Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying ...neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5−/− mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
•Spinal B5-I interneurons function to inhibit itch•B5-I neurons release the kappa opioid dynorphin•Kappa opioid signaling bidirectionally modulates itch within the spinal cord•Spinal B5-I interneurons mediate the inhibition of itch by menthol
Kardon et al. identify a population of spinal interneurons that function to inhibit itch. Release of the kappa opioid dynorphin from these neurons mediates the inhibition of itch by chemical counterstimuli such as menthol, suggesting that kappa opioids may be a broadly effective therapy for pathological itch.
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Jet grooming algorithms are widely used in experimental analyses at hadron colliders to remove contaminating radiation from within jets. While the algorithms perform a great service to the ...experiments, their intricate algorithmic structure and multiple parameters has frustrated precision theoretic understanding. In this paper, we demonstrate that one particular groomer called
soft drop
actually makes precision jet substructure easier. In particular, we derive a factorization formula for a large class of soft drop jet substructure observables, including jet mass. The essential observation that allows for this factorization is that, without the soft wide-angle radiation groomed by soft drop, all singular contributions are collinear. The simplicity and universality of the collinear limit in QCD allows us to show that to all orders, the normalized differential cross section has no contributions from non-global logarithms. It is also independent of process, up to the relative fraction of quark and gluon jets. In fact, soft drop allows us to define this fraction precisely. The factorization theorem also explains why soft drop observables are less sensitive to hadronization than their ungroomed counterparts. Using the factorization theorem, we resum the soft drop jet mass to next-to-next-to-leading logarithmic accuracy. This requires calculating some clustering effects that are closely related to corresponding effects found in jet veto calculations. We match our resummed calculation to fixed order results for both
e
+
e
−
→ dijets and
pp
→
Z
+
j
events, producing the first jet substructure predictions (groomed or ungroomed) to this accuracy for the LHC.
Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. ...How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.
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•Lactobacillus species sense intestinal iron levels and attenuate host iron absorption•Microbial metabolites DAP and reuterin are novel HIF-2α inhibitors•Gut microbial metabolites regulate intestinal iron storage via ferritin regulation•Gut microbiota can be therapeutically targeted for iron-related disorders
Das et al. show that gut microbiota regulate host iron metabolism. Lactobacillus species are the major bacterial players involved in sensing intestinal iron levels and attenuating host iron absorption. The authors further show that mammalian iron disorders can be therapeutically targeted by modulating microbial species or their metabolites.
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We generalize the relation between discontinuities of scattering amplitudes and cut diagrams to cover sequential discontinuities (discontinuities of discontinuities) in arbitrary momentum ...channels. The new relations are derived using time-ordered perturbation theory, and hold at phase-space points where all cut momentum channels are simultaneously accessible. As part of this analysis, we explain how to compute sequential discontinuities as monodromies and explore the use of the monodromy group in characterizing the analytic properties of Feynman integrals. We carry out a number of cross-checks of our new formulas in polylogarithmic examples, in some cases to all loop orders.
The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of ...neuroscience‐based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.
A series of photoresins suitable for the production of elastomeric objects via digital light processing additive manufacturing are reported. Notably, the printing procedure is readily accessible ...using only entry-level equipment under ambient conditions using visible light projection. The photoresin formulations were found to be modular in nature, and straightforward adjustments to the resin components enabled access to a range of compositions and mechanical properties. Collectively, the series includes silicones, hydrogels, and hybrids thereof. Printed test specimens displayed maximum elongations of up to 472% under tensile load, a tunable swelling behavior in water, and Shore A hardness values from 13.7 to 33.3. A combination of the resins was used to print a functional multimaterial three-armed pneumatic gripper. These photoresins could be transformative to advanced prototyping applications such as simulated human tissues, stimuli-responsive materials, wearable devices, and soft robotics.
Instrumented gait analysis (IGA) has been around for a long time but has never been shown to be useful for improving patient outcomes. In this study we demonstrate the potential utility of IGA by ...showing that machine learning models are better able to estimate treatment outcomes when they include both IGA and clinical (CLI) features compared to when they include CLI features alone.
We carried out a retrospective analysis of data from ambulatory children diagnosed with cerebral palsy who were seen at least twice at our gait analysis center. Individuals underwent a variety of treatments (including no treatment) between sequential gait analyses. We fit Bayesian Additive Regression Tree (BART) models that estimated outcomes for mean stance foot progression to demonstrate the approach. We built two models: one using CLI features only, and one using CLI and IGA features. We then compared the models' performance in detail. We performed similar, but less detailed, analyses for a number of other outcomes. All results were based on independent test data from a 70%/30% training/testing split.
The IGA model was more accurate than the CLI model for mean stance-phase foot progression outcomes (RMSEIGA = 11∘, RMSECLI = 13∘) and explained more than 1.5 × as much of the variance (R2IGA = .45, R2CLI = .28). The IGA model outperformed the CLI model for every level of treatment complexity, as measured by number of simultaneous surgeries. The IGA model also exhibited superior performance for estimating outcomes of mean stance-phase knee flexion, mean stance-phase ankle dorsiflexion, maximum swing-phase knee flexion, gait deviation index (GDI), and dimensionless speed.
The results show that IGA has the potential to be useful in the treatment planning process for ambulatory children diagnosed with cerebral palsy. We propose that the results of machine learning outcome estimators-including estimates of uncertainty-become the primary IGA tool utilized in the clinical process, complementing the standard medical practice of conducting a through patient history and physical exam, eliciting patient goals, reviewing relevant imaging data, and so on.
Orthopedic and neurological impairments (e.g., muscle contractures, spasticity) are often treated in children and young adults with cerebral palsy (CP). Due to challenges arising from combinatorics, ...research funding priorities, and medical practicalities, and despite extensive study, the evidence base is weak. Our goal was to estimate the short-term effectiveness of 13 common orthopedic and neurological treatments at four different levels of outcome in children and young adults diagnosed with CP. The outcome levels considered were body structures, specific gait kinematic deviations, overall gait kinematic deviations, and functional mobility. We used three well-establish causal inference approaches (direct matching, virtual twins, and Bayesian causal forests) and a large clinical gait analysis database to estimate the average treatment effect on the treated (ATT). We then examined the effectiveness across treatments, methods, and outcome levels. The dataset consisted of 2851 limbs from 933 individuals (some individuals underwent multiple treatment episodes). Current treatments have medium effects on body structures, but modest to minimal effects on gait and functional mobility. The median ATT of 13 common treatments in children and young adults with CP, measured as Cohen's D, bordered on medium at the body structures level (median IQR = 0.42 0.05, 0.60) and became smaller as we moved along the causal chain through specific kinematic deviations (0.21 0.01, 0.33), overall kinematic deviations (0.09 0.03, 0.19), and functional mobility (-0.01 -0.06, 0.13). Further work is needed to understand the source of heterogeneous treatment effects, which are large in this patient population. Replication or refutation of these findings by other centers will be valuable to establish the generalizability of these results and for benchmarking of best practices.
Walking is an important skill with positive impacts on health, function, and well-being. Many disorders impair walking and its positive impacts through a variety of complex and interrelated ...mechanisms. Any attempt to understand walking impairments, or the effects of interventions intended to treat these impairments, must respect this complexity. Therefore, our main objectives in conducting this study were to (1) propose a comprehensive model for quantifying the causes and consequences of walking impairments and (2) demonstrate the potential utility of the model for supporting clinical care and addressing basic scientific questions related to walking. To achieve these goals, we introduced a model, described by a directed acyclic graph, consisting of 10 nodes and 23 primary causal paths. We gave detailed descriptions of each node and path based on domain knowledge. We then demonstrated the model's utility using a large sample of gait data (N = 9504) acquired as part of routine care at a regional referral center. We analyzed five relevant examples that involved many of the model's nodes and paths. We computed causal effect magnitudes as Shapley values and displayed the overall importance of variables (mean absolute Shapley value), the variation of Shapley values with respect to underlying variables, and Shapley values for individual observations (case studies). We showed that the model was plausible, captured some well-known cause-effect relationships, provided new insights into others, and generated novel hypotheses requiring further testing through simulation or experiment. To aid in transparency, reproducibility, and future enhancements we have included an extensively commented Rmarkdown file and a deidentified data set.
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We present several classes of constraints on the discontinuities of Feynman integrals that go beyond the Steinmann relations. These constraints follow from a geometric formulation of the ...Landau equations that was advocated by Pham, in which the singularities of Feynman integrals correspond to critical points of maps between on-shell spaces. To establish our results, we review elements of Picard-Lefschetz theory, which connect the homotopy properties of the space of complexified external momenta to the homology of the combined space of on-shell internal and external momenta. An important concept that emerges from this analysis is the question of whether or not a pair of Landau singularities is compatible — namely, whether or not the Landau equations for the two singularities can be satisfied simultaneously. Under conditions we describe, sequential discontinuities with respect to non-compatible Landau singularities must vanish. Although we only rigorously prove results for Feynman integrals with generic masses in this paper, we expect the geometric and algebraic insights that we gain will also assist in the analysis of more general Feynman integrals.
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