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The 7th Birt-Hogg-Dubé (BHD) International Symposium convened virtually in October 2021. The meeting attracted more than 200 participants internationally and highlighted recent findings in a variety of areas, including genetic insight and molecular understanding of BHD syndrome, structure and function of the tumor suppressor Folliculin (FLCN), therapeutic and clinical advances as well as patients’ experiences living with this malady.

There is little information on the actual use of early synthetic organic pigments (SOPs) in art objects, especially those from before 1950. Their presence can, however, pose a challenge to conservation because their chemical composition, as well as their lightfastness and sensitivity to solvents, are often unknown. Here, a study on the non-invasive identification of SOPs in historic pre-1950 varnished paint-outs from artists’ materials manufacturer Royal Talens is presented. The paints were analysed using a handheld Raman device. Spectra were evaluated by recording the spectra of the same samples with a benchtop instrument. This study demonstrated that the identification of SOPs in varnished oil paints with a non-invasive approach is possible and rather straightforward. The handheld Raman device allowed us to identify fourteen SOPs from eight pigment classes. Besides the occurrence of expected and the known SOPs of this time period, there were also some surprising results, like the detection of the triarylcarbonium pigments PG2 and PB8, and the monoazo Mordant Yellow 1.

Background We previously demonstrated that APR-246 could be an efficient treatment option against neuroblastoma (NB), the most common pediatric extracranial solid tumor. APR-246’s mechanism of action is not completely understood and can differ between cell types. Here we investigate the involvement of well-known oncogenic pathways in NB’s response to APR-246. Methods A proteome profiler kinase assays and western blot analysis were used to identify the molecular pathways involved in the responses to APR-246. Bulk ATP levels were used to determine the viability of cells and the IC50 for APR-246. Cystine-FITC was used to measure the cellular uptake of cysteine. PmRNA5 was used to affect ERK1/2 and pshRNA1 was used to silence HSP27. An IMR-32 xenograft zebrafish embryo model was used to assess APR-246 and sulfasalazine efficacy in vivo. Results After APR-246 treatment, the most deregulated signaling protein identified was ERK1/2, an end-point kinase of the RAS-MAPK pathway. Induction of phospho-ERK1/2 resulted in increased glutathione (GSH) levels, increased cystine uptake and increased resistance of NB cells to APR-246. Using ERK1/2 inhibitors in combination with APR-246, we were able to categorize cells into synergistic and antagonistic groups. After co-treatment, these two groups differ by their levels of SLC7A11 and Hsp27 phosphorylation, cystine uptake and BIM expression. Using erastin and sulfasalazine, both inhibitors of SLC7A11 and activators of ferroptosis, we were able to reverse the antagonistic effects of ERK1/2 inhibitors and demonstrate a strong synergistic action in vitro and in vivo in zebrafish models. Conclusions These results demonstrated a pivotal role of the RAS-MAPK pathway in the NB cellular response to APR-246 via the modulation of intracellular concentrations of GSH and the transport of cystine, phosphorylation of Hsp27, and programed cell death. Combining APR-246 with RAS-MAPK pathway inhibitors can, in some cases, lead to antagonistic action, which can be reversed by combining APR-246 with the clinically approved drug sulfasalazine.

Synopsis The biological sciences are inherently interdisciplinary and important advances in biology cannot be made without collaboration. Despite the increasing emphasis on interdisciplinarity in higher education, science courses only rarely extend to content outside of the STEM discipline. Classes are typically taught by one faculty member in one discipline. To demonstrate relevance while addressing genuine community needs, faculty can use service-learning in their courses. Service-learning is an experiential learning strategy where students learn course content and additional relevant skills through completing service with a community partner. Community needs are frequently beyond the scope of a single course or discipline. In order to better meet community needs, an interdisciplinary collaboration provides a more comprehensive experience that highlights the application and interconnection of course content. This article presents a generalisable model for successful interdisciplinary collaborations. While the nature of course scheduling, academic department structure, and faculty workload can be barriers to collaboration between faculty, they are not insurmountable and accomplishable within this framework. The benefits to the students and the community far outweigh navigating these challenges. Using an interdisciplinary approach in teaching will not only enrich course content and expand student learning in multiple areas, but also increase collaboration within the academy while better meeting community needs.

Neuroblastoma is the most common extra-cranial solid tumor in children, representing approximately 8% of all malignant childhood tumors and 15% of pediatric cancer-related deaths. Recent sequencing and transcriptomics studies have demonstrated the RAS-MAPK pathway’s contribution to the development and progression of neuroblastoma. This review compiles up-to-date evidence of this pathway’s involvement in neuroblastoma. We discuss the RAS-MAPK pathway’s general functioning, the clinical implications of its deregulation in neuroblastoma, and current promising therapeutics targeting proteins involved in signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01967-x.

Increased macroautophagy/autophagy and lysosomal activity promote tumor growth, survival and chemo-resistance. During acute starvation, autophagy is rapidly engaged by AMPK (AMP-activated protein kinase) activation and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) inhibition to maintain energy homeostasis and cell survival. TFEB (transcription factor E3) and TFE3 (transcription factor binding to IGHM enhancer 3) are master transcriptional regulators of autophagy and lysosomal activity and their cytoplasm/nuclear shuttling is controlled by MTORC1-dependent multisite phosphorylation. However, it is not known whether and how the transcriptional activity of TFEB or TFE3 is regulated. We show that AMPK mediates phosphorylation of TFEB and TFE3 on three serine residues, leading to TFEB and TFE3 transcriptional activity upon nutrient starvation, FLCN (folliculin) depletion and pharmacological manipulation of MTORC1 or AMPK. Collectively, we show that MTORC1 specifically controls TFEB and TFE3 cytosolic retention, whereas AMPK is essential for TFEB and TFE3 transcriptional activity. This dual and opposing regulation of TFEB and TFE3 by MTORC1 and AMPK is reminiscent of the regulation of another critical regulator of autophagy, ULK1 (unc-51 like autophagy activating kinase 1). Surprisingly, we show that chemoresistance is mediated by AMPK-dependent activation of TFEB, which is abolished by pharmacological inhibition of AMPK or mutation of serine 466, 467 and 469 to alanine residues within TFEB. Altogether, we show that AMPK is a key regulator of TFEB and TFE3 transcriptional activity, and we validate AMPK as a promising target in cancer therapy to evade chemotherapeutic resistance. Abbreviations: ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: AMP-activated protein kinase; AMPKi: AMPK inhibitor, SBI-0206965; CA: constitutively active; CARM1: coactivator-associated arginine methyltransferase 1; CFP: cyan fluorescent protein; CLEAR: coordinated lysosomal expression and regulation; DKO: double knock-out; DMEM: Dulbecco’s modified Eagle’s medium; DMSO: dimethyl sulfoxide; DQ-BSA: self-quenched BODIPY® dye conjugates of bovine serum albumin; EBSS: Earle’s balanced salt solution; FLCN: folliculin; GFP: green fluorescent protein; GST: glutathione S-transferases; HD: Huntington disease; HTT: huntingtin; KO: knock-out; LAMP1: lysosomal associated membrane protein 1; MEF: mouse embryonic fibroblasts; MITF: melanocyte inducing transcription factor; MTORC1: MTOR complex 1; PolyQ: polyglutamine; RPS6: ribosomal protein S6; RT-qPCR: reverse transcription quantitative polymerase chain reaction; TCL: total cell lysates; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; TKO: triple knock-out; ULK1: unc-51 like autophagy activating kinase 1.

Polymer coatings on cellulosic fibres are widely used to enhance the natural fibre properties by improving, for example, the hydrophobicity and wet strength. Here, we investigate the effects of a terpolymer P(S-co-MABP-co-PyMA) coating on cotton linters and eucalyptus fibres to improve the resistance of cellulose fibres against wetness. Coated and uncoated fibres were characterised by using scanning electron microscopy, contact angle measurements, Raman spectroscopy and atomic force microscopy with the objective of correlating macroscopic properties such as the hydrophobicity of the fleece with microscopic properties such as the coating distribution and local nanomechanics. The scanning electron and fluorescence microscopy results revealed the distribution of the coating on the paper fleeces and fibres. Contact angle measurements proved the hydrophobic character of the coated fleece, which was also confirmed by Raman spectroscopy measurements that investigated the water uptake in single fibres. The water uptake also induced a change in the local mechanical properties, as measured by atomic force microscopy. These results verify the basic functionality of the hydrophobic coating on fibres and paper fleeces but call into question the homogeneity of the coating., Comment: 24 pages, 5 figures, submitted

The productive potential, apparent nitrogen conversion efficiency, nitrogen contained in the plant tissue, and apparent nitrogen recovery of Mombasa grass subjected to nitrogen fertilization (0, 100, 300, and 500 kg ha -1 ) and cutting heights were evaluated (0.20 and 0.40 m). The experimental design was a complete Randomized block with a 4 x 2 factorial arrangement, in plots subdivided over time with four replications. The dry mass production (DMP) was determined for the whole plant (PI) and its fractions, and only for the whole plant the apparent nitrogen conversion efficiency (ANCE), contained nitrogen (NC) and apparent nitrogen recovery (ANR). The residual heights evaluated did not interfere (P> 0.05) in the production results and the nitrogen dynamics. An effect (P

This study was designed to determine the effects of soybean silage (SS) in diets of dairy heifers on nutrient intake and digestibility, feeding behaviours, rumen fermentation, N utilisation, and mi...

Purpose: Adolescents and young adults (AYA) with cancer present a unique challenge to health care institutions. Their cancer diagnosis and treatment have a profound impact upon their health and well-being. Despite the various support services aimed at improving their quality of life, their needs and preferences are often underestimated or misjudged. Recent studies show that patients are empowered by the knowledge and support they receive online. Given the extensive use of social media among AYA, we aim to identify promises, challenges, and recommendations for integrating these platforms in AYA cancer care. Methodology: We systematically searched seven databases systematically: Scopus, PubMed, PsycInfo, Web of Science, CINAHL, SocINDEX, and Media. We placed no restriction on the type of methodology used in the studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used to frame the research. Results: Many studies argued that health care professionals need to integrate social media in their clinical practice to engage with patients' lifeworld. Social media were considered important allies in optimizing cancer care at all levels of support, ranging from information provision, treatment adherence, diet and exercise interventions, to professional, peer, and psychosocial self-care. Lack of research on the efficacy of social media in the context of psychosocial support was a commonly cited problem. A small number of publications paid attention to the inherent risks of promoting self-care online. Conclusion: Future studies should continue to pursue empirical research on the efficacy of online psychosocial care, while not neglecting the ethical challenges of social media research.

SARS-CoV-2 is a genetically engineered SARS-COV vector which has been embedded into the backbone of bacteriophage HP2 of Nontypeable Haemophilus Influenza (NTHi). The design of SARS-CoV-2’s spike (S) protein is notable for its ability to facilitate cellular entry via not only the ACE2 receptors but also ICAM-1 which becomes upregulated in a NTHI infection. Technologies used in the development of SARS-CoV-2 were patented by the Spanish National Research Council in 2006 and include methods for creating a SARS-COV vector for gene editing, particularly “gene silencing”, and vaccine administration via “virus particles”. This patent calls for the engineering of a SARS-COV vector using a helper virus such as HP2 for replication and/or transcription. According to this patent, the said system could be constructed using a genome of SARS-COV containing sequences encoding a heterologous reporter gene or a gene derived from a different infectious agent and the construction of a fulllength cDNA, which in the case of SARS-CoV-2 was most likely performed using hnRNP Q CRISPR Activation Plasmid (h) cDNA. Further, NTHI lysates increase exosome release in the human middle ear epithelial cells. Exosomes can regulate gene expression via their miRNAs. SARS-CoV-2 shares a 76% homology with SARS-COV which is an engineering requirement mentioned in the said patent. The patent also sets forth modification principles and sequences for engineering the ORF of gene 7a. This engineering can be observed as a structural analysis has revealed that SARS-CoV-2 ORF 7a has structural homology with ICAM-1. ORF 7a plays a vital role in virus tropism allowing SARS-CoV-2 to be “guided” to gene editing targets via the hosts inflammatory secretions. Manipulation of ORF 7a to evade the hosts natural defenses against virus tropism as well as the use of NTHI lysates can cause an excessive inflammatory response or a “cytokine storm” in high-risk populations who become infected with COVID-19. This mode of engineering would necessarily classify SARS-CoV-2 a biological weapon.

Transmembrane glycoprotein NMB (GPNMB) is a prognostic marker of poor outcome in patients with triple-negative breast cancer (TNBC). Glembatumumab Vedotin, an antibody drug conjugate targeting GPNMB, exhibits variable efficacy against GPNMB-positive metastatic TNBC as a single agent. We show that GPNMB levels increase in response to standard-of-care and experimental therapies for multiple breast cancer subtypes. While these therapeutic stressors induce GPNMB expression through differential engagement of the MiTF family of transcription factors, not all are capable of increasing GPNMB cell-surface localization required for Glembatumumab Vedotin inhibition. Using a FACS-based genetic screen, we discovered that suppression of heat shock protein 90 (HSP90) concomitantly increases GPNMB expression and cell-surface localization. Mechanistically, HSP90 inhibition resulted in lysosomal dispersion towards the cell periphery and fusion with the plasma membrane, which delivers GPNMB to the cell surface. Finally, treatment with HSP90 inhibitors sensitizes breast cancers to Glembatumumab Vedotin in vivo, suggesting that combination of HSP90 inhibitors and Glembatumumab Vedotin may be a viable treatment strategy for patients with metastatic TNBC.

IntroductionChildhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer.Methods and analysisThe Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models.DiscussionGECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects.Ethics and disseminationThe Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online.Trial registration numberNCT04702321.

Triphenylmethane based dyes became popular after their invention in 1858 due to their brilliant shades and high tinting strengths and were used not only as colourants for textile and paper dyeing, but also as pigments in artists' materials under the commercial name ‘Fanal®’. However, the extent of their use as pigments in artists’ paints has thus far remained unknown. Despite their bright colours, the characteristic low lightfastness of their dyes and pigments inspired further research for new precipitation methods to increase lightfastness, which ultimately resulted in precipitation using complex salts of phosphorus, tungsten, and molybdenum. The present study is based on archival source research from I.G. Farben, the former producer of Fanal®, and Royal Talens, an artists’ paint manufacturer that used these pigments. This research focuses on the history of developments in precipitation methodologies employed for early triphenylmethane dyes and the development of the various lines of Fanal® pigments in oil paints produced by the Dutch manufacturer Talens in the late 1920s and onwards. Historic literature sources, such as the Talens publication Kunstschildersmaterialen en Schildertechniek by Frits Kerdijk that document the application of Fanal® pigments, are also highlighted.

This study aimed to evaluate the effects of chitosan and homolactic microbial inoculant on fermentative losses, chemical composition, fermentative profile, and aerobic stability of whole-plant soybean silage (WPSS). Additionally, it was evaluated nutrients intake and digestibility of sheep fed increasing levels of WPSS. Thirty experimental silos were randomly allocated to one of the following treatments: 1) CON: control, WPSS without additives; 2) LPPA: WPSS with Lactobacillus plantarum and Pediococcus acidilactici; and 3) CHI: chitosan, WPSS with 5 g/kg of chitosan. Ten male sheep were used to evaluate increasing dietary levels of WPSS: 0, 200, 400, 600, and 800 g/kg of diet dry matter (DM). Additives increased silage lactic acid bacteria and decreased the count of mold and yeast, gas, and total losses. Silages treated with additives had lower pH, NH3-N, and ethanol concentrations and higher lactic and propionic acids relative to CON. LPPA-treated silos showed higher organic matter and non-fiber carbohydrates content than CHI-ones. Additives increased the aerobic stability of WPSS. The addition of WPSS in sheep diets linearly increased nutrients intake and digestibility. Chitosan and LPPA improve WPSS fermentation, aerobic stability, and nutritional value. The WPSS in substitution to Cynodon hay increases sheep feed intake and nutrients digestibility. RESUMO Este estudo objetivou avaliar os efeitos da adição de quitosana e inoculante homolático sobre as perdas fermentativas, composição química, perfil fermentativo e estabilidade aeróbia da silagem de planta inteira de soja (SPIS). Em adição, foi avaliado o consumo e a digestibilidade de nutrientes em ovinos alimentados com dietas contendo níveis crescentes de SPIS. Trinta silos experimentais foram aleatoriamente alocados a um dos seguintes tratamentos: 1) CON: controle, SPIS sem aditivos; 2) LPPA: SPIS com Lactobacillus plantarum e Pediococcus acidilactici; e 3) QUI: quitosana, SPIS com 5 g/kg de quitosana. Dez ovinos machos foram usados para avaliar os níveis dietéticos de SPIS: 0, 200, 400, 600 e 800 g/kg da matéria seca (MS). Os aditivos aumentaram a contagem de bactérias láticas e reduziram a contagem de fungos e leveduras e as perdas fermentativas totais da SPIS. Silagens tratadas com aditivos tiveram menores pH, N-NH3 e etanol e maiores concentrações de ácido lático e propiônico, quando comparadas ao tratamento controle. Silos tratados com LPPA apresentaram maiores teores de matéria orgânica e carboidratos não fibrosos do que aqueles do tratamento QUI. Os aditivos aumentaram a estabilidade aeróbia da SPIS. A adição de SPIS na dieta de ovinos aumentou linearmente o consumo e a digestibilidade dos nutrientes. Quitosana e inoculante microbiano homolático melhoram a fermentação, estabilidade aeróbia e o valor nutricional da SPIS. A substituição de feno de Cynodon por SIPS aumenta o consumo e a digestibilidade dos nutrientes em ovinos.