B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway

BACKGROUND: A recent study by Mishra and Hoon identified B-type natriuretic peptide (BNP) as an important peptide for itch transmission and proposed that BNP activates spinal natriuretic peptide receptor-A (NPRA) expressing neurons, which release gastrin releasing peptide (GRP) to activate GRP receptor (GRPR) expressing neurons to relay itch information from the periphery to the brain (Science 340:968–971, 2013). A central premise for the validity of this novel pathway is the absence of GRP in the dorsal root ganglion (DRG) neurons. To this end, they showed that Grp mRNA in DRG neurons is either absent or barely detectable and claimed that BNP but not GRP is a major neurotransmitter for itch in pruriceptors. They showed that NPRA immunostaining is perfectly co-localized with Grp-eGFP in the spinal cord, and a few acute pain behaviors in Nppb( -/- ) mice were tested. They claimed that BNP is an itch-selective peptide that acts as the first station of a dedicated neuronal pathway comprising a GRP-GRPR cascade for itch. However, our studies, along with the others, do not support their claims. FINDINGS: We were unable to reproduce the immunostaining of BNP and NPRA as shown by Mishra and Hoon. By contrast, we were able to detect Grp mRNA in DRGs using in situ hybridization and real time RT-PCR. We show that the expression pattern of Grp mRNA is comparable to that of GRP protein in DRGs. Pharmacological and genetic blockade of GRP-GRPR signaling does not significantly affect intrathecal BNP-induced scratching behavior. We show that BNP inhibits inflammatory pain and morphine analgesia. CONCLUSIONS: Accumulating evidence demonstrates that GRP is a key neurotransmitter in pruriceptors for mediating histamine-independent itch. BNP-NPRA signaling is involved in both itch and pain and does not function upstream of the GRP-GRPR dedicated neuronal pathway. The site of BNP action in itch and pain and its relationship with GRP remain to be clarified

Dynamic expression of cytokine and transcription factor genes during experimental Fasciola gigantica infection in buffaloes

Background Determining the mechanisms involved in the immune-pathogenesis of the tropical liver fluke, Fasciola gigantica, is crucial to the development of any effective therapeutic intervention. Here, we examined the differential gene expression of cytokines and transcription factors in the liver of F. gigantica-infected buffaloes, over the course of infection. Methods Water buffaloes (swamp type) were infected orally with 500 F. gigantica encysted metacercariae. Liver tissue samples were collected 3, 10, 28, 42, 70 and 98 days post-infection (dpi). Levels of gene expression of nine cytokines (IFN-γ, TGF-β, IL-1β, IL-4, IL-6, IL-10, IL-12B, IL-13 and IL-17A) and four transcription factors (T-bet, GATA-3, Foxp3 and ROR-γτ) were determined using quantitative real-time PCR (qRT-PCR). We evaluated any correlation between gene expression of these immune-regulatory factors and the severity of liver pathology. Results Histopathological examination revealed that cellular infiltration, hemorrhage and fibrosis without calcification in the liver parenchyma of infected buffaloes, increased over the course of infection. This progressive pathology was attributed to dysregulated and excessive inflammatory responses induced by infection. The early infection phase (3–10 dpi) was marked by a generalized immunosuppression and elevated TGF-β expression in order to facilitate parasite colonization. A mixed Th1/Th2 immune response was dominant from 28 to 70 dpi, to promote parasite survival while minimizing host tissue damage. During late infection (98 dpi), the response was biased towards Th1/Treg in order to inhibit the host’s Th2 protective response and promote chronic infection. Both IL-10 and IL-17A and the Th17/Treg balance, played key roles in mediating the inflammatory and immunoregulatory mechanisms in the liver during chronic fasciolosis. Conclusions Our data showed distinct CD4+ T helper (Th) polarization and cytokine dysregulation in response to F. gigantica infection in water buffaloes over the course of infection. Characterizing the temporal expression profiles for host immune genes during infection should provide important information for defining how F. gigantica adapts and survives in the liver of buffaloes and how host immune responses influence F. gigantica pathogenicity

Chronic itch development in sensory neurons requires BRAF signaling pathways

Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAF(Nav1.8) mice). We found that constitutive BRAF pathway activation in BRAF(Nav1.8) mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAF(Nav1.8) mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excitability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis– or dry skin–elicited itch; however, spinal ERK activation was not required for maintaining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation

Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission

We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling

Lost in UNet: Improving Infrared Small Target Detection by Underappreciated Local Features

Many targets are often very small in infrared images due to the long-distance imaging meachnism. UNet and its variants, as popular detection backbone networks, downsample the local features early and cause the irreversible loss of these local features, leading to both the missed and false detection of small targets in infrared images. We propose HintU, a novel network to recover the local features lost by various UNet-based methods for effective infrared small target detection. HintU has two key contributions. First, it introduces the "Hint" mechanism for the first time, i.e., leveraging the prior knowledge of target locations to highlight critical local features. Second, it improves the mainstream UNet-based architecture to preserve target pixels even after downsampling. HintU can shift the focus of various networks (e.g., vanilla UNet, UNet++, UIUNet, MiM+, and HCFNet) from the irrelevant background pixels to a more restricted area from the beginning. Experimental results on three datasets NUDT-SIRST, SIRSTv2 and IRSTD1K demonstrate that HintU enhances the performance of existing methods with only an additional 1.88 ms cost (on RTX Titan). Additionally, the explicit constraints of HintU enhance the generalization ability of UNet-based methods. Code is available at https://github.com/Wuzhou-Quan/HintU

Unifying constitutive law of vibroconvective turbulence in microgravity

The emergence of unified constitutive law is a hallmark of convective turbulence, i.e., $Nu \sim Ra^\beta$ with $\beta \approx 0.3$ in the classical and $\beta=1/2$ in the ultimate regime, where the Nusselt number $Nu$ measures the global heat transport and the Rayleigh number $Ra$ quantifies the strength of thermal forcing. In recent years, vibroconvective flows have been attractive due to its ability to drive flow instability and generate ``artificial gravity'', which have potential to effective heat and mass transport in microgravity. However, the existence of constitutive laws in vibroconvective turbulence remains unclear. To address this issue, we carry out direct numerical simulations in a wide range of frequencies and amplitudes, and report that the heat transport exhibits a universal scaling law $Nu \sim a^{-1} Re_\mathrm{os}^\beta$ where $a$ is the vibration amplitude, $Re_\mathrm{os}$ is the oscillational Reynolds number, and $\beta$ is the universal exponent. We find that the dynamics of boundary layers plays an essential role in vibroconvective heat transport, and the $Nu$-scaling exponent $\beta$ is determined by the competition between the thermal boundary layer (TBL) and vibration-induced oscillating boundary layer (OBL). Then a physical model is proposed to explain the change of scaling exponent from $\beta=2$ in the OBL-dominant regime to $\beta = 4/3$ in the TBL-dominant regime. We conclude that vibroconvective turbulence in microgravity defines a distinct universality class of convective turbulence. This work elucidates the emergence of universal constitutive laws in vibroconvective turbulence, and opens up a new avenue for generating a controllable effective heat transport under microgravity or even microfluidic environment in which gravity is nearly absent.Comment: 18 pages, 3 figure

AntGPT: Can Large Language Models Help Long-term Action Anticipation from Videos?

Can we better anticipate an actor's future actions (e.g. mix eggs) by knowing what commonly happens after his/her current action (e.g. crack eggs)? What if we also know the longer-term goal of the actor (e.g. making egg fried rice)? The long-term action anticipation (LTA) task aims to predict an actor's future behavior from video observations in the form of verb and noun sequences, and it is crucial for human-machine interaction. We propose to formulate the LTA task from two perspectives: a bottom-up approach that predicts the next actions autoregressively by modeling temporal dynamics; and a top-down approach that infers the goal of the actor and plans the needed procedure to accomplish the goal. We hypothesize that large language models (LLMs), which have been pretrained on procedure text data (e.g. recipes, how-tos), have the potential to help LTA from both perspectives. It can help provide the prior knowledge on the possible next actions, and infer the goal given the observed part of a procedure, respectively. To leverage the LLMs, we propose a two-stage framework, AntGPT. It first recognizes the actions already performed in the observed videos and then asks an LLM to predict the future actions via conditioned generation, or to infer the goal and plan the whole procedure by chain-of-thought prompting. Empirical results on the Ego4D LTA v1 and v2 benchmarks, EPIC-Kitchens-55, as well as EGTEA GAZE+ demonstrate the effectiveness of our proposed approach. AntGPT achieves state-of-the-art performance on all above benchmarks, and can successfully infer the goal and thus perform goal-conditioned "counterfactual" prediction via qualitative analysis. Code and model will be released at https://brown-palm.github.io/AntGP

Serum levels of cytokines in water buffaloes experimentally infected with Fasciola gigantica

Fasciola gigantica infection in water buffaloes causes significant economic losses especially 27 in developing countries. Although modulation of the host immune response by cytokine 28 neutralization or vaccination is a promising approach to control infection with this parasite, our 29 understanding of cytokine's dynamic during F. gigantica infection is limited. To address this, 30 we quantified the levels of serum cytokines produced in water buffaloes following experimental 31 infection with F. gigantica. Five buffaloes were infected via oral gavage with 500 viable F. 32 gigantica metacercariae and blood samples were collected from buffaloes one week before 33 infection and for 13 consecutive weeks thereafter. The levels of 10 cytokines in serum samples 34 were simultaneously determined using ELISA. F. gigantica failed to elicit the production of 35 various pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-2, IL-6, IL-12, and 36 IFN-γ. On the other hand, evidence of a Th2 type response was detected, but only early in the 37 course of parasite colonization and included modest increase in the levels of IL-10 and IL-13. 38 The results also revealed suppression of the immune responses as a feature of chronic F. 39 gigantica infection in buffaloes. Taken together, F. gigantica seems to elicit a modest Th2 40 response at early stage of infection in order to downregulate harmful Th1- and Th17-type 41 inflammatory responses in experimentally infected buffaloes. The full extent of anti-F. 42 gigantica immune response and its relation to pathogenesis requires further study