Retinoic acid signaling acts via Hox1 to establish the posterior limit of the pharynx in the chordate amphioxus

In the invertebrate chordate amphioxus, as in vertebrates, retinoic acid (RA) specifies position along the anterior/posterior axis with elevated RA signaling in the middle third of the endoderm setting the posterior limit of the pharynx. Here we show that AmphiHox1 is also expressed in the middle third of the developing amphioxus endoderm and is activated by RA signaling. Knockdown of AmphiHox1 function with an antisense morpholino oligonucleotide shows that AmphiHox1 mediates the role of RA signaling in setting the posterior limit of the pharynx by repressing expression of pharyngeal markers in the posterior foregut/midgut endoderm. The spatiotemporal expression of these endodermal genes in embryos treated with RA or the RA antagonist BMS009 indicates that Pax1/9, Pitx and Notch are probably more upstream than Otx and Nodal in the hierarchy of genes repressed by RA signaling. This work highlights the potential of amphioxus, a genomically simple, vertebrate-like invertebrate chordate, as a paradigm for understanding gene hierarchies similar to the more complex ones of vertebrates

An exciton-polariton laser based on biologically produced fluorescent protein

We thank A. Clemens (TU Dresden, Germany) for technical support with protein preparation and C. Murawski (U St Andrews, UK) for support with TDAF deposition. We acknowledge support from the ERC Starting Grant ABLASE (640012), the Scottish Funding Council (via SUPA), the European Union Marie Curie Career Integration Grant (PCIG12-GA-2012-334407), studentship funding through the EPSRC CM-DTC (EP/L015110/1) and the EPSRC Hybrid Polaritonics program grant (EP/M025330/1). S.H. gratefully acknowledges support by the Royal Society and the Wolfson Foundation and M.S. gratefully acknowledges support from a MSCA IF (659213).Under adequate conditions, cavity-polaritons form a macroscopic coherent quantum state, known as polariton condensate (PC). Compared to Wannier-Mott polaritons in inorganic semiconductors, the localized Frenkel polaritons in organic emitter materials show weaker interaction with each other but stronger coupling to light, which recently enabled the first realization of a PC at room temperature. However, this required ultrafast optical pumping which limits the applications of organic PCs. Here, we demonstrate room-temperature PCs of cavity-polaritons in simple laminated microcavities filled with the biologically produced enhanced green fluorescent protein (eGFP). The unique molecular structure of eGFP prevents exciton annihilation even at high excitation densities, thus facilitating PCs under conventional nanosecond pumping. Condensation is clearly evidenced by a distinct threshold, an interaction-induced blueshift of the condensate, long-range coherence and the presence of a second threshold at higher excitation density which is associated with the onset of photon lasing.Publisher PDFPeer reviewe

Self-reactive human CD4 T cell clones form unusual immunological synapses

Recognition of self–peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR–pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease

What works to increase charitable donations? A meta-review with meta-meta-analysis

Many charities rely on donations to support their work addressing some of the world’s most pressing problems. We conducted a meta-review to determine what interventions work to increase charitable donations. We found 21 systematic reviews incorporating 1339 primary studies and over 2,139,938 participants. Our meta-meta-analysis estimated the average effect of an intervention on charitable donation size and incidence: r = 0.08 (95% CI [0.03, 0.12]). Due to limitations in the included systematic reviews, we are not certain this estimate reflects the true overall effect size. The most robust evidence found suggests charities could increase donations by (1) emphasising individual beneficiaries, (2) increasing the visibility of donations, (3) describing the impact of the donation, and (4) enacting or promoting tax-deductibility of the charity. We make recommendations for improving primary research and reviews about charitable donations, and how to apply the meta-review findings to increase charitable donations

Developing Recombinant Antibodies by Phage Display Against Infectious Diseases and Toxins for Diagnostics and Therapy

Antibodies are essential molecules for diagnosis and treatment of diseases caused by pathogens and their toxins. Antibodies were integrated in our medical repertoire against infectious diseases more than hundred years ago by using animal sera to treat tetanus and diphtheria. In these days, most developed therapeutic antibodies target cancer or autoimmune diseases. The COVID-19 pandemic was a reminder about the importance of antibodies for therapy against infectious diseases. While monoclonal antibodies could be generated by hybridoma technology since the 70ies of the former century, nowadays antibody phage display, among other display technologies, is robustly established to discover new human monoclonal antibodies. Phage display is an in vitro technology which confers the potential for generating antibodies from universal libraries against any conceivable molecule of sufficient size and omits the limitations of the immune systems. If convalescent patients or immunized/infected animals are available, it is possible to construct immune phage display libraries to select in vivo affinity-matured antibodies. A further advantage is the availability of the DNA sequence encoding the phage displayed antibody fragment, which is packaged in the phage particles. Therefore, the selected antibody fragments can be rapidly further engineered in any needed antibody format according to the requirements of the final application. In this review, we present an overview of phage display derived recombinant antibodies against bacterial, viral and eukaryotic pathogens, as well as microbial toxins, intended for diagnostic and therapeutic applications

Association of Mortality and Risk of Epilepsy With Type of Acute Symptomatic Seizure After Ischemic Stroke and an Updated Prognostic Model

IMPORTANCE: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. OBJECTIVE: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. EXPOSURES: Type of acute symptomatic seizure. MAIN OUTCOMES AND MEASURES: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). RESULTS: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. CONCLUSIONS AND RELEVANCE: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up

Design of a dual species atom interferometer for space

Atom interferometers have a multitude of proposed applications in space including precise measurements of the Earth's gravitational field, in navigation & ranging, and in fundamental physics such as tests of the weak equivalence principle (WEP) and gravitational wave detection. While atom interferometers are realized routinely in ground-based laboratories, current efforts aim at the development of a space compatible design optimized with respect to dimensions, weight, power consumption, mechanical robustness and radiation hardness. In this paper, we present a design of a high-sensitivity differential dual species $^{85}$Rb/$^{87}$Rb atom interferometer for space, including physics package, laser system, electronics and software. The physics package comprises the atom source consisting of dispensers and a 2D magneto-optical trap (MOT), the science chamber with a 3D-MOT, a magnetic trap based on an atom chip and an optical dipole trap (ODT) used for Bose-Einstein condensate (BEC) creation and interferometry, the detection unit, the vacuum system for $10^{-11}$ mbar ultra-high vacuum generation, and the high-suppression factor magnetic shielding as well as the thermal control system. The laser system is based on a hybrid approach using fiber-based telecom components and high-power laser diode technology and includes all laser sources for 2D-MOT, 3D-MOT, ODT, interferometry and detection. Manipulation and switching of the laser beams is carried out on an optical bench using Zerodur bonding technology. The instrument consists of 9 units with an overall mass of 221 kg, an average power consumption of 608 W (819 W peak), and a volume of 470 liters which would well fit on a satellite to be launched with a Soyuz rocket, as system studies have shown.Comment: 30 pages, 23 figures, accepted for publication in Experimental Astronom

STE-QUEST - Test of the Universality of Free Fall Using Cold Atom Interferometry

In this paper, we report about the results of the phase A mission study of the atom interferometer instrument covering the description of the main payload elements, the atomic source concept, and the systematic error sources

Machi: Neighborhood and Small Town—The Foundation for Urban Transformation in Japan

The term machi, signifying both neighborhood and small town, is a key element for understanding Japanese urban form and city planning. After tracing the origins of the term, this article explores the historic and contemporary significance of the concept and its particular spatial and socioeconomic forms. The article then argues that the concept of machi influenced the ways in which Japanese planners picked up foreign concepts through the nineteenth and particularly the twentieth century, absorbing some ideas and rejecting others. Building on their perception of the city as composed of urban units that allowed for planning in patchwork patterns, leading Japanese planners carefully selected models—independently of international appreciation—making, for example, the book The New Town by the German planner Gottfried Feder a standard reference. The article concludes by arguing that foreign observers must understand the concept of machi to comprehend contemporary Japanese neighborhoods, city life, and urban forms

Covid-19 triage in the emergency department 2.0: how analytics and AI transform a human-made algorithm for the prediction of clinical pathways

The Covid-19 pandemic has pushed many hospitals to their capacity limits. Therefore, a triage of patients has been discussed controversially primarily through an ethical perspective. The term triage contains many aspects such as urgency of treatment, severity of the disease and pre-existing conditions, access to critical care, or the classification of patients regarding subsequent clinical pathways starting from the emergency department. The determination of the pathways is important not only for patient care, but also for capacity planning in hospitals. We examine the performance of a human-made triage algorithm for clinical pathways which is considered a guideline for emergency departments in Germany based on a large multicenter dataset with over 4,000 European Covid-19 patients from the LEOSS registry. We find an accuracy of 28 percent and approximately 15 percent sensitivity for the ward class. The results serve as a benchmark for our extensions including an additional category of palliative care as a new label, analytics, AI, XAI, and interactive techniques. We find significant potential of analytics and AI in Covid-19 triage regarding accuracy, sensitivity, and other performance metrics whilst our interactive human-AI algorithm shows superior performance with approximately 73 percent accuracy and up to 76 percent sensitivity. The results are independent of the data preparation process regarding the imputation of missing values or grouping of comorbidities. In addition, we find that the consideration of an additional label palliative care does not improve the results