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Abstract Changes of mRNA 3’UTRs by alternative polyadenylation (APA) have been associated to numerous pathologies, but the mechanisms and consequences often remain enigmatic. By combining transcriptomics, proteomics and recombinant viruses we show that all tested strains of IAV, including A/PR/8/34(H1N1) (PR8) and A/Cal/07/2009 (H1N1) (Cal09), cause APA. We mapped the effect to the highly conserved glycine residue at position 184 (G184) of the viral non-structural protein 1 (NS1). Unbiased mass spectrometry-based analyses indicate that NS1 causes APA by perturbing the function of CPSF4 and that this function is unrelated to virus-induced transcriptional shutoff. Accordingly, IAV strain PR8, expressing an NS1 variant with weak CPSF binding, does not induce host shutoff but only APA. However, recombinant IAV (PR8) expressing NS1(G184R) lacks binding to CPSF4 and thereby also the ability to cause APA. Functionally, the impaired ability to induce APA leads to an increased inflammatory cytokine production and an attenuated phenotype in a mouse infection model. Investigating diverse viral infection models showed that APA induction is a frequent ability of many pathogens. Collectively, we propose that targeting of the CPSF complex, leading to widespread alternative polyadenylation of host transcripts, constitutes a general immunevasion mechanism employed by a variety of pathogenic viruses.

Many different animal species are susceptible to SARS-CoV-2, including a few Canidae (domestic dog and raccoon dog). So far, only experimental evidence is available concerning SARS-CoV-2 infections in red foxes (Vulpes vulpes). This is the first report of SARS-CoV-2 RNA detection in a sample from a red fox. The RT-qPCR-positive fox was zoo-kept together with another fox and two bears in the Swiss Canton of Zurich. Combined material from a conjunctival and nasal swab collected for canine distemper virus diagnostics tested positive for SARS-CoV-2 RNA with Ct values of 36.9 (E gene assay) and 35.7 (RdRp gene assay). The sample was analysed for SARS-CoV-2 within a research project testing residual routine diagnostic samples from different animal species submitted between spring 2020 and December 2022 to improve knowledge on SARS-CoV-2 infections within different animal species and investigate their potential role in a One Health context. Within this project, 246 samples from 153 different animals from Swiss zoos and other wild animal species all tested SARS-CoV-2 RT-qPCR and/or serologically negative so far, except for the reported fox. The source of SARS-CoV-2 in the fox is unknown. The fox disappeared within the naturally structured enclosure, and the cadaver was not found. No further control measures were undertaken.

Abstract Second malignant neoplasms (SMN) after primary childhood acute lymphoblastic leukemia (ALL) are rare. Among 1487 ALL patients diagnosed between 1981 and 2010 in Austria, the 10‐year cumulative incidence of an SMN was 1.1% ± 0.3%. There was no difference in the 10‐year incidence of SMNs with regard to diagnostic‐, response‐ and therapy‐related ALL characteristics except for a significantly higher incidence in patients with leukocytes ≥50.0 G/L at ALL diagnosis (2.1% ± 1.0% vs. 0% for 20.0–50.0 G/L, and 1.0% ± 0.3% for

For archival pathogens, like pH1N1 Influenza A virus the causative agent of 1918/19 pandemic, only few whole genome sequences exist. Here, Patrono et al. provide one complete and two partial genomes from Germany and find variation in two sites in the nucleoprotein gene in pandemic samples compared to pre-pandemic samples, that are associated with resistance to host antiviral response, pointing at a possible viral adaptation to humans.

Whether there are conserved nucleic acid (NA) binding proteins across species is not fully known. Using data from human, mouse and fly, the authors identify common binders, implicate TAOKs and show that these kinases bind NAs across species and promote virus defence in mammalian cells.

BackgroundDespite recent developments, the role of sirolimus in the heterogeneous spectrum of vascular anomalies is yet to be defined, in terms of indication, dosage, and therapy duration, recognizing both its potential and limitations.MethodsWe retrospectively analyzed 16 children with vascular anomalies treated with sirolimus in two pediatric centers between 2014 and 2020 [male: n = 7, the median age at diagnosis: 4.6 months (range, 0–281.4)]. In addition, repetitive volumetric analyses of the vascular anomalies were performed when possible (11 cases).ResultsTen patients were diagnosed with vascular malformations and 6 with vascular tumors. The mean therapy duration was 27.2 months (range, 3.5–65). The mean sirolimus level was 8.52 ng/ml (range, 5.38–12.88). All patients except one with central conducting lymphatic anomaly responded to sirolimus, with the most noticeable volume reduction in the first 4–6 months. Additional administration of vincristine was needed in five patients with kaposiform hemangioendothelioma and yielded a response, even in cases, refractory to sirolimus monotherapy. As a single agent, sirolimus led to impressive improvement in a patient with another vascular tumor—advanced epithelioid hemangioendothelioma. Complicated vascular malformations required long-term sirolimus therapy. Side effects of sirolimus included mucositis and laboratory abnormalities. No major infectious episodes were recorded. An infant with COVID-19, diagnosed while on sirolimus therapy, presented with a mild course.ConclusionIn the current series, we reported limitations of sirolimus as monotherapy, addressing the need to redefine its indications, and explore combination regimens and multimodal treatment strategies. Tools for objective evaluation of response trends over time could serve as a basis for the establishment of future therapeutic algorithms.

Abstract Background Recent advances in sequencing have facilitated large-scale analyses of the metagenomic composition of different samples, including the environmental microbiome of air, water, and soil, as well as the microbiome of living humans and other animals. Analyses of the microbiome of ancient human samples may provide insights into human health and disease, as well as pathogen evolution, but the field is still in its very early stages and considered highly challenging. Results The metagenomic and pathogen content of Egyptian mummified individuals from different time periods was investigated via genetic analysis of the microbial composition of various tissues. The analysis of the dental calculus’ microbiome identified Red Complex bacteria, which are correlated with periodontal diseases. From bone and soft tissue, genomes of two ancient pathogens, a 2200-year-old Mycobacterium leprae strain and a 2000-year-old human hepatitis B virus, were successfully reconstructed. Conclusions The results show the reliability of metagenomic studies on Egyptian mummified individuals and the potential to use them as a source for the extraction of ancient pathogen DNA.

Hansen’s disease (leprosy), mainly caused by infection with Mycobacterium leprae, has accompanied humanity for thousands of years. Although currently rare in Europe, there are over 200,000 new infections annually in South East Asia, Africa, and South America. Over the years many disciplines – palaeopathology, ancient DNA and other ancient biomolecules, and history – have contributed to a better understanding of leprosy’s past, in particular its history in medieval Europe. We discuss their contributions and potential, especially in relation to the role of inter-species transmission, an unexplored phenomenon in the disease’s history. Here, we explore the potential of interdisciplinary approaches that understand disease as a biosocial phenomenon, which is a product of both infection with M. leprae and social behaviours that facilitate transmission and spread. Genetic evidence of M. leprae isolated from archaeological remains combined with systematic zooarchaeological and historical analysis would not only identify when and in what direction transmission occurred, but also key social behaviours and motivations that brought species together. In our opinion, this combination is crucial to understand the disease’s zoonotic past and current potential.

Viral infections have a large impact on society, leading to major human and economic losses and even global instability. So far, many viral infections, including human cytomegalovirus (HCMV) infection, are treated with a small repertoire of drugs, often accompanied by the occurrence of resistant mutants.

Metasurfaces are two-dimensional nanostructures that allow unprecedented control of light through engineering the amplitude, phase, and polarization across meta-atom resonators. Adding tunability to metasurface components would boost their potential and unlock a vast array of new application possibilities such as dynamic beam steering, tunable metalenses, and reconfigurable meta-holograms, to name a few. We present here high-index meta-atoms, resonators, and metasurfaces reconfigured by thermal effects, across the near to mid-infrared spectral ranges. We study thermal tunability in group IV and group IV-VI semiconductors, as well as in phase-transition materials, and demonstrate large dynamic resonance frequency shifts accompanied by significant amplitude and phase modulation in metasurfaces and resonators. We highlight the importance of high-Q resonances along with peak performance of thermal and thermo-optic effects, for efficient and practical reconfigurable devices. This paper paves the way to efficient high-Q reconfigurable and active infrared metadevices.

Introduction: Ewing sarcomas of the chest wall, historically known as “Askin tumors” represent highly aggressive pediatric malignancies with a reported 5-year survival ranging only between 40 and 60% in most studies. Multimodal oncological treatment according to specific Ewing sarcoma protocols and radical “en-bloc” resection with simultaneous chest wall repair are key factors for long-term survival. However, the surgical complexity depends on tumor location and volume and potential infiltrations into lung, pericardium, diaphragm, esophagus, spine and major vessels. Thus, the question arises, which surgical specialties should join their comprehensive skills when approaching a child with Ewing sarcoma of the chest wall.Patients and Methods: All pediatric patients with Ewing sarcomas of the chest wall treated between 1990 and 2020 were analyzed focusing on complete resection, chest wall reconstruction, surgical complications according to Clavien-Dindo (CD) and survival. Patients received neo-adjuvant chemotherapy according to the respective Ewing sarcoma protocols. Depending on tumor location and organ infiltration, a multi-disciplinary surgical team was orchestrated to perform radical en-bloc resection and simultaneous chest wall repair.Results: Thirteen consecutive patients (seven boys and six girls) were included. Median age at presentation was 10.9 years (range 2.2–21 years). Neo-adjuvant chemotherapy (n = 13) and irradiation (n = 3) achieved significant reduction of the median tumor volume (305.6 vs. 44 ml, p < 0.05). En-bloc resection and simultaneous chest wall reconstruction was achieved without major complications despite multi-organ involvement. Postoperatively, one patient with infiltration of the costovertebral joint and laminectomy required surgical re-intervention (CD IIIb). 11/13 patients were treated with clear resections margins (R1 resection in one patient with infiltration of the costovertebral joint and marginal resection

Archaeological and historical records had shown ancient Egypt before and after Ptolemaic and Roman periods to be a hub of human migration and exchange. Here, Schuenemann and colleagues analyse ancient mitochondrial and nuclear DNA to investigate the genetic history of Egypt.

Persistent virus infection continuously produces non-self nucleic acids that activate cell-intrinsic immune responses. However, the antiviral defense evolved as a transient, acute phase response and the effects of persistently ongoing stimulation onto cellular homeostasis are not well understood. To study the consequences of long-term innate immune activation, we expressed the NS5B polymerase of Hepatitis C virus (HCV), which in absence of viral genomes continuously produces immune-stimulatory RNAs. Surprisingly, within 3 weeks, NS5B expression declined and the innate immune response ceased. Proteomics and functional analyses indicated a reduced proliferation of those cells most strongly stimulated, which was independent of interferon signaling but required mitochondrial antiviral signaling protein (MAVS) and interferon regulatory factor 3 (IRF3). Depletion of MAVS or IRF3, or overexpression of the MAVS-inactivating HCV NS3/4A protease not only blocked interferon responses but also restored cell growth in NS5B expressing cells. However, pan-caspase inhibition could not rescue the NS5B-induced cytostasis. Our results underline an active counter selection of cells with prolonged innate immune activation, which likely constitutes a cellular strategy to prevent persistent virus infections.

Early diagnosis of primary immunodeficiency disorders (PID) is vital and allows directed treatment, especially in syndromes with severe or profound combined immunodeficiency. In PID patients with perinatal CMV or other opportunistic, invasive infections (e.g., Pneumocystis or Aspergillus), multi-organ morbidity may already arise within the first months of life, before hematopoietic stem cell transplantation (HSCT) or gene therapy can be undertaken, compromising the definitive treatment and outcome. Deficiency of Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP deficiency) causes an autosomal recessive, WAS-like syndrome with early-onset combined immunodeficiency that has been described in three pedigrees to date. While WAS typically includes combined immunodeficiency, microthrombocytopenia, and eczema, the clinical and laboratory phenotypes of WIP-deficient patients–including lymphocyte subsets, platelets, lymphocyte proliferation in vitro, and IgE—varied widely and did not entirely recapitulate WAS, impeding early diagnosis in the reported patients. To elucidate the phenotype of WIP deficiency, we provide a comprehensive synopsis of clinical and laboratory features of all hitherto-described patients (n = 6) and WIP negative mice. Furthermore, we summarize the treatment modalities and outcomes of these patients and review in detail the course of one of them who was successfully treated with serial, unconditioned, maternal, HLA-identical donor lymphocyte infusions (DLI) against life-threatening, invasive CMV infection, followed by a TCRαβ/CD19-depleted, treosulfan/melphalan-conditioned, peripheral blood HSCT and repetitive, secondary-prophylactic, CMV-specific DLI with 1-year post-HSCT follow-up. This strategy could be useful in other patients with substantial premorbidity, considered “too bad to transplant,” who have an HLA-identical family donor, to eliminate infections and bridge until definitive treatment.

Objective: Primary infection with human herpes virus 6 (mainly HHV-6B) commonly occurs in the first 2 years of life leading to persistence and the possibility of virus reactivation later in life. Consequently, a specific cellular immune response is essential for effective control of virus reactivation. We have studied cell-mediated immune response to HHV-6 (U54) in healthy children and adolescents.Materials and Methods: By flow cytometry, the amount of cytokine (interferon gamma—IFN- γ, interleukin 2—IL-2, tumor necrosis factor alpha—TNF-α) secreting T-cells were measured after 10 days of pre-sensitization and 6 h of re-stimulation with mixtures of pooled overlapping peptides from U54, staphylococcal enterotoxin B (SEB, positive control), or Actin (negative control) in healthy children and adolescents without any underlying immune disorder or infectious disease.Results: All individuals showed a virus-specific response for at least one cytokine in either CD4+ or CD8+ cells. Percentages of individuals with HHV-6-specific TNF-α response in CD4+ (48% of individuals) as well as CD8+ (56% of individuals) were always the highest. Our data show significantly higher frequencies of HHV-6-specific TNF-α producing CD8+ T-cells in individuals older than 10 years of life (p = 0.033). Additionally, the frequency of HHV-6 specific TNF-α producing CD8+ T-cells positively correlated with the age of the individuals. Linear regression analysis showed a positive relation between age and frequency of HHV-6-specific TNF-α producing CD8+ T-cells.Conclusion: Results indicate that T-cell immune response against HHV-6 is commonly detectable in healthy children and adolescents with higher frequencies of antigen-specific T-cells in older children and adolescents possibly reflecting repeated stimulation by viral persistence and subclinical reactivation.

Studying ancient DNA allows us to retrace the evolutionary history of human pathogens, such as Mycobacterium leprae, the main causative agent of leprosy. Leprosy is one of the oldest recorded and most stigmatizing diseases in human history. The disease was prevalent in Europe until the 16th century and is still endemic in many countries with over 200,000 new cases reported annually. Previous worldwide studies on modern and European medieval M. leprae genomes revealed that they cluster into several distinct branches of which two were present in medieval Northwestern Europe. In this study, we analyzed 10 new medieval M. leprae genomes including the so far oldest M. leprae genome from one of the earliest known cases of leprosy in the United Kingdom-a skeleton from the Great Chesterford cemetery with a calibrated age of 415-545 C.E. This dataset provides a genetic time transect of M. leprae diversity in Europe over the past 1500 years. We find M. leprae strains from four distinct branches to be present in the Early Medieval Period, and strains from three different branches were detected within a single cemetery from the High Medieval Period. Altogether these findings suggest a higher genetic diversity of M. leprae strains in medieval Europe at various time points than previously assumed. The resulting more complex picture of the past phylogeography of leprosy in Europe impacts current phylogeographical models of M. leprae dissemination. It suggests alternative models for the past spread of leprosy such as a wide spread prevalence of strains from different branches in Eurasia already in Antiquity or maybe even an origin in Western Eurasia. Furthermore, these results highlight how studying ancient M. leprae strains improves understanding the history of leprosy worldwide.

Nominal unification calculates substitutions that make terms involving binders equal modulo alpha-equivalence. Although nominal unification can be seen as equivalent to Miller's higher-order pattern unification, it has properties, such as the use of first-order terms with names (as opposed to alpha-equivalence classes) and that no new names need to be generated during unification, which set it clearly apart from higher-order pattern unification. The purpose of this paper is to simplify a clunky proof from the original paper on nominal unification and to give an overview over some results about nominal unification.

Although bone marrow transplantation (BMT) from an HLA identical sibling is considered as treatment of choice in pediatric patients with severe aplastic anemia (SAA), a significant number of them experience graft failure (GF) after BMT. We report a case of an 8-year-old male patient with SAA who presented with a complicated posttransplant course due to parvovirus B19 infection and GF. A subsequent attempt to support the graft by antithymocyte globulin (ATG) and a peripheral stem cell boost resulted in transitory autologous recovery of hematopoiesis followed by mixed chimerism, supported by donor lymphocyte infusions (DLIs) and finally graft rejection with relapse of SAA. Permanent complete chimerism was achieved by a second BMT. Dynamics of graft function, measured by a single nucleotide polymorphism (SNPs) analysis, are discussed.

Nominal Isabelle is a definitional extension of the Isabelle/HOL theorem prover. It provides a proving infrastructure for reasoning about programming language calculi involving named bound variables (as opposed to de-Bruijn indices). In this paper we present an extension of Nominal Isabelle for dealing with general bindings, that means term constructors where multiple variables are bound at once. Such general bindings are ubiquitous in programming language research and only very poorly supported with single binders, such as lambda-abstractions. Our extension includes new definitions of alpha-equivalence and establishes automatically the reasoning infrastructure for alpha-equated terms. We also prove strong induction principles that have the usual variable convention already built in.

Hemophagocytic lymphohistiocytosis (HLH) during childhood cancer treatment is a rare adverse event posing major diagnostic and therapeutic challenges. Between 1995 and 2006, 6 children developed HLH while on conventional chemotherapy (n=4) or after allogeneic stem cell transplantation (n=2). Treatment of HLH included dexamethasone and etoposide, 2 children additionally received infliximab or daclizumab. Three children survived, whereas 3 children died 2, 5, and 47 days after diagnosis of HLH. HLH is a severe adverse event of childhood cancer therapy. Early diagnosis and immediate initiation of adequate treatment are mandatory to overcome this severe condition.