The TESS-Keck Survey. VIII. Confirmation of a Transiting Giant Planet on an Eccentric 261 Day Orbit with the Automated Planet Finder Telescope*

We report the discovery of TOI-2180 b, a 2.8 M J giant planet orbiting a slightly evolved G5 host star. This planet transited only once in Cycle 2 of the primary Transiting Exoplanet Survey Satellite (TESS) mission. Citizen scientists identified the 24 hr single-transit event shortly after the data were released, allowing a Doppler monitoring campaign with the Automated Planet Finder telescope at Lick Observatory to begin promptly. The radial velocity observations refined the orbital period of TOI-2180 b to be 260.8 ± 0.6 days, revealed an orbital eccentricity of 0.368 ± 0.007, and discovered long-term acceleration from a more distant massive companion. We conducted ground-based photometry from 14 sites spread around the globe in an attempt to detect another transit. Although we did not make a clear transit detection, the nondetections improved the precision of the orbital period. We predict that TESS will likely detect another transit of TOI-2180 b in Sector 48 of its extended mission. We use giant planet structure models to retrieve the bulk heavy-element content of TOI-2180 b. When considered alongside other giant planets with orbital periods over 100 days, we find tentative evidence that the correlation between planet mass and metal enrichment relative to stellar is dependent on orbital properties. Single-transit discoveries like TOI-2180 b highlight the exciting potential of the TESS mission to find planets with long orbital periods and low irradiation fluxes despite the selection biases associated with the transit method.

Scaling up experimental social, behavioral, and economic science

The standard experimental paradigm in the social, behavioral, and economic sciences is extremely limited. Although recent advances in digital technologies and crowdsourcing services allow individual experiments to be deployed and run faster than in traditional physical labs, a majority of experiments still focus on one-off results that do not generalize easily to real-world contexts or even to other variations of the same experiment. As a result, there exist few universally acknowledged findings, and even those are occasionally overturned by new data. We argue that to achieve replicable, generalizable, scalable and ultimately useful social and behavioral science, a fundamental rethinking of the model of virtual-laboratory style experiments is required. Not only is it possible to design and run experiments that are radically different in scale and scope than was possible in an era of physical labs; this ability allows us to ask fundamentally different types of questions than have been asked historically of lab studies. We posit, however, that taking full advantage of this new and exciting potential will require four major changes to the infrastructure, methodology, and culture of experimental science: (1) significant investments in software design and participant recruitment, (2) innovations in experimental design and analysis of experimental data, (3) adoption of new models of collaboration, and (4) a new understanding of the nature and role of theory in experimental social and behavioral science. We conclude that the path we outline, although ambitious, is well within the power of current technology and has the potential to facilitate a new class of scientific advances in social, behavioral and economic studies.This paper emerged from discussions at a workshop held by the Computational Social Science Lab at the University of Pennsylvania in January 2020. The work was supported by James and Jane Manzi Analytics Fund and the Alfred P. Sloan Foundation.

Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

In humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1–2% of patients with autism spectrum disorders—a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance

In a biologic therapeutic landscape that requires versatility in targeting specificity, valency and half-life modulation, the monomeric Fc fusion platform holds exciting potential for the creation of a class of monovalent protein therapeutics that includes fusion proteins and bispecific targeting molecules. Here we report a structure-guided approach to engineer monomeric Fc molecules to adapt multiple versions of half-life extension modifications. Co-crystal structures of these monomeric Fc variants with Fc neonatal receptor (FcRn) shed light into the binding interactions that could serve as a guide for engineering the half-life of antibody Fc fragments. These engineered monomeric Fc molecules also enabled the generation of a novel monovalent bispecific molecular design, which translated the FcRn binding enhancement to improvement of in vivo serum half-life.

Systematic Evolution of Ligands by Exponential Enrichment Technologies and Aptamer-Based Applications: Recent Progress and Challenges in Precision Medicine of Infectious Diseases

Infectious diseases are considered as a pressing challenge to global public health. Accurate and rapid diagnostics tools for early recognition of the pathogen, as well as individualized precision therapy are essential for controlling the spread of infectious diseases. Aptamers, which were screened by systematic evolution of ligands by exponential enrichment (SELEX), can bind to targets with high affinity and specificity so that have exciting potential in both diagnosis and treatment of infectious diseases. In this review, we provide a comprehensive overview of the latest development of SELEX technology and focus on the applications of aptamer-based technologies in infectious diseases, such as targeted drug-delivery, treatments and biosensors for diagnosing. The challenges and the future development in this field of clinical application will also be discussed.

Small Molecule Microcrystal Electron Diffraction for the Pharmaceutical Industry–Lessons Learned From Examining Over Fifty Samples

The emerging field of microcrystal electron diffraction (MicroED) is of great interest to industrial researchers working in the drug discovery and drug development space. The promise of being able to routinely solve high-resolution crystal structures without the need to grow large crystals is very appealing. Despite MicroED’s exciting potential, adoption across the pharmaceutical industry has been slow, primarily owing to a lack of access to specialized equipment and expertise. Here we present our experience building a small molecule MicroED service pipeline for members of the pharmaceutical industry. In the past year, we have examined more than fifty small molecule samples submitted by our clients, the majority of which have yielded data suitable for structure solution. We also detail our experience determining small molecule MicroED structures of pharmaceutical interest and offer some insights into the typical experimental outcomes. This experience has led us to conclude that small molecule MicroED adoption will continue to grow within the pharmaceutical industry where it is able to rapidly provide structures inaccessible by other methods.

Virtual Migration through Online Freelancing: Evidence from Bangladesh

Youth unemployment is a major issue in many developing countries, particularly in locations not well connected with large urban markets. A limited number of available job opportunities in urban centres may reduce the benefit of policies that encourage rural–urban migration. In this project, we investigated the feasibility of ‘virtual migration’, by training rural youth in Bangladesh to become online freelancers, enabling them to export their labour services to a global online marketplace. We did this by setting up a ‘freelancing incubator’, which provided the necessary workspace and infrastructure – specifically, high-speed internet connectivity and computers. Close mentoring was also provided to participants to assist in navigating the competitive online marketplace. We show the exciting potential of online work for improving the incomes of poor youth in developing countries. We also highlight the constraints to this type of work: financing constraints for the high training cost, access to the necessary work infrastructure, and soft skills requirements to succeed in the market. We also shed light on some promising possibilities for innovative financial contracts and for ‘freelancing incubators’ or ‘virtual exporting companies’ to assist students in their sourcing of work and skills development.

Structure vs. Function of TRIB1—Myeloid Neoplasms and Beyond

The Tribbles family of proteins—comprising TRIB1, TRIB2, TRIB3 and more distantly related STK40—play important, but distinct, roles in differentiation, development and oncogenesis. Of the four Tribbles proteins, TRIB1 has been most well characterised structurally and plays roles in diverse cancer types. The most well-understood role of TRIB1 is in acute myeloid leukaemia, where it can regulate C/EBP transcription factors and kinase pathways. Structure–function studies have uncovered conformational switching of TRIB1 from an inactive to an active state when it binds to C/EBPα. This conformational switching is centred on the active site of TRIB1, which appears to be accessible to small-molecule inhibitors in spite of its inability to bind ATP. Beyond myeloid neoplasms, TRIB1 plays diverse roles in signalling pathways with well-established roles in tumour progression. Thus, TRIB1 can affect both development and chemoresistance in leukaemia; glioma; and breast, lung and prostate cancers. The pervasive roles of TRIB1 and other Tribbles proteins across breast, prostate, lung and other cancer types, combined with small-molecule susceptibility shown by mechanistic studies, suggests an exciting potential for Tribbles as direct targets of small molecules or biomarkers to predict treatment response.

Insights into the Antimicrobial Potential of Dithiocarbamate Anions and Metal-Based Species

Bacterial infection remains a worldwide problem that requires urgent addressing. Overuse and poor disposal of antibacterial agents abet the emergence of bacterial resistance mechanisms. There is a clear need for new approaches for the development of antibacterial therapeutics. Herein, the antibacterial potential of molecules based on dithiocarbamate anions, of general formula R(R’)NCS2(−), and metal salts of transition metals and main group elements, is summarized. Preclinical studies show a broad range of antibacterial potential, and these investigations are supported by appraisals of possible biological targets and mechanisms of action to guide chemical syntheses. This bibliographic review of the literature points to the exciting potential of dithiocarbamate-based therapeutics in the crucial battle against bacteria. Additionally, included in this overview, for the sake of completeness, is mention of the far fewer studies on the antifungal potential of dithiocarbamates and even less work conducted on antiparasitic behavior.

CircRNAs have the potential to aid in the diagnosis and treatment of lipid diseases

CircRNAs have the potential to aid in the diagnosis and treatment of lipid diseases, and further study and development is needed in the future. Further advancements, for example, are required in disease-oriented critical circRNA screening technology, which can analyze differentially expressed circRNAs in different tissues and screen out the key circRNAs, providing valuable biomarkers for diagnosis or targets to treat lipid disorder diseases. We need to figure out how to modulate circRNA expression upstream, such as biogenesis and decay, or how to directly upregulate or downregulate certain circRNA expression, setting the framework for clinical intervention in certain critical circRNA in the etiology of certain lipid disorders illness. Understanding the principles governing circRNAsponging mciroRNAs is critical because it will aid in the development of new nucleic acid treatments for lipid diseases.Engineered circRNA with bulged miRNA binding sites effectively sponged the miRNA132/212 family and attenuated myocardial hypertrophy with a low dosage requirement, extended half-lives, high efficiency, and stability when compared to the antagomir, suggesting that it has exciting potential as a novel therapeutic tool. These studies will pave the way for circRNAs to be employed as diagnostic biomarkers or therapeutic targets for lipid diseases in the clinic.