Heterogeneity in Kv2 Channel Expression Shapes Action Potential Characteristics and Firing Patterns in CA1 versus CA2 Hippocampal Pyramidal Neurons.

The CA1 region of the hippocampus plays a critical role in spatial and contextual memory, and has well-established circuitry, function and plasticity. In contrast, the properties of the flanking CA2 pyramidal neurons (PNs), important for social memory, and lacking CA1-like plasticity, remain relatively understudied. In particular, little is known regarding the expression of voltage-gated K+ (Kv) channels and the contribution of these channels to the distinct properties of intrinsic excitability, action potential (AP) waveform, firing patterns and neurotransmission between CA1 and CA2 PNs. In the present study, we used multiplex fluorescence immunolabeling of mouse brain sections, and whole-cell recordings in acute mouse brain slices, to define the role of heterogeneous expression of Kv2 family Kv channels in CA1 versus CA2 pyramidal cell excitability. Our results show that the somatodendritic delayed rectifier Kv channel subunits Kv2.1, Kv2.2, and their auxiliary subunit AMIGO-1 have region-specific differences in expression in PNs, with the highest expression levels in CA1, a sharp decrease at the CA1-CA2 boundary, and significantly reduced levels in CA2 neurons. PNs in CA1 exhibit a robust contribution of Guangxitoxin-1E-sensitive Kv2-based delayed rectifier current to AP shape and after-hyperpolarization potential (AHP) relative to that seen in CA2 PNs. Our results indicate that robust Kv2 channel expression confers a distinct pattern of intrinsic excitability to CA1 PNs, potentially contributing to their different roles in hippocampal network function

Identification of novel arsenic resistance genes in yeast

Arsenic is a toxic metalloid that affects human health by causing numerous diseases and by being used in the treatment of acute promyelocytic leukemia. Saccharomyces cerevisiae (budding yeast) has been extensively utilized to elucidate the molecular mechanisms underlying arsenic toxicity and resistance in eukaryotes. In this study, we applied a genomic DNA overexpression strategy to identify yeast genes that provide arsenic resistance in wild-type and arsenic-sensitive S. cerevisiae cells. In addition to known arsenic-related genes, our genetic screen revealed novel genes, including PHO86, VBA3, UGP1, and TUL1, whose overexpression conferred resistance. To gain insights into possible resistance mechanisms, we addressed the contribution of these genes to cell growth, intracellular arsenic, and protein aggregation during arsenate exposure. Overexpression of PHO86 resulted in higher cellular arsenic levels but no additional effect on protein aggregation, indicating that these cells efficiently protect their intracellular environment. VBA3 overexpression caused resistance despite higher intracellular arsenic and protein aggregation levels. Overexpression of UGP1 led to lower intracellular arsenic and protein aggregation levels while TUL1 overexpression had no impact on intracellular arsenic or protein aggregation levels. Thus, the identified genes appear to confer arsenic resistance through distinct mechanisms but the molecular details remain to be elucidated

Ecchymotic Purpura of the Breast Revealing a Locally Advanced Breast Cancer: An Exceptional Presentation of a Carcinomatous Mastitis

A 79-year-old woman was treated at our department for a neoplasm of the left breast. It was discovered following the spontaneous appearance of a localized ecchymotic lesion of the breast. The only clinical sign was this purpura, with no notion of trauma. The lesion was homogeneous, oval, and measuring 4 × 5 cm, and it was stable for 2 months. The patient had no history of thrombocytopenia and no known allergy. The physical examination was not very helpful and did not find any palpable breast lesion besides a 1-cm left axillary lymphadenopathy. Breast screening revealed a solid, poorly delineated structure of 11 mm. Biopsies were taken and revealed a NOS grade II invasive carcinoma, triple negative, with a Ki-67 proliferation index of 15%. The axillary cytology was positive. Faced with this atypical presentation, a skin biopsy was performed on the bruise in order to exclude skin invasion. Histology showed the presence of carcinomatous lymphatic dermal emboli which could correspond to a mammary origin as well as extravasation of blood in the dermis explaining this ecchymotic aspect. Bone scintigraphy found discrete uptake in the rib cage, spine, and pelvis, suspicious in this context, but a benign origin could not be ruled out. Neoadjuvant chemotherapy was initiated before mastectomy and left axillary node dissection. It was an atypical and rare clinical presentation of advanced breast cancer with no similar case found in the literature. Usually, the presence of emboli with carcinomatous cells obstructing the lymphatic vessels is related to inflammatory breast cancer or carcinomatous mastitis. The authors nevertheless point out that although the presence of tumor emboli in the dermal lymphatic vessels is favorable to the diagnosis, it is not required. In addition, dermal lymphatic invasion without a typical clinical presentation is not sufficient to confirm the diagnosis of carcinomatous mastitis. An important diagnostic criterion is the rapidity of aggravation of the symptoms, which, even if it was not obvious in our case, was present with progressive evolution of the skin lesion over several weeks. The skin lesion of our patient could also make us suspect a primary breast angiosarcoma. This possibility was quickly eliminated in the absence of vascular tumor proliferation on the various biopsies. Any acute purpura is a serious disease to be diagnosed urgently, and a skin biopsy is indicated

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

The toxic metalloid arsenic causes widespread misfolding and aggregation of cellular proteins. How these protein aggregates are formed in vivo, the mechanisms by which they affect cells and how cells prevent their accumulation is not fully understood. To find components involved in these processes, we performed a genome-wide imaging screen and identified Saccharomyces cerevisiae deletion mutants with either enhanced or reduced protein aggregation levels during arsenite exposure. We show that many of the identified factors are crucial to safeguard protein homeostasis (proteostasis) and to protect cells against arsenite toxicity. The hits were enriched for various functions including protein biosynthesis and transcription, and dedicated follow-up experiments highlight the importance of accurate transcriptional and translational control for mitigating protein aggregation and toxicity during arsenite stress. Some of the hits are associated with pathological conditions, suggesting that arsenite-induced protein aggregation may affect disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress identified in this current study provides a valuable resource and a framework for further elucidation of the mechanistic details of metalloid toxicity and pathogenesis. This article has an associated First Person interview with the first authors of the paper

A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo

Experiments with replication-competent SARS-CoV-2 were performed in the Biomedicum BSL3 core facility, Karolinska Institutet. We thank Jonas Klingström for providing Calu-3 cells and sharing the Swedish SARS-CoV-2 isolate, and Alex Sigal from the Africa Health Research Institute for providing the beta variant (B.1.351/501Y.V2) isolate. We thank Penny Moore and the NICD (South Africa) for providing the B.1.351/beta variant spike plasmid, which was generated using funding from the South African Medical Research Council. We gratefully acknowledge the G2P-UK National Virology consortium funded by MRC/UKRI (grant ref: MR/W005611/1.) and the Barclay Lab at Imperial College for providing the B.1.617.2 spike plasmid. All cryo-EM data were collected in the Karolinska Institutet’s 3D-EM facility. We thank Agustin Ure for assistance with figure generation and Tomas Nyman (Protein Science Facility at KI) for providing access to SPR instruments. L.H. was supported by the David och Astrid Hageléns stiftelse, the Clas Groschinskys Minnesfond and a Jonas Söderquist’s scholarship. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 101003653 (CoroNAb), to B.M. and G.M.M. B.M.H. is supported by the Knut and Alice Wallenberg Foundation (KAW 2017.0080 and KAW 2018.0080). The work was supported by project grants from the Swedish Research Council to E.S. (2020-02682), B.M.H. (2017-6702 and 2018-3808), B.M. (2018-02381) and to G.M.M. (2018-03914 and 2018-03843). E.S. is supported by Karolinska Institutet Foundation Grants, National Molecular Medicine Program Grants, and the grants from the SciLifeLab National COVID-19 Research Program, financed by the Knut and Alice Wallenberg Foundation. We thank National Microscopy Infrastructure, NMI (VR-RFI 2016-00968).N

Guidelines for the characterization and use of fibre optic sensors: basic definitions and a proposed standard for FBG-based strain sensors

This paper describes the outcome of two groups which are involved in the specification of guidelines for fibre optic sensors performance and testing. The "Guideline for use of fibre optic sensors" from the COST-299 guideline group, and the "Optical Strain Sensor based on Fibre Bragg Grating" from the GESA guideline group of the VDI - "The Association of German Engineers". Through appropriate specifications and definitions, both guidelines aim at enabling better understanding of fibre optic sensors characteristics and performances. A concise view into the structure of the guidelines is presented, emphasizing important aspects. The English version of the two guidelines will be available in autumn 2009

Guideline for Use of Fibre Optic Sensors

Development of standards and guidelines for performance specifications and testing for fibre optic sensors has been discussed since the mid-nineties of the last century in the scientific community as well as in the industry. Very global standards for the use of fibre optic components in data communication and telecommunication have been available for more than 20 years. Guidelines or substantial standards for fibre optic sensors are rather an exception. The first standard draft on generic specification of fibre optic sensors has been published in 1995 (IEC 61757-1:1995); the first draft for a specific type of fibre sensor - the fibre optic gyroscope - was published in 1996 (IEEE Standard Specification Format Guide and Test Procedures for Single-Axis Interferometric Fiber Optic Gyros; Working Draft P952/D24). Some terms used in fibre optic communication are quite close to the terminology typically used in fibre optic sensor technology. However, there are a huge number of specific issues associated with specifically fibre optic sensing systems. These items are not considered in existing guidelines or standards. For instance, standards for fibre optic sensors have to cover characteristic details related to the respective physical sensor mechanism, to the sensor response for different measurands, to the application, and finally to specific environmental conditions. Naturally, it is not possible to cover either all different aspects of fibre optic sensors in one standard or a set of harmonized standards. This very complex matter requires specific guidelines for specific sensor types (e.g. distributed sensors, point sensors such as fibre Bragg grating (FBG) sensors, sensors for mechanical measurands such as strain, deformation, biological and chemical sensors or sensors for physical quantities such as pressure, humidity, and ionizing radiation). In order to define clear guidelines and/or regulations for appropriate characterization of performance specifications and better understanding of frequently used fibre optic sensors, particular activity has been established within the European COST Action 299 “FIDES” (Optical Fibres for New Challenges Facing the Information Society) in the framework of its Working Group 4: “New Challenges in Fibre Optic Sensors”

ARTEFACTS: How do we want to deal with the future of our one and only planet?

The European Commission’s Science and Knowledge Service, the Joint Research Centre (JRC), decided to try working hand-in-hand with leading European science centres and museums. Behind this decision was the idea that the JRC could better support EU Institutions in engaging with the European public. The fact that European Union policies are firmly based on scientific evidence is a strong message which the JRC is uniquely able to illustrate. Such a collaboration would not only provide a platform to explain the benefits of EU policies to our daily lives but also provide an opportunity for European citizens to engage by taking a more active part in the EU policy making process for the future. A PILOT PROGRAMME To test the idea, the JRC launched an experimental programme to work with science museums: a perfect partner for three compelling reasons. Firstly, they attract a large and growing number of visitors. Leading science museums in Europe have typically 500 000 visitors per year. Furthermore, they are based in large European cities and attract local visitors as well as tourists from across Europe and beyond. The second reason for working with museums is that they have mastered the art of how to communicate key elements of sophisticated arguments across to the public and making complex topics of public interest readily accessible. That is a high-value added skill and a crucial part of the valorisation of public-funded research, never to be underestimated. Finally museums are, at present, undergoing something of a renaissance. Museums today are vibrant environments offering new techniques and technologies to both inform and entertain, and attract visitors of all demographics.JRC.H.2-Knowledge Management Methodologies, Communities and Disseminatio

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)