Miracle-dz/UniFAR-FTUs huggingface dataset:
Quality of Life Analysis of HPV-Positive Oropharyngeal Cancer Patients in a Randomized Trial of Reduced-Dose Versus Standard Chemoradiotherapy: 5-Year Follow-Up

Background Human papillomavirus-positive oropharyngeal carcinoma (HPVOPC) portends a more favorable prognosis compared to environmentally related oropharynx cancer (EROPC). Patients with HPVOPC may be overtreated and endure unnecessary long-term toxicities. Methods Patients with untreated locally advanced HPVOPC received induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) and were randomized to standard chemoradiotherapy (sdCRT) (70 Gy) or reduced-dose chemoradiotherapy (rdCRT) (56 Gy) with weekly carboplatin. Patients were followed for changes in five validated quality of life (QoL) surveys: MD Anderson Dysphagia Inventory and Symptom Inventory for head and neck cancer (MDADI, MDASI-HN), Xerostomia Questionnaire (XQ), and European Organization for Research and Treatment of Cancer Questionnaire (EORTC) with head and neck module (EORTC HN). The secondary endpoints of this study were 5-year progression-free survival (PFS) and overall survival (OS). Results Twenty patients were enrolled and randomized to rdCRT (n = 12) or sdCRT (n = 8). Median follow-up was 88 months. At 5 years, difference in QoL changes all favored the rdCRT arm and two QoL scales reached statistical significance (EORTC global health score: 11.49 vs. -23.94, P = 0.014; EORTC symptom scale: -7.76 vs. 15.19, P = 0.015). The 5-year PFS and OS were 87.5% and 83.3% for sdCRT and rdCRT, respectively. Conclusions Therefore, rdCRT after TPF in HPVOPC is feasible in accordance with the earlier results of the Quarterback Trial and long-term follow-up. These limited results are more favorable in specific QoL domains compared to those of sdCRT and demonstrate equivalent long-term survival. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT01706939, The Quarterback Trial [NCT 01706939].
Trained Immunity Contribution to Autoimmune and Inflammatory Disorders

A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to autoimmune diseases, while autoinflammation results from a hyper-functional innate immune system. Aside from their differences, many studies suggest that monocytes and macrophages (Mo/Ma) significantly contribute to the development of both types of disease. Mo/Ma are innate immune cells that promote an immune-modulatory, pro-inflammatory, or repair response depending on the microenvironment. However, understanding the contribution of these cells to different immune disorders has been difficult due to their high functional and phenotypic plasticity. Several factors can influence the function of Mo/Ma under the landscape of autoimmune/autoinflammatory diseases, such as genetic predisposition, epigenetic changes, or infections. For instance, some vaccines and microorganisms can induce epigenetic changes in Mo/Ma, modifying their functional responses. This phenomenon is known as trained immunity. Trained immunity can be mediated by Mo/Ma and NK cells independently of T and B cell function. It is defined as the altered innate immune response to the same or different microorganisms during a second encounter. The improvement in cell function is related to epigenetic and metabolic changes that modify gene expression. Although the benefits of immune training have been highlighted in a vaccination context, the effects of this type of immune response on autoimmunity and chronic inflammation still remain controversial. Induction of trained immunity reprograms cellular metabolism in hematopoietic stem cells (HSCs), transmitting a memory-like phenotype to the cells. Thus, trained Mo/Ma derived from HSCs typically present a metabolic shift toward glycolysis, which leads to the modification of the chromatin architecture. During trained immunity, the epigenetic changes facilitate the specific gene expression after secondary challenge with other stimuli. Consequently, the enhanced pro-inflammatory response could contribute to developing or maintaining autoimmune/autoinflammatory diseases. However, the prediction of the outcome is not simple, and other studies propose that trained immunity can induce a beneficial response both in AIF and autoimmune conditions by inducing anti-inflammatory responses. This article describes the metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions.
A Generative View of Rationality and Growing Awareness†

In this paper we contrast bounded and ecological rationality with a proposed alternative, generative rationality. Ecological approaches to rationality build on the idea of humans as “intuitive statisticians” while we argue for a more generative conception of humans as “probing organisms. ” We first highlight how ecological rationality’s focus on cues and statistics is problematic for two reasons: (a) the problem of cue salience, and (b) the problem of cue uncertainty. We highlight these problems by revisiting the statistical and cue-based logic that underlies ecological rationality, which originate from the misapplication of concepts in psychophysics (e.g., signal detection, just-noticeable-differences). We then work through the most popular experimental task in the ecological rationality literature—the city size task—to illustrate how psychophysical assumptions have informally been linked to ecological rationality. After highlighting these problems, we contrast ecological rationality with a proposed alternative, generative rationality. Generative rationality builds on biology—in contrast to ecological rationality’s focus on statistics. We argue that in uncertain environments cues are rarely given or available for statistical processing. Therefore we focus on the psychogenesis of awareness rather than psychophysics of cues. For any agent or organism, environments “teem” with indefinite cues, meanings and potential objects, the salience or relevance of which is scarcely obvious based on their statistical or physical properties. We focus on organism-specificity and the organism-directed probing that shapes awareness and perception. Cues in teeming environments are noticed when they serve as cues-for-something, requiring what might be called a “cue-to-clue” transformation. In this sense, awareness toward a cue or cues is actively “grown. ” We thus argue that perception might more productively be seen as the presentation of cues and objects rather than their representation. This generative approach not only applies to relatively mundane organism (including human) interactions with their environments—as well as organism-object relationships and their embodied nature—but also has significant implications for understanding the emergence of novelty in economic settings. We conclude with a discussion of how our arguments link with—but modify—Herbert Simon’s popular “scissors” metaphor, as it applies to bounded rationality and its implications for decision making in uncertain, teeming environments.
Dysfunction in the Interaction of Information Between and Within the Bilateral Primary Sensory Cortex

Background Interhemispheric and intrahemispheric long-range synchronization and information communication are crucial features of functional integration between the bilateral hemispheres. Previous studies have demonstrated that disrupted functional connectivity (FC) exists in the bilateral hemispheres of patients with carpal tunnel syndrome (CTS), but they did not clearly clarify the phenomenon of central dysfunctional connectivity. This study aimed to further investigate the potential mechanism of the weakened connectivity of primary somatosensory cortex (S1) based on a precise template. Methods Patients with CTS (n = 53) and healthy control subjects (HCs) (n = 23) participated and underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. We used FC to investigate the statistical dependency of the whole brain, effective connectivity (EC) to analyze time-dependent effects, and voxel-mirrored homotopic connectivity (VMHC) to examine the coordination of FC, all of which were adopted to explore the change in interhemispheric and intrahemispheric S1. Results Compared to the healthy controls, we significantly found a decreased strength of the two connectivities in the interhemispheric S1hand, and the results of EC and VMHC were basically consistent with FC in the CTS. The EC revealed that the information output from the dominant hemisphere to the contralateral hemisphere was weakened. Conclusion This study found that maladjusted connections between and within the bilateral S1 revealed by these methods are present in patients with CTS. The dominant hemisphere with deafferentation weakens its effect on the contralateral hemisphere. The disturbance in the bilateral S1 provides reliable evidence to understand the neuropathophysiological mechanisms of decreased functional integration in the brains of patients with CTS.
Colouring coral larvae for tracking dispersal

Ecologists have long sought to understand larval dispersal characteristics of benthic marine invertebrates. Direct quantification of coral larvae dispersal has proven challenging, in part due to their complex life-history, minute size, and widespread dispersal at the scale of kilometres. Instead, indirect methods such as particle modelling, chemical signatures, and genetic correlation are often used in dispersal studies. Here, we develop a direct method of quantifying larval dispersal by applying vital stains to coral larvae, allowing differentiation and direct tracking of millions of larvae from the pelagic dispersal stage through to the sedentary stages of attachment and metamorphosis on coral reefs. Neutral red and Nile blue stains were extremely effective at staining coral larvae, while alizarin red and calcein blue showed no visible results. Differences in toxicity to vital stains was noted among species, with Acropora spp. exhibiting decreased larval survival and settlement, while Merulinidae spp. were unaffected. By experimenting with different incubation times and concentrations, our results indicate that neutral red can be effectively applied for short periods (<20 minutes) at low concentrations (1-100 mg l-1), whereas Nile blue requires longer stain times (>60 minutes) at higher concentrations (100-1000 mg l-1). The strong colour of both neutral red and Nile blue stains was retained by newly settled larvae in lab settings upwards of five days following settlement, providing a direct method of differentiating between newly settled larvae on reefs. Field-validation of Nile blue applied to coral larvae from wild-captured coral slicks demonstrates the efficacy of staining across a diverse range of coral taxa. Vital staining provides a simple, rapid (<60 mins), and low cost (
Motifizer: a tool for parsing high-throughput sequencing datasets and quantitative comparative analyses of transcription factor-binding sites

Background Comparative analysis of Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), combined with transcriptomics data (RNA-seq), can provide critical insights into gene regulatory networks controlled by transcription factors in a given biological context. While multiple programs exist, which need to be individually installed and executed to generate such information, a user-friendly tool with low system requirements which combines the various computational processes into one package, using a docker container, is lacking. Results In this study, we present a user-interactive, infrastructure-independent computational pipeline, called Motifizer, which uses open source tools for processing ChIP-Seq and RNA-seq datasets. Motifizer performs extensive analysis of raw input data, performing peak calling, de-novo motif analysis and differential gene expression analysis on ChIP and RNA-seq datasets. Additionally, Motifizer can be used for analysis and quantitative comparison of transcription factor binding sites in user defined genomic regions. Motifizer also allows easy addition and/or changes of parameters, thereby adding to the versatility of the tool. Conclusion The Motifizer tool is an easy to use tool which uses a docker container system to install and execute ChIP-seq and RNA-seq data parsing. The Analysis module of Motifizer can be employed to identify putative targets involved in gene regulatory networks. Motifizer can be accessed by a large user base and does not require programming skill by the user. Motifizer can be locally installed from the repository (https://github.com/abhikbhattacharjee/Motifizer)
mRNAid, an open-source platform for therapeutic mRNA design and optimization strategies

Recent COVID-19 vaccines unleashed the potential of mRNA-based therapeutics. mRNA optimization is indispensable for reducing immunogenicity, ensuring stability, and maximizing protein output. We present mRNAid, an experimentally validated software for mRNA optimization and visualization that generates mRNA sequences with comparable if not superior characteristics to commercially optimized sequences. To encompass all aspects of mRNA design, we also interrogated the impact of uridine content, nucleoside analogs and UTRs on expression and immunogenicity.
Host range expansion of Shigella phage Sf6 evolves through the dual roles of its tailspike

The first critical step in a virus’s infection cycle is attachment to its host. This interaction is precise enough to ensure the virus will be able to productively infect the cell, but some flexibility can be beneficial to enable co-evolution and host range switching or expansion. Like many bacterial viruses, bacteriophage Sf6 utilizes a two-step process to recognize and attach to its host, Shigella flexneri. Sf6 first recognizes the lipopolysaccharide (LPS) structure of S. flexneri, then binds to either outer membrane protein (Omp) A or OmpC. This phage typically infects serotype Y strains but can also form small, turbid plaques on serotype 2a2 with greatly reduced plating efficiency, suggesting inefficient infection. To examine the interactions between Sf6 and this sub-optimal host, phage were experimentally evolved using mixed populations of S. flexneri serotypes Y and 2a2. The recovered mutants could infect serotype 2a2 with greater efficiency than the ancestral Sf6, forming clear plaques on both serotypes. All mutations mapped to two distinct regions of the tailspike protein: 1) adjacent to, but not part of, the LPS binding site near the N-terminus; and 2) at the distal, C-terminal tip of the protein. Rather than weak interactions between the Sf6 tailspike and 2a2 O-antigen, LPS of this serotype appears to inhibit infection by binding the wild-type particles more strongly, effectively removing them from the environment. These mutations reduce the inhibitory effect by either reducing electrostatic interactions with the O-antigen or increasing reliance on the Omp secondary receptors.
A Multimodal Approach to Investigate the Neural Mechanisms of Real World Social Vision

Eye tracking and other behavioral measurements collected from patient-participants in their hospital rooms afford a unique opportunity to study immersive natural behavior for basic and clinical-translational research, and also requires addressing important logistical, technical, and ethical challenges. Hospital rooms provide the opportunity to richly capture both clinically relevant and ordinary natural behavior. As clinical settings, they add the potential to study the relationship between behavior and physiology by collecting physiological data synchronized to behavioral measures from participants. Combining eye-tracking, other behavioral measures, and physiological measurements enables clinical-translational research into understanding the participants' disorders and clinician-patient interactions, as well as basic research into natural, real world behavior as participants eat, read, converse with friends and family, etc. Here we describe a paradigm in individuals undergoing surgical treatment for epilepsy who spend 1-2 weeks in the hospital with electrodes implanted in their brain to determine the source of their seizures. This provides the unique opportunity to record behavior using eye tracking glasses customized to address clinically-related ergonomic concerns, synchronized direct neural recordings, use computer vision to assist with video annotation, and apply multivariate machine learning analyses to multimodal data encompassing hours of natural behavior. We discuss the acquisition, quality control, annotation, and analysis pipelines to study the neural basis of real world social and affective perception during natural conversations with friends and family in participants with epilepsy. We also discuss clinical, logistical, and ethical and privacy considerations that must be addressed to acquire high quality multimodal data in this setting.
Unexpected inhibition of motor function by dopamine activation of D 1 / D 2 co-expressing striatal neurons

The central function of the striatum and its dopaminergic (DA) afference in motor control and integration of cognitive and emotional processes is commonly explained by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing DA D1 receptorand D2 receptor (D1-SPNs and D2-SPNs), respectively, regardless of SPNs co-expressing these two receptors (D1/D2-SPNs). Here, after developing an approach that enables to target these hybrid SPNs, we demonstrated that, although these SPNs are rare, they play a major role in guiding the motor function of the other two main populations and convey a DA-mediated antagonistic motor brake. D1/D2-SPNs project exclusively to the external globus pallidus (GPe) and have specific electrophysiological features with distinctive integration of DA signals. Optogenetic stimulation and loss-of-function experiments indicated that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this third unacknowledged population of D1/D2 co-expressing neurons, which orchestrates the fine-tuning of DA regulation in the thalamo-cortico-striatal loops. One-Sentence Summary: D1/D2 striatal output promotes dopamine-induced motor inhibition
Decision heuristics in contexts exploiting intrinsic skill

Heuristics can inform human decision making in complex environments through a reduction of computational requirements (accuracy-resource trade-off) and a robustness to overparameterisation (less-is-more). However, tasks capturing the efficiency of heuristics typically ignore action proficiency in determining rewards. The requisite movement parameterisation in sensorimotor control questions whether heuristics preserve efficiency when actions are nontrivial. We developed a novel action selection-execution task requiring joint optimisation of action selection and spatio-temporal skillful execution. Optimal choices could be determined by a simple spatial heuristic, or by more complex planning. Computational models of action selection parsimoniously distinguished human participants who adopted the heuristic from those using a more complex planning strategy. Broader comparative analyses then revealed that participants using the heuristic showed combined decisional (selection) and skill (execution) advantages, consistent with a less-is-more framework. In addition, the skill advantage of the heuristic group was predominantly in the core spatial features that also shaped their decision policy, evidence that the dimensions of information guiding action selection might be yoked to salient features in skill learning. Author Summary We often must choose between actions and then execute them, e.g., a tennis player chooses between a forehand and backhand and then skilfully executes the shot. To select actions, the player might plan their action with either shot, and select whichever simulated outcome is more advantageous. However, a more efficient approach might instead be to use a “heuristic”, i.e., a simpler rule, such as, forehand always on one side of the court, and backhand on the other. In this work, we look at whether styles of planning are related to physical skill performing actions, e.g., would a more skillful tennis player be more likely to use planning or a heuristic? We use a new task that requires people to choose and execute complex actions. Regarding choices, we use computational modeling to identify which people use some degree of planning, and which people use a simpler heuristic. Then, regarding action execution, we reveal that heuristic decision makers are in fact more skilled. However, they are not superiorly skilled in all aspects of performance, showing an advantage solely in the aspect of skill most closely linked to the information (spatial) they use for their heuristic. We therefore reveal the first ever evidence that a relation exists between the complexity of our action-related decisions and how broadly we learn associated motor behaviour.
Factors determining distributions of rainforest Drosophila shift from 1 interspecific competition to high temperature with decreasing elevation

: 41 Species turnover with elevation is a widespread phenomenon and provides 42 valuable information on why and how ecological communities might reorganize as 43 the climate warms. Tropical mountains typically have pronounced thermal gradients 44 and intense species interactions, providing a testing ground for investigating the 45 relationship between thermal tolerances and biotic interactions as the proximate 46 factors determining species’ distributions. We investigated thermal tolerances and 47 interspecific competition as causes of species turnover in the nine most abundant 48 species of Drosophila along elevational gradients in the Australian Wet Tropics. 49 Upper thermal limits varied less among species than lower thermal limits; 50 nonetheless, at low elevation sites, these small differences determined the 51 composition of communities through environmental sorting. In contrast, community 52 composition at cool, high elevations was driven by interspecific competition rather 53 than tolerance to low temperatures. These results run counter to common 54 assumptions about the role of abiotic and biotic factors in structuring communities 55 along thermal gradients, and indicate that tropical insects may be vulnerable to 56 future warming wherever their distributions lie along elevational and other 57 temperature gradients. 58