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Certain cutaneous human papillomaviruses (HPVs), which are ubiquitous and acquired early during childhood, can cause a variety of skin tumors and are likely involved in the development of non-melanoma skin cancer, especially in immunosuppressed patients. Hence, the burden of these clinical manifestations demands for a prophylactic approach. To evaluate whether protective efficacy of a vaccine is potentially translatable to patients, we used the rodent Mastomys coucha that is naturally infected with Mastomys natalensis papillomavirus (MnPV). This skin type papillomavirus induces not only benign skin tumours, such as papillomas and keratoacanthomas, but also squamous cell carcinomas, thereby allowing a straightforward read-out for successful vaccination in a small immunocompetent laboratory animal. Here, we examined the efficacy of a virus-like particle (VLP)-based vaccine on either previously or newly established infections. VLPs raise a strong and long-lasting neutralizing antibody response that confers protection even under systemic long-term cyclosporine A treatment. Remarkably, the vaccine completely prevents the appearance of benign as well as malignant skin tumors. Protection involves the maintenance of a low viral load in the skin by an antibody-dependent prevention of virus spread. Our results provide first evidence that VLPs elicit an effective immune response in the skin under immunocompetent and immunosuppressed conditions in an outbred animal model, irrespective of the infection status at the time of vaccination. These findings provide the basis for the clinical development of potent vaccination strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation.

Nephrotoxicity caused by drug or chemical exposure involves complex mechanisms as well as a temporal integration of injury and repair responses in different nephron segments. Distinct cellular transcriptional programs regulate the time-dependent tissue injury and regeneration responses. Whole kidney transcriptome analysis cannot dissect the complex spatio-temporal injury and regeneration responses in the different nephron segments. Here, we used laser capture microdissection of formalin-fixed paraffin embedded sections followed by whole genome targeted RNA-sequencing-TempO-Seq and co-expression gene-network (module) analysis to determine the spatial–temporal responses in rat kidney glomeruli (GM), cortical proximal tubules (CPT) and outer-medulla proximal tubules (OMPT) comparison with whole kidney, after a single dose of the nephrotoxicant cisplatin. We demonstrate that cisplatin induced early onset of DNA damage in both CPT and OMPT, but not GM. Sustained DNA damage response was strongest in OMPT coinciding with OMPT specific inflammatory signaling, actin cytoskeletal remodeling and increased glycolytic metabolism with suppression of mitochondrial activity. Later responses reflected regeneration-related cell cycle pathway activation and ribosomal biogenesis in the injured OMPT regions. Activation of modules containing kidney injury biomarkers was strongest in OMPT, with OMPT Clu expression highly correlating with urinary clusterin biomarker measurements compared the correlation of Kim1. Our findings also showed that whole kidney responses were less sensitive than OMPT. In conclusion, our LCM-TempO-Seq method reveals a detailed spatial mechanistic understanding of renal injury/regeneration after nephrotoxicant exposure and identifies the most representative mechanism-based nephron segment specific renal injury biomarkers. Graphical Abstract Highlights • Different nephron segments exhibit distinct transcriptomic perturbation with different degrees of sensitivity. • Sustained activation of DNA damage responses upon cisplatin exposure is linked to progressive outcomes of injured nephron regions. • Mechanistic kidney injury biomarkers such as urinary clusterin outperform conventional biomarkers in reflecting the condition of the damaged nephron segments.

Major rivers are unique linear structures because they serve different purposes simultaneously: A habitat and dispersal route for flora and fauna as well as a navigation route, the site for recreational and economic activities and a source for drinking water and irrigation. In recent years, it has become increasingly clear that waterways must be developed in an environmentally and economically sustainable and socially responsible manner. The Federal Ministry of Transport and Digital Infrastructure (BMVI) and its specialised agencies – the Waterways and Shipping Administration of the German Federal Government (WSV), the Federal Institute of Hydrology (BfG) and the Federal Waterways Engineering and Research Institute (BAW) – are aiming to achieve this goal by integrating environmental issues into the development and maintenance of waterways. This paper aims to fill the gap on the one hand between scientific analyses of ecological freshwater status and proposals for its improvement, and, on the other hand, bringing this knowledge into practical realisation. Recent activities at the German federal waterways are exemplarily reviewed on the basis of applied research projects, local projects, political programmes and progressive legislation.

Reforming the United Nations Security Council has been on the agenda of the General Assembly for over two decades. However, structural reform of the Council remains elusive. This research paper will seek to explain why after so many years nearly all 193 states within the UN remain actively seized on the matter of reform, and ongoing commitment to Council reform can be observed. In order to properly analyze SC reform efforts and the various obstacles along the way, this paper emphasizes states’ motivations during the reform process. This thesis argues that although states work on the same objective, namely that of reforming the UNSC, they do so for varying reasons. With the help of new institutionalist theory, an argument is formed that highlights how certain states are more driven by strategic calculations and self-interest, while others are more normatively motivated, and thus are more driven by what is considered appropriate. Furthermore, this thesis highlights that despite only lukewarm support for reform from certain states, not a single state can publicly denounce Council reform, because the reform issue itself has become an ingrained norm. Emphasis will be given to structural reform, such as increasing the size of the Council, as well as improving the SC’s working methods. Despite the lack of formal reform, the SC has continually proven to be adaptive in order to remain relevant well into the 21st century.

Certain cutaneous human papillomaviruses (HPVs), which are ubiquitous and acquired early during childhood, can cause a variety of skin tumors and are likely involved in the development of non-melanoma skin cancer, especially in immunosuppressed patients. Hence, the burden of these clinical manifestations demands for a prophylactic approach. To evaluate whether protective efficacy of a vaccine is potentially translatable to patients, we used the rodent Mastomys coucha that is naturally infected with Mastomys natalensis papillomavirus (MnPV). This skin type papillomavirus induces not only benign skin tumours, such as papillomas and keratoacanthomas, but also squamous cell carcinomas, thereby allowing a straightforward read-out for successful vaccination in a small immunocompetent laboratory animal. Here, we examined the efficacy of a virus-like particle (VLP)-based vaccine on either previously or newly established infections. VLPs raise a strong and long-lasting neutralizing antibody response that confers protection even under systemic long-term cyclosporine A treatment. Remarkably, the vaccine completely prevents the appearance of benign as well as malignant skin tumors. Protection involves the maintenance of a low viral load in the skin by an antibody-dependent prevention of virus spread. Our results provide first evidence that VLPs elicit an effective immune response in the skin under immunocompetent and immunosuppressed conditions in an outbred animal model, irrespective of the infection status at the time of vaccination. These findings provide the basis for the clinical development of potent vaccination strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation.

In Russia, almost $20 billion must be invested over the next 10 years in the production, processing & transport of oil. A significant part of the necessary capital must be obtained from international capital markets. German banks have already taken on a leading role in allocating consortium credit. In the process, environmental & social standards have thus far hardly played a role in informing the banks' decisions -- even though the oil industry is among the greatest polluters of Russia's environment. Tables, Figures. Adapted from the source document.

Nephrotoxicity caused by drug or chemical exposure involves different mechanisms and nephron segments as well as a complex temporal integration of injury and repair responses. Distinct cellular transcriptional programs regulate the time-dependent tissue injury and regeneration responses. Whole kidney transcriptome analysis cannot dissect the complex the nephron segment spatio-temporal injury and regeneration responses. Here, we used laser capture microdissection of formalin-fixed paraffin embedded sections followed by whole genome targeted RNA-sequencing-TempO-Seq and co-expression gene-network (module) analysis to determine the spatial-temporal responses in rat kidney glomeruli (GM), cortical proximal tubules (CPT) and outer-medulla proximal tubules (OMPT) comparison with whole kidney, after a single dose of the nephrotoxicant cisplatin. We demonstrate that cisplatin induced early onset of DNA damage in both CPT and OMPT, but not GM. Sustained DNA damage response was strongest in OMPT coinciding with OMPT specific inflammatory signaling, actin cytoskeletal remodeling and increased glycolytic metabolism coincident with suppression of mitochondrial activity. Later responses reflected regeneration-related cell cycle pathway activation and ribosomal biogenesis in the injured OMPT regions. Activation of modules containing kidney injury biomarkers was strongest in the OMPT, with OMPT Clu expression best correlating with urinary clusterin biomarker measurements compared the correlation of Kim1. Our findings also showed that whole kidney responses were less sensitive than OMPT. In conclusion, our LCM-TempO-Seq method reveals a detailed spatial mechanistic understanding of renal injury/regeneration after nephrotoxicant exposure and identifies the most representative mechanism-based nephron segment specific renal injury biomarkers.Competing Interest StatementThe authors have declared no competing interest.

Im Rußland müssen in den nächsten zehn Jahren jährlich knapp zwanzig Milliarden Dollar in die Förderung, die Verarbeitung und den Transport von Erdöl investiert werden. Ein wichtiger Teil des benötigten Kapitals muß auf dem internationalen Kapitalmarkt bezogen werden. Schon heute sind deutsche Banken bei der Vergabe internationaler Konsortialkredite führend beteiligt. Umwelt- und Sozialstandards spielen dabei bislang kaum eine Rolle. Dabei gehört die Ölindustrie zu den größten Umweltverschmutzern in Rußland. In Russia, almost $20 billion must be invested over the next 10 years in the production, processing and transport of oil. A significant part of the necessary capital must be obtained from international capital markets. German banks have already taken on a leading role in allocating consortium credit. In the process, environmental and social standards have thus far hardly played a role in informing the banks' decisions - even though the oil industry is among the greatest polluters of Russia's environment.

The Omicron variant of SARS-CoV-2 infected many vaccinated and convalescent individuals 1 – 3 . Despite the reduced protection from infection, individuals who received three doses of an mRNA vaccine were highly protected from more serious consequences of infection 4 . Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving three mRNA vaccine doses 5 , 6 . We find that the third dose is accompanied by an increase in, and evolution of, receptor-binding domain (RBD)-specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the second dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared with antibodies obtained after the second dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells, which differed from persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analysed neutralizing antibodies in the memory compartment after the third mRNA vaccine dose neutralized the Omicron variant. Thus, individuals receiving three doses of an mRNA vaccine have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help to explain why a third dose of a vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease. A third dose of an mRNA vaccine against SARS-CoV-2 results in an expanded B cell repertoire that produces antibodies with increased potency and breadth.

Feedback inhibition of humoral immunity by antibodies was first documented in 1909 1 . Subsequent studies showed that, depending on the context, antibodies can enhance or inhibit immune responses 2 , 3 . However, little is known about how pre-existing antibodies influence the development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity anti-SARS-CoV-2 monoclonal antibodies and subsequently two doses of an mRNA vaccine 4 – 8 . We found that the recipients of the monoclonal antibodies produced antigen-binding and neutralizing titres that were only fractionally lower compared than in control individuals. However, the memory B cells of the individuals who received the monoclonal antibodies differed from those of control individuals in that they predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations and showed altered receptor binding domain (RBD) target specificity, consistent with epitope masking. Moreover, only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The mechanism underlying these findings was examined in experiments in mice that showed that germinal centres formed in the presence of the same antibodies were dominated by low-affinity B cells. Our results indicate that pre-existing high-affinity antibodies bias germinal centre and memory B cell selection through two distinct mechanisms: (1) by lowering the activation threshold for B cells, thereby permitting abundant lower-affinity clones to participate in the immune response; and (2) through direct masking of their cognate epitopes. This may in part explain the shifting target profile of memory antibodies elicited by booster vaccinations 9 . Pre-existing high-affinity antibodies alter germinal centre and memory B cell selection by lowering the activation threshold for B cells and through direct masking of their cognate epitopes, thereby permitting a diverse set of abundant lower-affinity clones targeting alternate epitopes to participate in the immune response.