Miracle-dz/UniFAR-FTUs huggingface dataset:
Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways

Significance Interactions between the immune system and nervous system regulate chronic pain. Cytokines are well-known immune-regulatory molecules that have activities beyond regulation of the immune system, including regulation of pain pathways. We identified that fusion of regulatory cytokines interleukin (IL)-4 and IL-10 into the fusion protein IL4–10 FP provides unexpected properties to inhibit pain by clustering the respective receptor chains of both cytokines in sensory neurons. IL4–10 FP promotes unique signaling pathways and gene-expression profiles that resolve chronic inflammatory pain. Thus IL4–10 FP is an immune biologic that effectively inhibits pain by activating pain-resolution pathways in sensory neurons through clustering of cytokine receptors. This unique effect discriminates IL4–10 FP from a combination therapy with individual regulatory cytokines. New therapeutic approaches to resolve persistent pain are highly needed. We tested the hypothesis that manipulation of cytokine receptors on sensory neurons by clustering regulatory cytokine receptor pairs with a fusion protein of interleukin (IL)-4 and IL-10 (IL4–10 FP) would redirect signaling pathways to optimally boost pain-resolution pathways. We demonstrate that a population of mouse sensory neurons express both receptors for the regulatory cytokines IL-4 and IL-10. This population increases during persistent inflammatory pain. Triggering these receptors with IL4–10 FP has unheralded biological effects, because it resolves inflammatory pain in both male and female mice. Knockdown of both IL4 and IL10 receptors in sensory neurons in vivo ablated the IL4–10 FP-mediated inhibition of inflammatory pain. Knockdown of either one of the receptors prevented the analgesic gain-of-function of IL4–10 FP. In vitro, IL4–10 FP inhibited inflammatory mediator-induced neuronal sensitization more effectively than the combination of cytokines, confirming its superior activity. The IL4–10 FP, contrary to the combination of IL-4 and IL-10, promoted clustering of IL-4 and IL-10 receptors in sensory neurons, leading to unique signaling, that is exemplified by activation of shifts in the cellular kinome and transcriptome. Interrogation of the potentially involved signal pathways led us to identify JAK1 as a key downstream signaling element that mediates the superior analgesic effects of IL4–10 FP. Thus, IL4–10 FP constitutes an immune-biologic that clusters regulatory cytokine receptors in sensory neurons to transduce unique signaling pathways required for full resolution of persistent inflammatory pain.
Behavioral responses across a mosaic of ecosystem states restructure a sea otter–urchin trophic cascade

Significance Ecological processes that enhance or dampen the likelihood of shifts between top-down (i.e., predator-driven) and bottom-up (i.e., resource-driven) forcing underpin community regulation, functioning, and stability. Here, we demonstrate how the behavioral response of an apex predator to changes in prey behavior and condition (i.e., energetic profitability) can dramatically alter the strength of top-down forcing and enhance the role (or relative contribution) of bottom-up community regulation, depending on the spatial organization of diverse ecosystem states. These results highlight the role of consumer and predator trait-mediated responses to resource mosaics that are common throughout the natural world and enhance understanding of reciprocal feedbacks between top-down and bottom-up forcing on the regional stability of ecosystems. Consumer and predator foraging behavior can impart profound trait-mediated constraints on community regulation that scale up to influence the structure and stability of ecosystems. Here, we demonstrate how the behavioral response of an apex predator to changes in prey behavior and condition can dramatically alter the role and relative contribution of top-down forcing, depending on the spatial organization of ecosystem states. In 2014, a rapid and dramatic decline in the abundance of a mesopredator (Pycnopodia helianthoides) and primary producer (Macrocystis pyrifera) coincided with a fundamental change in purple sea urchin (Strongylocentrotus purpuratus) foraging behavior and condition, resulting in a spatial mosaic of kelp forests interspersed with patches of sea urchin barrens. We show that this mosaic of adjacent alternative ecosystem states led to an increase in the number of sea otters (Enhydra lutris nereis) specializing on urchin prey, a population-level increase in urchin consumption, and an increase in sea otter survivorship. We further show that the spatial distribution of sea otter foraging efforts for urchin prey was not directly linked to high prey density but rather was predicted by the distribution of energetically profitable prey. Therefore, we infer that spatially explicit sea otter foraging enhances the resistance of remnant forests to overgrazing but does not directly contribute to the resilience (recovery) of forests. These results highlight the role of consumer and predator trait-mediated responses to resource mosaics that are common throughout natural ecosystems and enhance understanding of reciprocal feedbacks between top-down and bottom-up forcing on the regional stability of ecosystems.
Loss of expression of both miR-15/16 loci in CML transition to blast crisis

Significance The mechanisms that promote the transition from chronic phase to blast crisis (BC) in chronic myeloid leukemia (CML) patients are not fully described. Given the loss of miR-15/16 loci is critical in the development of myeloid and lymphocytic leukemia, here we evaluated the correlation between the expression of miR-15a/16 and miR-15b/16 with the transition of CML from chronic phase to BC. A significant reduction of miR-15a, miR-15b, and miR-16 expression and an overexpression of their targets, such as Bmi-1, ROR1, and Bcl-2, can describe the progression from chronic phase to BC. This study suggests that targeting different oncogenes activated by the same genetic/epigenetic alteration could represent an important advancement in the treatment of BC CML. Despite advances that have improved the treatment of chronic myeloid leukemia (CML) patients in chronic phase, the mechanisms of the transition from chronic phase CML to blast crisis (BC) are not fully understood. Considering the key role of miR-15/16 loci in the pathogenesis of myeloid and lymphocytic leukemia, here we aimed to correlate the expression of miR-15a/16 and miR-15b/16 to progression of CML from chronic phase to BC. We analyzed the expression of the two miR-15/16 clusters in 17 CML patients in chronic phase and 22 patients in BC and in 11 paired chronic phase and BC CML patients. BC CMLs show a significant reduction of the expression of miR-15a/-15b/16 compared to CMLs in chronic phase. Moreover, BC CMLs showed an overexpression of miR-15/16 direct targets such as Bmi-1, ROR1, and Bcl-2 compared to CMLs in chronic phase. This study highlights the loss of both miR-15/16 clusters as a potential oncogenic driver in the transition from chronic phase to BC in CML patients.
Structural and functional dissection of reovirus capsid folding and assembly by the prefoldin-TRiC/CCT chaperone network

Significance Protein folding and oligomeric complex assembly are essential for protein homeostasis. These processes are orchestrated by a network of host chaperones that interact with nascent and formed polypeptides. We investigated the mechanism by which a ubiquitous, essential, molecular chaperone, TRiC, folds an aggregation-prone protein subunit of a viral capsid. Structural studies, mass spectrometry, and in vitro folding and assembly experiments provided insights into the mechanism by which TRiC, in cooperation with a cochaperone, prefoldin, folds and assembles protein multimers. As the principles of protein folding and assembly are evolutionarily conserved, these findings likely point to common functions for TRiC and prefoldin in assembling a diversity of intracellular protein complexes. Intracellular protein homeostasis is maintained by a network of chaperones that function to fold proteins into their native conformation. The eukaryotic TRiC chaperonin (TCP1-ring complex, also called CCT for cytosolic chaperonin containing TCP1) facilitates folding of a subset of proteins with folding constraints such as complex topologies. To better understand the mechanism of TRiC folding, we investigated the biogenesis of an obligate TRiC substrate, the reovirus σ3 capsid protein. We discovered that the σ3 protein interacts with a network of chaperones, including TRiC and prefoldin. Using a combination of cryoelectron microscopy, cross-linking mass spectrometry, and biochemical approaches, we establish functions for TRiC and prefoldin in folding σ3 and promoting its assembly into higher-order oligomers. These studies illuminate the molecular dynamics of σ3 folding and establish a biological function for TRiC in virus assembly. In addition, our findings provide structural and functional insight into the mechanism by which TRiC and prefoldin participate in the assembly of protein complexes.
Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension

Significance Inflammatory signals are thought to be crucial for the pathogenesis of PAH; however, the underlying mechanism is still largely unknown. In this study, we demonstrate that AHR makes a causal contribution to the pathogenesis of PAH, activating a focal inflammatory response in the lungs and promoting infiltration of immune cells from the bone marrow. Furthermore, we found that PAH patients with higher AHR agonistic activity in sera are more susceptible to severe clinical events than those with lower activity. Because conventional therapy for pulmonary hypertension targeting pulmonary artery vasodilation has limited efficacy against severe PAH, the AHR-signaling pathway represents a promising therapeutic target for PAH. In addition, AHR agonistic activity in serum represents a biomarker for PAH. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague–Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague–Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr−/−) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+ rats, but not in Ahr−/− rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+ IL-21+ T cells and MRC1+ macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH.
β2-adrenoceptor ligand efficacy is tuned by a two-stage interaction with the Gαs C terminus

Significance An outstanding challenge in GPCR pharmacology is quantifying the system-independent functional effects of ligand-receptor interactions. Current efforts to measure ligand efficacy at the level of the receptor (i.e., molecular efficacy) are limited by the requirement of extensive purification of receptor and G proteins to homogeneity. In this study, we present an accessible, scalable technology for the single point measurement of the molecular efficacy of GPCR ligands. Integrating this technology with insights from molecular dynamics simulations, we reveal that the transition of the G protein from an intermediate to a fully coupled interaction with the GPCR is a structural determinant of ligand molecular efficacy. Classical pharmacological models have incorporated an “intrinsic efficacy” parameter to capture system-independent effects of G protein–coupled receptor (GPCR) ligands. However, the nonlinear serial amplification of downstream signaling limits quantitation of ligand intrinsic efficacy. A recent biophysical study has characterized a ligand “molecular efficacy” that quantifies the influence of ligand-dependent receptor conformation on G protein activation. Nonetheless, the structural translation of ligand molecular efficacy into G protein activation remains unclear and forms the focus of this study. We first establish a robust, accessible, and sensitive assay to probe GPCR interaction with G protein and the Gα C terminus (G-peptide), an established structural determinant of G protein selectivity. We circumvent the need for extensive purification protocols by the single-step incorporation of receptor and G protein elements into giant plasma membrane vesicles (GPMVs). We use previously established SPASM FRET sensors to control the stoichiometry and effective concentration of receptor–G protein interactions. We demonstrate that GPMV-incorporated sensors (v-SPASM sensors) provide enhanced dynamic range, expression-insensitive readout, and a reagent level assay that yields single point measurements of ligand molecular efficacy. Leveraging this technology, we establish the receptor–G-peptide interaction as a sufficient structural determinant of this receptor-level parameter. Combining v-SPASM measurements with molecular dynamics (MD) simulations, we elucidate a two-stage receptor activation mechanism, wherein receptor–G-peptide interactions in an intermediate orientation alter the receptor conformational landscape to facilitate engagement of a fully coupled orientation that tunes G protein activation.
3D-Printing Hands that Feel

Amputation is always a devastating experience. In addition to the loss of function or sensation, the lowered body image leaves deeper emotional impacts on the victims and their loved ones. For various reasons, traumatic injuries and vascular diseases like diabetes [4] are common for particularly upper limb loss. According to the World Health Organization, there are more than 10 million people with hand amputations worldwide, 80% of whom are in developing countries. Unfortunately, only less than 3% have access to affordable prostheses [1-3]. Over the past few decades, there have been major advances in commercial prosthetic hands, enabling control over six degrees of freedom (flexion/extension in all five digits and thumb rotation).
Feature Grouping–based Trajectory Outlier Detection over Distributed Streams

Owing to a wide variety of deployment of GPS-enabled devices, tremendous amounts of trajectories have been generated in distributed stream manner. It opens up new opportunities to track and analyze the moving behaviors of the entities. In this work, we focus on the issue of outlier detection over distributed trajectory streams, where the outliers refer to a few entities whose motion behaviors are significantly different from their local neighbors. In view of skewed distribution property and evolving nature of trajectory data, and on-the-fly detection requirement over distributed streams, we first design a high-efficiency outlier detection solution. It consists of identifying abnormal trajectory fragment and exceptional fragment cluster at the remote sites and then detecting abnormal evolving object at the coordinator site. Further, given that outlier detection accuracy would be damaged due to using inappropriate proximity thresholds or a few trajectory data not having sufficient neighbors at the remote sites, we extract proximity thresholds of different regions and spatial context relationship of each region from historical data to improve the precision. Built upon this is an improved version consisting of off-line modeling phase and on-line detection phase. During the on-line phase, the proximity thresholds that are derived from historical trajectories during the off-line phase are leveraged to assist in detecting abnormal trajectory fragments and exceptional fragment clusters at the remote sites. Additionally, at the coordinator site, the detection results of some remote sites can be refined by incorporating those of other remote sites with neighborhood relationship. Extensive experimental results on real data demonstrate that our proposed methods own high detection validity, less communication cost and linear scalability for online identifying outliers over distributed trajectory streams.
The Benefit of Focusing on Air Pollution Instead of Climate Change: How Discussing Power Plant Emissions in the Context of Air Pollution, Rather than Climate Change, Influences Perceived Benefits, Costs, and Political Action for Policies to Limit Emissions

This experiment examines how framing power plant emissions in terms of air pollution or climate change, and in terms of health or environmental impacts, influences perceived benefits and costs of policies to reduce emissions and intentions to take political action that supports such policies. A moderated-mediation model reveals that focusing on air pollution, instead of climate change, has a positive significant indirect influence on intended political action through the serial mediators of perceived benefits and costs. Political ideology moderates the association between perceived benefits and political action. No framing effects are observed in the comparison between health and environmental impacts.
Effect of harvest and delaying controlled atmosphere storage conditions on core breakdown incidence in 'conference' pears

A logistic regression model was built to describe the effect of picking time and the most relevant commercially applied storage factors on the incidence of core breakdown in pears (Pyrus communis L. cv. Conference). The statistical analysis showed that the probability of core breakdown depended on several variables in a more complicated way than assumed before. In general, more mature fruit, stored at lower O-2 and higher CO2 concentrations, at a higher temperature and for longer times are more susceptible to core breakdown. However, delaying the controlled atmosphere (CA) conditions for 21 days decreased the core breakdown incidence efficiently even for late-picked fruit. Together with a proper delay of CA, a sufficiently high O-2 concentration during CA was most important. The model was validated with data of 16 orchards gathered over five harvest seasons in two countries which gives it a wide validity range and a high practical relevance. (C) 2002 Silsoc Research Institute. Published by Elsevier Science Ltd. All rights reserved.
Social Selection and the Evolution of Maladaptation

Evolution by natural selection is often viewed as a process that inevitably leads to adaptation, or an increase in population fitness over time. However, maladaptation, an evolved decrease in fitness, may also occur in response to natural selection under some conditions. Social selection, which arises from the effects of social partners on fitness, has been identified as a potential cause of maladaptation, but we lack a general rule identifying when social selection should lead to a decrease in population mean fitness. Here we use a quantitative genetic model to develop such a rule. We show that maladaptation is most likely to occur when social selection is strong relative to nonsocial selection and acts in an opposing direction. In this scenario, the evolution of traits that impose fitness costs on others may outweigh evolved gains in fitness for the individual, leading to a net decrease in population mean fitness. Further, we find that maladaptation may also sometimes occur when phenotypes of interacting individuals negatively covary. We outline the biological situations where maladaptation in response to social selection can be expected, provide both quantitative genetic and phenotypic versions of our derived result, and suggest what empirical work would be needed to test it. We also consider the effect of social selection on inclusive fitness and support previous work showing that inclusive fitness cannot suffer an evolutionary decrease. Taken together, our results show that social selection may decrease population mean fitness when it opposes individual-level selection, even as inclusive fitness increases. Subject area Quantitative genetics and Mendelian inheritance
In Silico Logical Modelling to Uncover Cooperative Interactions in Cancer

The multistep development of cancer involves the cooperation between multiple molecular lesions, as well as complex interactions between cancer cells and the surrounding tumour microenvironment. The search for these synergistic interactions using experimental models made tremendous contributions to our understanding of oncogenesis. Yet, these approaches remain labour intensive and challenging. To tackle such a hurdle, an integrative, multidisciplinary effort is required. In this article, we highlight the use of logical computational models combined to experimental validations as an effective approach to identify cooperative mechanisms and therapeutic strategies in the context of cancer biology. In silico models overcome limitations of reductionist approaches by capturing tumour complexity, and by generating powerful testable hypotheses. We review representative examples of logical models reported in the literature and their validation. We then provide further analyses of our logical model of Epithelium to Mesenchymal Transition (EMT), searching for additional cooperative interactions involving inputs from the tumour microenvironment and gain of function mutations in NOTCH.
Joint inference of adaptive and demographic history from temporal population genomic data

Disentangling the effects of selection and drift is a long-standing problem in population genetics. Simulations show that pervasive selection may bias the inference of demography. Ideally, models for the inference of demography and selection should account for the interaction between these two forces. With simulation-based likelihood-free methods such as Approximate Bayesian Computation (ABC), demography and selection parameters can be jointly estimated. We propose to use the ABC-Random Forests framework to jointly infer demographic and selection parameters from temporal population genomic data (e.g. experimental evolution, monitored populations, ancient DNA). Our framework allowed the separation of demography (census size, N) from the genetic drift (effective population size, Ne) and the estimation of genome-wide parameters of selection. Selection parameters informed us about the adaptive potential of a population (the scaled mutation rate of beneficial mutations, θb), the realized adaptation (the number of mutation under strong selection), and population fitness (genetic load). We applied this approach to a dataset of feral populations of honey bees (Apis mellifera) collected in California, and we estimated parameters consistent with the biology and the recent history of this species.