilepsy Society 2022

With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery