Exploitation and exploration in text evolution. Quantifying planning and translation flows during writing

Writing is a complex process at the center of much of modern human activity. Despite it appears to be a linear process, writing conceals many highly non-linear processes. Previous research has focused on three phases of writing: planning, translation and transcription, and revision. While research has shown these are non-linear, they are often treated linearly when measured. Here, we introduce measures to detect and quantify subcycles of planning (exploration) and translation (exploitation) during the writing process. We apply these to a novel dataset that recorded the creation of a text in all its phases, from early attempts to the finishing touches on a final version. This dataset comes from a series of writing workshops in which, through innovative versioning software, we were able to record all the steps in the construction of a text. More than 60 junior researchers in science wrote a scientific essay intended for a general readership. We recorded each essay as a writing cloud, defined as a complex topological structure capturing the history of the essay itself. Through this unique dataset of writing clouds, we expose a representation of the writing process that quantifies its complexity and the writer's efforts throughout the draft and through time. Interestingly, this representation highlights the phases of "translation flow", where authors improve existing ideas, and exploration, where creative deviations appear as the writer returns to the planning phase. These turning points between translation and exploration become rarer as the writing process progresses and the author approaches the final version. Our results and the new measures introduced have the potential to foster the discussion about the non-linear nature of writing and support the development of tools that can support more creative and impactful writing processes

A novel SARS-CoV-2 (T Cell) vaccine candidate designed using the iVAX platform

EpiVax, Inc., a Rhode Island-based Biotechnology company, develops vaccines that exploit T cell immunity using the innovative iVAX vaccine antigen design platform. The premise of our strategy is the crucial role T cells play in development of protective antibody and cell-mediated immunity in natural infection. Because vaccines aim to recapitulate protective immune responses in infection, a vaccine should effectively harness T cell immunity to be protective. The significance of T cell immunity is underscored by COVID-19. Efficacy trial and real-world COVID-19 vaccine data for different vaccine modalities show a single vaccine dose is as much as 90% effective starting 14 days post-administration, when 100% of vaccinees have functional CD4 and CD8 T cells but no detectable neutralizing antibodies. As T cells support the SARS-CoV-2 antibody response, clear virus-infected cells, and may be required to block transmission, we set out to develop a vaccine designed by iVAX to enhance T cell immunity and provide long lasting protection. Please click Download on the upper right corner to see the full abstract

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam

Evaluating the quality of research co-production: Research Quality Plus for Co-Production (RQ + 4 Co-Pro)

Background Co-production is an umbrella term used to describe the process of generating knowledge through partnerships between researchers and those who will use or benefit from research. Multiple advantages of research co-production have been hypothesized, and in some cases documented, in both the academic and practice record. However, there are significant gaps in understanding how to evaluate the quality of co-production. This gap in rigorous evaluation undermines the potential of both co-production and co-producers. Methods This research tests the relevance and utility of a novel evaluation framework: Research Quality Plus for Co-Production (RQ + 4 Co-Pro). Following a co-production approach ourselves, our team collaborated to develop study objectives, questions, analysis, and results sharing strategies. We used a dyadic field-test design to execute RQ + 4 Co-Pro evaluations amongst 18 independently recruited subject matter experts. We used standardized reporting templates and qualitative interviews to collect data from field-test participants, and thematic assessment and deliberative dialogue for analysis. Main limitations include that field-test participation included only health research projects and health researchers and this will limit perspective included in the study, and, that our own co-production team does not include all potential perspectives that may add value to this work. Results The field test surfaced strong support for the relevance and utility of RQ + 4 Co-Pro as an evaluation approach and framework. Research participants shared opportunities for fine-tuning language and criteria within the prototype version, but also, for alternative uses and users of RQ + 4 Co-Pro. All research participants suggested RQ + 4 Co-Pro offered an opportunity for improving how co-production is evaluated and advanced. This facilitated our revision and publication herein of a field-tested RQ + 4 Co-Pro Framework and Assessment Instrument. Conclusion Evaluation is necessary for understanding and improving co-production, and, for ensuring co-production delivers on its promise of better health.. RQ + 4 Co-Pro provides a practical evaluation approach and framework that we invite co-producers and stewards of co-production—including the funders, publishers, and universities who increasingly encourage socially relevant research—to study, adapt, and apply

Evaluating research co-production: protocol for the Research Quality Plus for Co-Production (RQ+ 4 Co-Pro) framework.

Background Research co-production is an umbrella term used to describe research users and researchers working together to generate knowledge. Research co-production is used to create knowledge that is relevant to current challenges and to increase uptake of that knowledge into practice, programs, products, and/or policy. Yet, rigorous theories and methods to assess the quality of co-production are limited. Here we describe a framework for assessing the quality of research co-production—Research Quality Plus for Co-Production (RQ+ 4 Co-Pro)—and outline our field test of this approach. Methods Using a co-production approach, we aim to field test the relevance and utility of the RQ+ 4 Co-Pro framework. To do so, we will recruit participants who have led research co-production projects from the international Integrated Knowledge Translation Research Network. We aim to sample 16 to 20 co-production project leads, assign these participants to dyadic groups (8 to 10 dyads), train each participant in the RQ+ 4 Co-Pro framework using deliberative workshops and oversee a simulation assessment exercise using RQ+ 4 Co-Pro within dyadic groups. To study this experience, we use a qualitative design to collect participant demographic information and project demographic information and will use in-depth semi-structured interviews to collect data related to the experience each participant has using the RQ+ 4 Co-Pro framework. Discussion This study will yield knowledge about a new way to assess research co-production. Specifically, it will address the relevance and utility of using RQ+ 4 Co-Pro, a framework that includes context as an inseparable component of research, identifies dimensions of quality matched to the aims of co-production, and applies a systematic and transferable evaluative method for reaching conclusions. This is a needed area of innovation for research co-production to reach its full potential. The findings may benefit co-producers interested in understanding the quality of their work, but also other stewards of research co-production. Accordingly, we undertake this study as a co-production team representing multiple perspectives from across the research enterprise, such as funders, journal editors, university administrators, and government and health organization leaders

Immune Responses Elicited in Tertiary Lymphoid Tissues Display Distinctive Features

During chronic inflammation, immune effectors progressively organize themselves into a functional tertiary lymphoid tissue (TLT) within the targeted organ. TLT has been observed in a wide range of chronic inflammatory conditions but its pathophysiological significance remains unknown. We used the rat aortic interposition model in which a TLT has been evidenced in the adventitia of chronically rejected allografts one month after transplantation. The immune responses elicited in adventitial TLT and those taking place in spleen and draining lymph nodes (LN) were compared in terms of antibody production, T cell activation and repertoire perturbations. The anti-MHC humoral response was more intense and more diverse in TLT. This difference was associated with an increased percentage of activated CD4+ T cells and a symmetric reduction of regulatory T cell subsets. Moreover, TCR repertoire perturbations in TLT were not only increased and different from the common pattern observed in spleen and LN but also “stochastic,” since each recipient displayed a specific pattern. We propose that the abnormal activation of CD4+ T cells promotes the development of an exaggerated pathogenic immune humoral response in TLT. Preliminary findings suggest that this phenomenon i) is due to a defective immune regulation in this non-professional inflammatory-induced lymphoid tissue, and ii) also occurs in human chronically rejected grafts

Rpb1 Sumoylation in Response to UV Radiation or Transcriptional Impairment in Yeast

Covalent modifications of proteins by ubiquitin and the Small Ubiquitin-like MOdifier (SUMO) have been revealed to be involved in a plethora of cellular processes, including transcription, DNA repair and DNA damage responses. It has been well known that in response to DNA damage that blocks transcription elongation, Rpb1, the largest subunit of RNA polymerase II (Pol II), is ubiquitylated and subsequently degraded in mammalian and yeast cells. However, it is still an enigma regarding how Pol II responds to damaged DNA and conveys signal(s) for DNA damage-related cellular processes. We found that Rpb1 is also sumoylated in yeast cells upon UV radiation or impairment of transcription elongation, and this modification is independent of DNA damage checkpoint activation. Ubc9, an E2 SUMO conjugase, and Siz1, an E3 SUMO ligase, play important roles in Rpb1 sumoylation. K1487, which is located in the acidic linker region between the C-terminal domain and the globular domain of Rpb1, is the major sumoylation site. Rpb1 sumoylation is not affected by its ubiquitylation, and vice versa, indicating that the two processes do not crosstalk. Abolishment of Rpb1 sumoylation at K1487 does not affect transcription elongation or transcription coupled repair (TCR) of UV-induced DNA damage. However, deficiency in TCR enhances UV-induced Rpb1 sumoylation, presumably due to the persistence of transcription-blocking DNA lesions in the transcribed strand of a gene. Remarkably, abolishment of Rpb1 sumoylation at K1487 causes enhanced and prolonged UV-induced phosphorylation of Rad53, especially in TCR-deficient cells, suggesting that the sumoylation plays a role in restraining the DNA damage checkpoint response caused by transcription-blocking lesions. Our results demonstrate a novel covalent modification of Rpb1 in response to UV induced DNA damage or transcriptional impairment, and unravel an important link between the modification and the DNA damage checkpoint response

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery