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Metal formates sometimes occur as degradation products on heritage objects due to the use of wood products or other sources of formic acid and formaldehyde. They are often related to alkaline surfaces which transform formaldehyde directly into formate. The dominant role of formate on alkaline surfaces, for example in glass-induced metal corrosion (GIM) or calcium carbonate degradation, was explored in the Stuttgart research on rare heritage corrosion products. This review discusses these findings together with those from the literature: ocurrences of sodium and potassium formate on glass, calcium formate and calcium acetate-formate phases on calcareous materials, magnesium formate on Sorel cement and dolomitic sandstone, lead formate on metal and pigments, cadmium formate on coated objects, as well as various copper and zinc formates on copper alloys. In the latter cases, formates dominate as glass-induced metal corrosion products. The formation of formates constitutes irreversible damage, degrading the material of heritage objects. Therefore, preventive conservation needs to remove all sources of carbonyl pollutants in order to avoid such corrosion.

Introduction Acute and late toxicity was analysed for prostate cancer patients with bilateral hip prostheses, who received fixed field intensity modulated radiotherapy (IMRT). The aims were (1) to establish whether toxicity rates differed from those of a control group with normal hips, (2) to develop a volumetric modulated arc therapy (VMAT) approach for patients with prostheses and (3) to compare doses to bladder and rectum for the control group, prostheses group and VMAT replans for the prostheses group. Methods Genitourinary (GU) and gastrointestinal (GI) toxicity was scored using Common Terminology Criteria for Adverse Events version 5.0. The incidence of grade 2 or worse (G2+) toxicity was compared using Fisher’s exact test. Dose volume histograms (DVHs) and mean doses to organs at risk (OARs) were compared using signed rank tests. Results There were 17 patients in the prostheses group and 50 in the control group. Acute and late GU toxicity was similar. G2+ late GI toxicity incidence was 31% for the prostheses group and 14% for the control group ( p  = 0.14). Significant differences ( p  < 0.05) were seen between the OAR DVHs of the prostheses group who had IMRT and the control group for a range of intermediate doses. The rectum mean dose was significantly different ( p  < 0.001), but no difference was seen for the bladder mean dose ( p  = 0.08). Conclusions No significant differences were seen in GU and GI toxicity incidence between patients with bilateral hip prostheses and a control group. The DVHs for bladder and rectum were significantly higher for patients with prostheses planned with IMRT. Replanning using a VMAT technique significantly reduced doses to the OARs, whilst maintaining good planning target volume coverage.

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis. The shattering of chromosomes is a dramatic early event in tumourigenesis and is termed chromothripsis. Here, the authors examine chromothripsis across 28 tumour types and show that 49% of cancers exhibit features of chromothripsis.

Many heritage objects consist of glass in contact with metals. By ion exchange with absorbed water, alkaline aqueous films are formed on the glass surface. They contain sodium and/or potassium, hydroxide, and carbonate (uptake of carbon dioxide) ions. These electrolytes induce corrosion while in contact with metal. Surprisingly, this phenomenon has only been realised by research in Stuttgart in the last two decades. About 350 affected objects were detected in the meantime in a number of heritage collections. Because of the special electrolytes, unusual corrosion products are often formed. The unknown structure and formula of three of them could be determined by modern X-ray powder diffraction data evaluation. One example is the basic potassium lead carbonate, KOH‧2PbCO3, detected on a pewter lid of a glass jug. The sodium analogon of already known structure was found in hollow glass balls mirrored on the inside with molten lead. Chalconatronite, Na2[Cu(CO3)2]‧3H2O, is known as a corrosion product of copper alloys in contact with soda solutions (here: from glass degradation). Exposed to acetic acid emissions (e.g., from wood), it transforms to a sodium copper acetate carbonate of hitherto undetermined structure. The ubiquitous pollutant formaldehyde reacts directly to formate in the alkaline medium provided by glass degradation. On copper alloys in contact with glass, formates are, therefore, frequent: Na4Cu4O(HCOO)8(OH)2‧4H2O in 50% of all cases and in 33% Cu2(HCOO)(OH)3. Zinc (from brass) forms Zn(HCOO)2‧2H2O and Zn4Cu3(Zn1−xCux)6(HCOO)8 (OH)18·6H2O. There are a number of other corrosion products, e.g., containing zinc and carboxylates awaiting further characterisation. Preventive conservation needs to slow down corrosion by dry storage (not lower than 35% rH). Pollutants need to be avoided by careful selection of materials for storage, display, and conservation.

Climate change is reducing the extent of cold aquatic habitats and their unique biodiversity in mountain areas. However, a variety of cold rocky landforms (CRLs) are thermally buffered and feed cold springs (<2 °C) that may represent climate refugia for cold-adapted organisms. These landforms, hitherto overlooked by freshwater research, include rock glaciers, debris-covered glaciers, talus slopes, protalus ramparts, and young moraines. Here, we investigated the warm-season water temperature of 228 springs from clean (ice) glaciers, CRLs, and reference slopes (not sourced by any of these features) in 13 mountain ranges of Europe, South America, and North America. Only springs from glaciers (90%) and CRLs (45%) had average stream temperatures below the thermal optimum for coldwater organisms of 2 °C. Springs fed by CRLs were 3 °C–5 °C (up to 9 °C) colder than those from nearby reference slopes. In general, cold springs were rarer in Mediterranean/semi-arid climates than in temperate and sub-polar climates. Landforms comprising barren and coarse rocky surfaces or ice/rock mix, having a simple or absent soil/vegetation structure, and higher likelihood of permafrost more often supported cold springs. When water temperatures were compared to air temperature, most CRL springs were thermally buffered against warm periods, cumulative heat, and daily temperature fluctuations. With cold conditions maintained in a variety of climates and mountain landscapes, CRL springs in mountains likely have high conservation value. We call for integrated ecological and hydrological research for these ecosystems, aimed at understanding their potential as climate refugia.

Alpine cold ice caps are sensitive indicators of local climate. The adequate interpretation of this information in an ice core requires detailed in situ glaciological and meteorological records, of which there are few. The Weißseespitze summit ice cap (3499 m) presents an ideal case to compare past and present climate and mass balance, with limited ice flow, but close to 6000 years locked into about 10 m of ice. First-ever meteorological observations at the ice dome have revealed that over 3 years of observation most of the accumulation took place between October and December and from April to June. In the colder winter months, between January and March, wind erosion prevents accumulation. Melt occurred between June and September, ice was only affected during short periods, mainly in August, which caused ice losses of up to 0.6 m (i.e. ~ 5% of the total ice thickness). Historical data points at a loss of of 34.9 ± 10.0 m between 1893 and 2018 and almost balanced conditions between 1893 and 1914. The local evidence of ice loss lays the basis for the interpretation of past gaps in the ice core records as past warm/melt events.

Usher syndrome (USH) is the most common form of monogenic deaf‐blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin‐encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas‐mediated gene repair or gene therapy in vitro . AAV‐based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo . Synopsis The full phenotypic spectrum of Usher Syndrome is reflected in a pig model carrying a patient‐specific mutation after partial humanization of the porcine USH1C gene. Retinal function in USH1C pigs was improved when harmonin expression was reconstituted by AAV‐mediated gene therapy. Partial humanization of the porcine USH1C gene was facilitated by the high degree of sequence conservation in the N‐terminal region of harmonin. Vision loss within the first year of life in USH1C pigs was consistently indicated by behavior tests, clinical examination and morphological analysis. Early onset of vision loss was correlated to disrupted photoreceptor cell architecture. Ciliopathy mechanisms and their therapeutic correction were investigated in primary cells of USH1C individuals. Local application and therapeutic efficacy of AAV‐mediated treatments was examined in USH1C pigs in vivo . Graphical Abstract The full phenotypic spectrum of Usher Syndrome is reflected in a pig model carrying a patient‐specific mutation after partial humanization of the porcine USH1C gene. Retinal function in USH1C pigs was improved when harmonin expression was reconstituted by AAV‐mediated gene therapy.

Autoimmune response to cardiac troponin I (TnI) induces inflammation and fibrosis in the myocardium. High-mobility group box 1 (HMGB1) is a multifunctional protein that exerts proinflammatory activity by mainly binding to receptor for advanced glycation end products (RAGE). The involvement of the HMGB1–RAGE axis in the pathogenesis of inflammatory cardiomyopathy is yet not fully understood. Using the well-established model of TnI-induced experimental autoimmune myocarditis (EAM), we demonstrated that both local and systemic HMGB1 protein expression was elevated in wild-type (wt) mice after TnI immunization. Additionally, pharmacological inhibition of HMGB1 using glycyrrhizin or anti-HMGB1 antibody reduced inflammation in hearts of TnI-immunized wt mice. Furthermore, RAGE knockout (RAGE-ko) mice immunized with TnI showed no structural or physiological signs of cardiac impairment. Moreover, cardiac overexpression of HMGB1 using adeno-associated virus (AAV) vectors induced inflammation in the hearts of both wt and RAGE-ko mice. Finally, patients with myocarditis displayed increased local and systemic HMGB1 and soluble RAGE (sRAGE) expression. Together, our study highlights that HMGB1 and its main receptor, RAGE, appear to be crucial factors in the pathogenesis of TnI-induced EAM, because inhibition of HMGB1 and ablation of RAGE suppressed inflammation in the heart. Moreover, the proinflammatory effect of HMGB1 is not necessarily dependent on RAGE only. Other receptors of HMGB1 such as Toll-like receptors (TLRs)may also be involved in disease pathogenesis. These findings could be confirmed by the clinical relevance of HMGB1 and sRAGE. Therefore, blockage of one of these molecules might represent a novel therapeutic strategy in the treatment of autoimmune myocarditis and inflammatory cardiomyopathy.

Detailed knowledge of Holocene climate and glaciers dynamics is essential for sustainable development in warming mountain regions. Yet information about Holocene glacier coverage in the Alps before the Little Ice Age stems mostly from studying advances of glacier tongues at lower elevations. Here we present a new approach to reconstructing past glacier low stands and ice-free conditions by assessing and dating the oldest ice preserved at high elevations. A previously unexplored ice dome at Weißseespitze summit (3500 m), near where the “Tyrolean Iceman” was found, offers almost ideal conditions for preserving the original ice formed at the site. The glaciological settings and state-of-the-art micro-radiocarbon age constraints indicate that the summit has been glaciated for about 5900 years. In combination with known maximum ages of other high Alpine glaciers, we present evidence for an elevation gradient of neoglaciation onset. It reveals that in the Alps only the highest elevation sites remained ice-covered throughout the Holocene. Just before the life of the Iceman, high Alpine summits were emerging from nearly ice-free conditions, during the start of a Mid-Holocene neoglaciation. We demonstrate that, under specific circumstances, the old ice at the base of high Alpine glaciers is a sensitive archive of glacier change. However, under current melt rates the archive at Weißseespitze and at similar locations will be lost within the next two decades.