More than meets the eye: The role of microglia in healthy and diseased retina

Microglia are the main resident immune cells of the nervous system and as such they are involved in multiple roles ranging from tissue homeostasis to response to insults and circuit refinement. While most knowledge about microglia comes from brain studies, some mechanisms have been confirmed for microglia cells in the retina, the light-sensing compartment of the eye responsible for initial processing of visual information. However, several key pieces of this puzzle are still unaccounted for, as the characterization of retinal microglia has long been hindered by the reduced population size within the retina as well as the previous lack of technologies enabling single-cell analyses. Accumulating evidence indicates that the same cell type may harbor a high degree of transcriptional, morphological and functional differences depending on its location within the central nervous system. Thus, studying the roles and signatures adopted specifically by microglia in the retina has become increasingly important. Here, we review the current understanding of retinal microglia cells in physiology and in disease, with particular emphasis on newly discovered mechanisms and future research directions

Achromatopsia: Genetics and Gene Therapy

Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3- and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application

The mechanism for directional hearing in fish

Locating sound sources such as prey or predators is critical for survival in many vertebrates. Terrestrial vertebrates locate sources by measuring the time delay and intensity difference of sound pressure at each ear1-5. Underwater, however, the physics of sound makes interaural cues very small, suggesting that directional hearing in fish should be nearly impossible6. Yet, directional hearing has been confirmed behaviourally, although the mechanisms have remained unknown for decades. Several hypotheses have been proposed to explain this remarkable ability, including the possibility that fish evolved an extreme sensitivity to minute interaural differences or that fish might compare sound pressure with particle motion signals7,8. However, experimental challenges have long hindered a definitive explanation. Here we empirically test these models in the transparent teleost Danionella cerebrum, one of the smallest vertebrates9,10. By selectively controlling pressure and particle motion, we dissect the sensory algorithm underlying directional acoustic startles. We find that both cues are indispensable for this behaviour and that their relative phase controls its direction. Using micro-computed tomography and optical vibrometry, we further show that D. cerebrum has the sensory structures to implement this mechanism. D. cerebrum shares these structures with more than 15% of living vertebrate species, suggesting a widespread mechanism for inferring sound direction

ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group

Circulating tumour DNA (ctDNA); Liquid biopsy; Precision medicineDNA tumoral circulant (ctDNA); Biòpsia líquida; Medicina de precisióADN tumoral circulante (ctDNA); Biopsia líquida; Medicina de precisiónCirculating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue-based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false-negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease or molecular relapse, has high evidence of clinical validity in anticipating future relapse in many cancers. Molecular residual disease/molecular relapse detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations before clinical progression, and in screening asymptomatic people for cancer. Recommendations for reporting of results, future development of ctDNA assays and future clinical research are made.This project was funded by the European Society for Medical Oncology (no grant number)

Space Odyssey: An Experimental Software Security Analysis of Satellites

Satellites are an essential aspect of our modern society and have contributed significantly to the way we live today, most notable through modern telecommunications, global positioning, and Earth observation. In recent years, and especially in the wake of the New Space Era, the number of satellite deployments has seen explosive growth. Despite its critical importance, little academic research has been con- ducted on satellite security and, in particular, on the security of onboard firmware. This lack likely stems from by now outdated assumptions on achieving security by obscurity, effectively preventing meaningful research on satellite firmware. In this paper, we first provide a taxonomy of threats against satellite firmware. We then conduct an experimental security analysis of three real-world satellite firmware images. We base our analysis on a set of real-world attacker models and find several security-critical vulnerabilities in all analyzed firmware images. The results of our experimental security assessment show that modern in-orbit satellites suffer from different software security vulnerabilities and often a lack of proper access protection mechanisms. They also underline the need to overcome prevailing but obsolete assumptions. To substantiate our observations, we also performed a survey of 19 professional satellite developers to obtain a comprehensive picture of the satellite security landscape

Experimental consolidation and absolute measurement of the nat C(p,x)11 C nuclear activation cross section at 100 MeV for particle therapy physics

The natC(p,x)11C reaction has been discussed in detail in the past [EXFOR database, Otuka et al. (Nuclear Data Sheets 120:272–276, 2014)]. However, measured activation cross sections by independent experiments are up to 15% apart. The aim of this study is to investigate underlying reasons for these observed discrepancies between different experiments and to determine a new consensus reference cross section at 100 MeV. Therefore, the experimental methods described in the two recent publications [Horst et al. (Phys Med Biol https://doi.org/10.1088/1361-6560/ab4511 [Titel anhand dieser DOI in Citavi-Projekt übernehmen] , 2019) and Bäcker et al. (Nuclear Instrum Methods Phys Res B 454:50–55, 2019)] are compared in detail and all experimental parameters are investigated for their impact on the results. For this purpose, a series of new experiments is performed. With the results of the experiments a new reference cross section of (68±3) mb is derived at (97±3) MeV proton energy. This value combined with the reliably measured excitation function could provide accurate cross section values for the energy region of proton therapy. Because of the well-known gamma-ray spectrometer used and the well-defined beam characteristics of the treatment machine at the proton therapy center, the experimental uncertainties on the absolute cross section could be reduced to 3%. Additionally, this setup is compared to the in-beam measurement setup from the second study presented in the literature (Horst et al. 2019). Another independent validation of the measurements is performed with a PET scanner

ER Stress-Induced Aggresome Trafficking of HtrA1 Protects Against 1! Proteotoxicity

High temperature requirement A1 (HtrA1) belongs to an ancient protein family that is linked to various human disorders. The precise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrA1 remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is implicated in unfolded protein response. In highly secretory cells of the retinal pigmented epithelia, endoplasmic reticulum (ER) stress upregulated HtrA1. HtrA1 co-localized with vimentin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions displayed reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mammalian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis

Multimodal Communication in a Noisy Environment: A Case Study of the Bornean Rock Frog Staurois parvus

High background noise is an impediment to signal detection and perception. We report the use of multiple solutions to improve signal perception in the acoustic and visual modality by the Bornean rock frog, Staurois parvus. We discovered that vocal communication was not impaired by continuous abiotic background noise characterised by fast-flowing water. Males modified amplitude, pitch, repetition rate and duration of notes within their advertisement call. The difference in sound pressure between advertisement calls and background noise at the call dominant frequency of 5578 Hz was 8 dB, a difference sufficient for receiver detection. In addition, males used several visual signals to communicate with conspecifics with foot flagging and foot flashing being the most common and conspicuous visual displays, followed by arm waving, upright posture, crouching, and an open-mouth display. We used acoustic playback experiments to test the efficacy-based alerting signal hypothesis of multimodal communication. In support of the alerting hypothesis, we found that acoustic signals and foot flagging are functionally linked with advertisement calling preceding foot flagging. We conclude that S. parvus has solved the problem of continuous broadband low-frequency noise by both modifying its advertisement call in multiple ways and by using numerous visual signals. This is the first example of a frog using multiple acoustic and visual solutions to communicate in an environment characterised by continuous noise