Archaerhodopsin variants with enhanced voltage-sensitive fluorescence in mammalian and Caenorhabditis elegans neurons

Probing the neural circuit dynamics underlying behaviour would benefit greatly from improved genetically encoded voltage indicators. The proton pump ​Archaerhodopsin-3 (​Arch), an optogenetic tool commonly used for neuronal inhibition, has been shown to emit voltage-sensitive fluorescence. Here we report two ​Arch variants with enhanced radiance (Archers) that in response to 655 nm light have 3–5 times increased fluorescence and 55–99 times reduced photocurrents compared with ​Arch WT. The most fluorescent variant, Archer1, has 25–40% fluorescence change in response to action potentials while using 9 times lower light intensity compared with other ​Arch-based voltage sensors. Archer1 is capable of wavelength-specific functionality as a voltage sensor under red light and as an inhibitory actuator under green light. As a proof-of-concept for the application of ​Arch-based sensors in vivo, we show fluorescence voltage sensing in behaving Caenorhabditis elegans. Archer1’s characteristics contribute to the goal of all-optical detection and modulation of activity in neuronal networks in vivo

Rapidly Decaying Supernova 2010X: A Candidate ".Ia" Explosion

We present the discovery, photometric and spectroscopic follow-up observations of SN 2010X (PTF 10bhp). This supernova decays exponentially with tau_d=5 days, and rivals the current recordholder in speed, SN 2002bj. SN 2010X peaks at M_r=-17mag and has mean velocities of 10,000 km/s. Our light curve modeling suggests a radioactivity powered event and an ejecta mass of 0.16 Msun. If powered by Nickel, we show that the Nickel mass must be very small (0.02 Msun) and that the supernova quickly becomes optically thin to gamma-rays. Our spectral modeling suggests that SN 2010X and SN 2002bj have similar chemical compositions and that one of Aluminum or Helium is present. If Aluminum is present, we speculate that this may be an accretion induced collapse of an O-Ne-Mg white dwarf. If Helium is present, all observables of SN 2010X are consistent with being a thermonuclear Helium shell detonation on a white dwarf, a ".Ia" explosion. With the 1-day dynamic-cadence experiment on the Palomar Transient Factory, we expect to annually discover a few such events.Comment: 6 pages, 5 figures; Minor Changes; Note correction in Fig 4 caption; published by ApJ

IGSF4 is a novel TCR ζ-chain–interacting protein that enhances TCR-mediated signaling

The expression of cell surface molecule, IGSF4, on human and mouse T cells associate with the TCR ζ-chain and colocalizes to the c-SMAC to enhance cytokine production and adhesion to APCs

Early Target Cells of Measles Virus after Aerosol Infection of Non-Human Primates

Measles virus (MV) is highly infectious, and has long been thought to enter the host by infecting epithelial cells of the respiratory tract. However, epithelial cells do not express signaling lymphocyte activation molecule (CD150), which is the high-affinity cellular receptor for wild-type MV strains. We have generated a new recombinant MV strain expressing enhanced green fluorescent protein (EGFP), based on a wild-type genotype B3 virus isolate from Khartoum, Sudan (KS). Cynomolgus macaques were infected with a high dose of rMVKSEGFP by aerosol inhalation to ensure that the virus could reach the full range of potential target cells throughout the entire respiratory tract. Animals were euthanized 2, 3, 4 or 5 days post-infection (d.p.i., n = 3 per time point) and infected (EGFP+) cells were identified at all four time points, albeit at low levels 2 and 3 d.p.i. At these earliest time points, MV-infected cells were exclusively detected in the lungs by fluorescence microscopy, histopathology and/or virus isolation from broncho-alveolar lavage cells. On 2 d.p.i., EGFP+ cells were phenotypically typed as large mononuclear cells present in the alveolar lumen or lining the alveolar epithelium. One to two days later, larger clusters of MV-infected cells were detected in bronchus-associated lymphoid tissue (BALT) and in the tracheo-bronchial lymph nodes. From 4 d.p.i. onward, MV-infected cells were detected in peripheral blood and various lymphoid tissues. In spite of the possibility for the aerosolized virus to infect cells and lymphoid tissues of the upper respiratory tract, MV-infected cells were not detected in either the tonsils or the adenoids until after onset of viremia. These data strongly suggest that in our model MV entered the host at the alveolar level by infecting macrophages or dendritic cells, which traffic the virus to BALT or regional lymph nodes, resulting in local amplification and subsequent systemic dissemination by viremia

Understanding the science-learning environment: a genetically sensitive approach.

Previous studies have shown that environmental influences on school science performance increase in importance from primary to secondary school. Here we assess for the first time the relationship between the science-learning environment and science performance using a genetically sensitive approach to investigate the aetiology of this link. 3000 pairs of 14-year-old twins from the UK Twins Early Development Study reported on their experiences of the science-learning environment and were assessed for their performance in science using a web-based test of scientific enquiry. Multivariate twin analyses were used to investigate the genetic and environmental links between environment and outcome. The most surprising result was that the science-learning environment was almost as heritable (43%) as performance on the science test (50%), and showed negligible shared environmental influence (3%). Genetic links explained most (56%) of the association between learning environment and science outcome, indicating gene–environment correlation

Discovery of a Cosmological, Relativistic Outburst via its Rapidly Fading Optical Emission

We report the discovery by the Palomar Transient Factory (PTF) of the transient source PTF11agg, which is distinguished by three primary characteristics: (1) bright (R_peak = 18.3 mag), rapidly fading (ΔR = 4 mag in Δt = 2 days) optical transient emission; (2) a faint (R = 26.2 ± 0.2 mag), blue (g' – R = 0.17 ± 0.29 mag) quiescent optical counterpart; and (3) an associated year-long, scintillating radio transient. We argue that these observed properties are inconsistent with any known class of Galactic transients (flare stars, X-ray binaries, dwarf novae), and instead suggest a cosmological origin. The detection of incoherent radio emission at such distances implies a large emitting region, from which we infer the presence of relativistic ejecta. The observed properties are all consistent with the population of long-duration gamma-ray bursts (GRBs), marking the first time such an outburst has been discovered in the distant universe independent of a high-energy trigger. We searched for possible high-energy counterparts to PTF11agg, but found no evidence for associated prompt emission. We therefore consider three possible scenarios to account for a GRB-like afterglow without a high-energy counterpart: an "untriggered" GRB (lack of satellite coverage), an "orphan" afterglow (viewing-angle effects), and a "dirty fireball" (suppressed high-energy emission). The observed optical and radio light curves appear inconsistent with even the most basic predictions for off-axis afterglow models. The simplest explanation, then, is that PTF11agg is a normal, on-axis long-duration GRB for which the associated high-energy emission was simply missed. However, we have calculated the likelihood of such a serendipitous discovery by PTF and find that it is quite small (≈2.6%). While not definitive, we nonetheless speculate that PTF11agg may represent a new, more common (>4 times the on-axis GRB rate at 90% confidence) class of relativistic outbursts lacking associated high-energy emission. If so, such sources will be uncovered in large numbers by future wide-field optical and radio transient surveys

Alliance of Genome Resources Portal: unified model organism research platform

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource

Alliance of Genome Resources Portal: unified model organism research platform

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource

Management of patients with advanced prostate cancer—metastatic and/or castration-resistant prostate cancer: report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022

Background: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. Objective: To present the voting results of the APCCC 2022. Design, setting, and participants: The experts voted on controversial questions where high- level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration- resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. Outcome measurements and statistical analysis: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration- resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. Results and limitations: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. Conclusions: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. Patient summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. Twitter summary: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. Take-home message: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration- resistant prostate cancer is summarised here

Witnessing the Early Growth and Life Cycle of Galaxies with KMOS3D

Near-infrared integral field unit (IFU) spectrographs are powerful tools for investigating galaxy evolution. We report on our recently completed multi-year KMOS3D survey of Halpha, [NII] and [SII] line emission of galaxies at redshift z ~ 0.7 - 2.7 with the K-band Multi-Object Spectrograph (KMOS) at the Very Large Telescope (VLT). With deep observations of 745 targets spanning over two orders of magnitude in galaxy mass, five billion years of cosmic time, and all levels of star formation, KMOS3D provides an unparalleled population-wide census of spatially-resolved kinematics, star formation, outflows and nebular gas conditions. The dataset sheds new light on the physical mechanisms driving the early growth and lifecycle of galaxies, and provides a rich legacy for the astronomical community