Modulation Function Research Articles

A Reconsideration of the Core and Matrix Classification of Thalamocortical Projections.

In 1998, Jones suggested a classification of thalamocortical projections into core and matrix divisions (Jones, 1998). In this classification, core projections are specific, topographical, innervate middle cortical layers, and serve to transmit specific information to the cortex for further analysis; matrix projections, in contrast, are diffuse, much less topographic, innervate upper layers, especially Layer 1, and serve a more global, modulatory function, such as affecting levels of arousal. This classification has proven especially influential in studies of thalamocortical relationships. Whereas it may be the case that a clear subset of thalamocortical connections fit the core motif, since they are specific, topographic, and innervate middle layers, we argue that there is no clear evidence for any single class that encompasses the remainder of thalamocortical connections as is claimed for matrix. Instead, there is great morphological variation in connections made by thalamocortical projections fitting neither a core nor matrix classification. We thus conclude that the core/matrix classification should be abandoned, because its application is not helpful in providing insights into thalamocortical interactions and can even be misleading. As one example of the latter, recent suggestions indicate that core projections are equivalent to first-order thalamic relays (i.e., those that relay subcortical information to the cortex) and matrix to higher-order relays (i.e., those that relay information from one cortical area to another), but available evidence does not support this relationship. All of this points to a need to replace the core/matrix grouping with a more complete classification of thalamocortical projections.

The use of stem cells in the treatment of diabetes mellitus and its complications - review

Introduction and purpose Diabetes is a disease resulting from impaired action or secretion of insulin. The number of patients currently amounts to approximately 422 million, and approximately 1.5 million deaths per year are directly attributed to this disease. Diabetes significantly reduces the quality of life and, if poorly controlled, can lead to serious complications. Mesenchymal stem cells are multipotent cells capable of differentiation. They have the ability to self-renew and have a modulating function. There are reports that they can be used in the treatment of this disease. The aim of the review was to present a new method of therapy and their possible effects. Material and methods The review was based on articles obtained from PubMed scientific database in the years 2015-2023, using the following keywords: diabetes mellitus, stem cells, diabetes complications. Results Implanted stem cells are able to transform into cells that produce and secrete insulin, and also enable better glycemic control. They can alleviate chronic inflammation and reduce fibrosis. Taking into account the complications that occur during long-term diabetes, the use of stem cells may be associated with improving the function of specific organs and tissues such as the kidneys, heart, eyes and nerves. Studies also report a positive effect of these cells on the healing process of wounds and ulcers. Conclusions Stem cells are a promising object of analysis. They can control glycemia and have a positive effect on the functioning of the kidneys, heart, eyes and nerves, and accelerate wound healing, but further, extensive research is needed to assess the effectiveness and safety of this therapy.

CircRNA Regulation of T Cells in Cancer: Unraveling Potential Targets.

T lymphocytes play a critical role in antitumor immunity, but their exhaustion poses a significant challenge for immune evasion by malignant cells. Circular RNAs (circRNAs), characterized by their covalently closed looped structure, have emerged as pivotal regulators within the neoplastic landscape. Recent studies have highlighted their multifaceted roles in cellular processes, including gene expression modulation and protein function regulation, which are often disrupted in cancer. In this review, we systematically explore the intricate interplay between circRNAs and T cell modulation within the tumor microenvironment. By dissecting the regulatory mechanisms through which circRNAs impact T cell exhaustion, we aim to uncover pathways crucial for immune evasion and T cell dysfunction. These insights can inform innovative immunotherapeutic strategies targeting circRNA-mediated molecular pathways. Additionally, we discuss the translational potential of circRNAs as biomarkers for therapeutic response prediction and as intervention targets. Our comprehensive analysis aims to enhance the understanding of immune evasion dynamics in the tumor microenvironment by facilitating the development of precision immunotherapy.

The Effect of Exosomes Isolated from Poly (I:C) Treated Human Wharton's Jelly Mesenchymal Stem Cells on CD4+CD25+Foxp3+ Regulatory T Cells.

Mesenchymal stem cells (MSCs) are a potential cell therapy candidate for autoimmune and inflammatory diseases due to their multilineage capacity and immune modulating function. MSCs exert immunomodulatory effects on target cells through the secretion of exosomes. Inflammatory conditions such as Toll-like receptors (TLRs) engagement can change the biological functions and immunomodulatory activities of MSCs and the contents of exosomes derived from MSCs are changed. Regulatory T-cells (Treg) are crucial for maintaining immune cell homeostasis and self-tolerance. Our study aimed to investigate the impact of isolated exosomes from hWJ-MSCs that were treated with Poly (I:C) on regulatory CD4 CD25 Foxp3 T-cells. MSCs were harvested from human umbilical cord Wharton's Jelly by explant method. Stem cells were treated by Polyinosinic-polycytidylic acid sodium salt (Poly (I:C)) for 48 hours. Exosomes were extracted from supernatant of cells and Scanning electron microscopy (SEM) and Dynamic light scattering (DLS) were performed for them. Peripheral blood mononuclear cells (PBMCs) isolated from the healthy donors were stimulated with PHA (Phytohemagglutinin) and co-cultured with Poly (I:C) treated hWJ-MSCs derived exosome and untreated hWJ-MSCs derived exosome or without hWJ-MSCs-derived exosome for 6 days. Then, frequency of CD4+CD25+ Foxp3+ regulatory T cells was measured by flow cytometry. Our results showed that exosomes isolated from Poly (I:C) treated hWJ-MSCs significantly increased frequency of CD4+CD25+ Foxp3+ regulatory T cells compared to the untreated hWJ-MSCs derived exosome group and control group. Stimulation by TLR3 improved the anti-inflammatory features of exosomes that were derived from hWJ-MSCs by increasing the frequency of Treg cells.

Highly Promising 2D/1D BP-C/CNT Bionic Opto-Olfactory Co-Sensory Artificial Synapses for Multisensory Integration.

The development of high-performance artificial synaptic neuromorphic devices poses a significant challenge in the creation of biomimetic sensing neural systems that seamlessly integrate both sensory and computational functionalities. In pursuit of this objective, promising bionic opto-olfactory co-sensory artificial synapse devices are constructed utilizing the BP-C/CNT (2D/1D) hybrid filter membrane as the resistive layer. Experimental results demonstrated that the devices seamlessly integrated the light modulation, gas detection, and biological synaptic functions into a single device while addressing the challenge with separating artificial synaptic devices from sensors. These devices offered the following advantages: 1) Simulating visual synapses, they can effectively replicate fundamental synaptic functions under both electrical and optical stimulation. 2) By emulating olfactory synapse responses to specific gases, they can achieve ultra-low detection limits and rapid identification of ethanol and acetone gases. 3) They enable photo-olfactory co-sensing simulations that mimic synaptic function under light-modulated pulse conditions in distinct gas environments, facilitating the study of synaptic learning rules and Pavlovian responses. This work provides a pioneering approach for exploring highly stable 2D BP-based optoelectronics and advancing the development of biomimetic neural systems.

38‐2: Multimodal Transistor‐Based 7T2C LTPS Pixel Circuit for Simultaneous PAM and PWM Control in μLED Display

We propose a 7T2C micro‐LED pixel circuit which uses a multimodal transistor (MMT) as driver for compact pulseamplitude and pulse‐width modulation (PAM + PWM) functionality. The LTPS circuit exploits the MMT's ability to maintain a constant drain current, controlled by its source gate, while the channel gate potential varies without interfering with the current magnitude. The MMT also affords a compact footprint and tolerance to large variations in drain‐source voltage caused by LED operating conditions or power supply I × R drops.

Extending CityGML with public input – social ADE

PurposeThis paper aims to enrich the 3D urban models with data contributed by citizens to support data-driven decision-making in urban infrastructure projects. We introduced a new application domain extension to CityGML (social – input ADE) to enable citizens to store, classify and exchange comments generated by citizens regarding infrastructure elements. The main goal of social – input ADE is to add citizens’ feedback as semantic objects to the CityGML model.Design/methodology/approachFirstly, we identified the key functionalities of the suggested ADE and how to integrate them with existing 3D urban models. Next, we developed a high-level conceptual design outlining the main components and interactions within the social-input ADE. Then we proposed a package diagram for the social – input ADE to illustrate the organization of model elements and their dependencies. We also provide a detailed discussion of the functionality of different modules in the social-input ADE.FindingsAs a result of this research, it has seen that informative streams of information are generated via mining the stored data. The proposed ADE links the information of the built environment to the knowledge of end-users and enables an endless number of socially driven innovative solutions.Originality/valueThis work aims to provide a digital platform for aggregating, organizing and filtering the distributed end-users’ inputs and integrating them within the city’s digital twins to enhance city models. To create a data standard for integrating attributes of city physical elements and end-users’ social information and inputs in the same digital ecosystem, the open data model CityGML has been used.

Discovery of a CCR2-targeting pepducin therapy for chronic pain

Targeting the CCL2/CCR2 chemokine axis has been shown to be effective at relieving pain in rodent models of inflammatory and neuropathic pain, therefore representing a promising avenue for the development of non-opioid analgesics. However, clinical trials targeting this receptor for inflammatory conditions and painful neuropathies have failed to meet expectations and have all been discontinued due to lack of efficacy. To overcome the poor selectivity of CCR2 chemokine receptor antagonists, we generated and characterized the function of intracellular cell-penetrating allosteric modulators targeting CCR2, namely pepducins. In vivo, chronic intrathecal administration of the CCR2-selective pepducin PP101 was effective in alleviating neuropathic and bone cancer pain. In the setting of bone metastases, we found that T cells infiltrate dorsal root ganglia (DRG) and induce long-lasting pain hypersensitivity. By acting on CCR2-expressing DRG neurons, PP101 attenuated the altered phenotype of sensory neurons as well as the neuroinflammatory milieu of DRGs, and reduced bone cancer pain by blocking CD4+ and CD8+ T cell infiltration. Notably, PP101 demonstrated its efficacy in targeting the neuropathic component of bone cancer pain, as evidenced by its anti-nociceptive effects in a model of chronic constriction injury of the sciatic nerve. Importantly, PP101-induced reduction of CCR2 signaling in DRGs did not result in deleterious tumor progression or adverse behavioral effects. Thus, targeting neuroimmune crosstalk through allosteric inhibition of CCR2 could represent an effective and safe avenue for the management of chronic pain.

Short-wavelength-infrared upconversion edge enhancement imaging based on a Laguerre-Gaussian composite vortex filter

Edge-enhanced imaging by spiral phase contrast has proven instrumental in revealing phase or amplitude gradients of an object, with notable applications spanning feature extraction, target recognition, and biomedical fields. However, systems deploying spiral phase plates encounter limitations in phase mask modulation, hindering the characterization of the modulation function during image reconstruction. To address this need, we propose and demonstrate an innovative nonlinear reconstruction method using a Laguerre-Gaussian composite vortex filter, which modulates the spectrum of the target. The involved nonlinear process spectrally transforms the incident short-wavelength-infrared (SWIR) signal from 1550 to 864 nm, subsequently captured by a silicon charge-coupled device. Compared with conventional schemes, our novel filtering method effectively suppresses the diffraction noise, significantly enhancing image contrast and resolution. By loading specific phase holograms on the spatial light modulator, bright-field imaging, isotropic, amplitude-controlled anisotropic, and directional second-order edge-enhanced imaging are realized. Anticipated applications for the proposed SWIR edge-enhanced imaging system encompass domains such as artificial intelligence recognition, deep tissue medical diagnostics, and non-destructive defect inspection. These applications underscore the valuable potential of our cutting-edge methodology in furthering both scientific exploration and practical implementations.

Microbiota and Gut-Liver Axis: An Unbreakable Bond?

The gut microbiota, amounting to approximately 100 trillion (1014) microbes represents a genetic repertoire that is bigger than the human genome itself. Evidence on bidirectional interplay between human and microbial genes is mounting. Microbiota probably play vital roles in diverse aspects of normal human metabolism, such as digestion, immune modulation, and gut endocrine function, as well as in the genesis and progression of many human diseases. Indeed, the gut microbiota has been most closely linked to various chronic ailments affecting the liver, although concrete scientific data are sparse. In this narrative review, we initially discuss the basic epidemiology of gut microbiota and the factors influencing their initial formation in the gut. Subsequently, we delve into the gut-liver axis and the evidence regarding the link between gut microbiota and the genesis or progression of various liver diseases. Finally, we summarise the recent research on plausible ways to modulate the gut microbiota to alter the natural history of liver disease.

On the design of Optimal Health Indicators for early fault detection and their statistical thresholds

This research presents a method for developing optimal health indicators for early fault detection in machine condition monitoring. The devised health indicators are optimal in the Neyman–Pearson sense, as they maximize the probability of detection while maintaining a constant false alarm rate. They are generated through a generalized likelihood ratio test that involves the probability density functions representing the healthy and faulty states. The essence of the approach lies in establishing a framework that defines optimal health indicators as functions of the partial derivatives of the healthy probability density function and a modulation function, representing the distortion of the probability density function in the faulty state. Specific modulation functions lead to the recovery of several traditional health indicators, including kurtosis, skewness, the crest factor, the clearance factor, the smoothness factor, the shape factor, the impulse factor, ℓp/ℓq-norms, the negentropy, among others. New health indicators are also derived. As the proposed optimal health indicators asymptotically follow a chi-squared distribution, they come with a statistical threshold. The study comprehensively outlines the methodology, with its performance assessed through simulated and experimental signals. The results reveal that the early transition from healthy to faulty can be well detected via the established optimal health indicators and their thresholds.

KAT7 serves as an oncogenic gene and regulates CCL3 expression via STAT1 signaling in osteosarcoma

Osteosarcoma, considered as the primary cause of malignant bone tumors in children, necessitates novel therapeutic strategies to enhance overall survival rates. KAT7, a histone acetyltransferase, exerts pivotal functions in gene transcription and immune modulation. In light of this, our study identified a significant upregulation of KAT7 in the mRNA and protein levels in human osteosarcoma, boosting cell proliferation in vivo and in vitro. In addition, KAT7-mediated H3K14ac activation induced MMP14 transcription, leading to increased expression and facilitation of osteosarcoma cell metastasis. Subsequent bioinformatics analyses highlighted a correlation between KAT7 and adaptive immune responses, indicating CCL3 as a downstream target of KAT7. Mechanistically, STAT1 was found to transcriptionally upregulate CCL3 expression. Furthermore, overexpression of KAT7 suppressed CCL3 secretions, whereas knockdown of KAT7 enhanced its release. Overall, these findings underscore the oncogenic role of KAT7 in regulating immune responses for osteosarcoma treatment.

Modulate stress distribution with bio-inspired irregular architected materials towards optimal tissue support

Natural materials typically exhibit irregular and non-periodic architectures, endowing them with compelling functionalities such as body protection, camouflage, and mechanical stress modulation. Among these functionalities, mechanical stress modulation is crucial for homeostasis regulation and tissue remodeling. Here, we uncover the relationship between stress modulation functionality and the irregularity of bio-inspired architected materials by a generative computational framework. This framework optimizes the spatial distribution of a limited set of basic building blocks and uses these blocks to assemble irregular materials with heterogeneous, disordered microstructures. Despite being irregular and non-periodic, the assembled materials display spatially varying properties that precisely modulate stress distribution towards target values in various control regions and load cases, echoing the robust stress modulation capability of natural materials. The performance of the generated irregular architected materials is experimentally validated with 3D printed physical samples — a good agreement with target stress distribution is observed. Owing to its capability to redirect loads while keeping a proper amount of stress to stimulate bone repair, we demonstrate the potential application of the stress-programmable architected materials as support in orthopedic femur restoration.

A Novel High-Precision Railway Obstacle Detection Algorithm Based on 3D LiDAR.

This article presents a high-precision obstacle detection algorithm using 3D mechanical LiDAR to meet railway safety requirements. To address the potential errors in the point cloud, we propose a calibration method based on projection and a novel rail extraction algorithm that effectively handles terrain variations and preserves the point cloud characteristics of the track area. We address the limitations of the traditional process involving fixed Euclidean thresholds by proposing a modulation function based on directional density variations to adjust the threshold dynamically. Finally, using PCA and local-ICP, we conduct feature analysis and classification of the clustered data to obtain the obstacle clusters. We conducted continuous experiments on the testing site, and the results showed that our system and algorithm achieved an STDR (stable detection rate) of over 95% for obstacles with a size of 15 cm × 15 cm × 15 cm in the range of ±25 m; at the same time, for obstacles of 10 cm × 10 cm × 10 cm, an STDR of over 80% was achieved within a range of ±20 m. This research provides a possible solution and approach for railway security via obstacle detection.

The efficiency of stem cell differentiation into functional beta cells for treating insulin-requiring diabetes: Recent advances and current challenges.

In recent years, the potential of stem cells (SCs) to differentiate into various types of cells, including β-cells, has led to a significant boost in development. The efficiency of this differentiation process and the functionality of the cells post-transplantation are crucial factors for the success of stem cell therapy in diabetes. Herein, this article reviews the current advances and challenges faced by stem cell differentiation into functional β-cells for diabetes treatment. In vitro, researchers have sought to enhance the differentiation efficiency of functional β-cells by mimicking the normal pancreatic development process, using gene manipulation, pharmacological and culture conditions stimulation, three-dimensional (3D) and organoid culture, or sorting for functional β-cells based on mature islet cell markers. Furthermore, in vivo studies have also looked at suitable transplantation sites, the enhancement of the transplantation microenvironment, immune modulation, and vascular function reconstruction to improve the survival rate of functional β-cells, thereby enhancing the treatment of diabetes. Despite these advancements, developing stem cells to produce functional β-cells for efficacious diabetes treatment is a continuous research endeavor requiring significant multidisciplinary collaboration, for the stem-cell-derived beta cells to evolve into an effective cellular therapy.

Smart seat cushion feasibility pilot study: automated interface pressure modulation of individuals with spinal cord Injury

This study investigates the functionality and feasibility of a novel smart seat cushion system designed for wheelchair users with spinal cord injuries. The cushion, equipped with air cells that serve as both sensors and actuators, was tested on 24 participants for its real-time pressure mapping, automated pressure redistribution, and pressure offloading functions. A commercial pressure mat was concurrently used to validate the cushion’s pressure modulation functions. Additionally, the perceived comfort of the cushion was evaluated using General Discomfort Assessment (GDA) and Discomfort Intensity (DIS) scores, which provided insights into participants’ overall comfort and discomfort levels. Real-time pressure profiles generated by the cushion resembled commercial pressure mat readings. During tests with individuals with spinal cord injury, the cushion was able to dynamically generate and display the real-time pressure profile of a seated individual with strong precision (correlation to commercial pressure mat: r ranging from 0.76 to 0.88), providing effective input into pressure modulation functions. Pressure redistribution algorithms eliminated peak pressure and reduced the overall pressure at the interface. Pressure offloading algorithms automatically identified the regions with the highest interface pressure and subsequently relieved the pressure from those areas. User feedback showed that the cushion was comfortable after redistribution and offloading. This work demonstrated the feasibility of an advanced smart seat cushion system for wheelchair users with spinal cord injuries. The cushion was capable of redistributing pressure evenly across the seating surface, ensuring user’s comfort. Additionally, it identifies and eliminates high-pressure points, further improving comfort and reducing the risk of pressure injuries.

Pre-clinical Pharmacology and Tolerability Characterization of a Novel KIRxICOS Targeting Bispecific CD8 Treg Modulator

Abstract Here we present an Fc-based bispecific CD8 Treg modulator that binds in cis to inhibitory KIR and ICOS receptors co-expressed by CD8 Treg designed to restore CD8 Treg functions. CD8 Treg dysfunctions include impaired cytotoxicity and insufficient longevity in autoimmune disease affected tissues. The KIRxICOS targeting bispecific molecule selectively enhances CD8 Treg killing, promoting their recruitment to and survival within disease affected tissues. Through in vitro, ex vivo, and in vivo evaluations in humanized mouse models, we assessed binding, specificity, and function of the KIRxICOS CD8 Treg Modulator, which boosted ICOS signaling in KIR-expressing CD8 Treg, without activating immune cells expressing only ICOS. It extended survival and reduced disease score in a humanized acute GvHD model, marked by a reduction of activated CD4 T cells and an increase of CD8 Treg. In antigen stimulated tissues, the KIRxICOS CD8 Treg modulator reduced CD4 derived proinflammatory cytokines and epithelial cell death. In vivo, the KIRxICOS molecule demonstrated antibody-like PK parameters. Repeat dose studies in huNSG(IL15Tg) mice indicated good tolerability without terminal toxicity or induction of proinflammatory serum cytokines. The evaluation of binding, impact on immune cell phenotypes, and pharmacology revealed immune cell binding without activation. Our preclinical data supports development of the KIRxICOS CD8 Treg modulator as a therapeutic in autoimmune disease.

The Role of Orexin Receptor Antagonists in Inhibiting Drug Addiction: A Review Article.

The orexinergic system and its receptors are involved in many physiological processes. Their functions in energy homeostasis, arousal, cognition, stress processing, endocrine functions, and pain modulation have been investigated. Many studies have shown that the orexinergic system cooperates with the dopaminergic system in the addiction process. Emerging evidence suggests that the orexinergic system can be effective in the induction of drug dependence and tolerance. Therefore, several researches have been conducted on the effect of orexin receptor (OXR) antagonists on reducing tolerance and dependence caused by drug abuse. Due to the significant growth of the studies on the orexinergic system, the current literature was conducted to collect the findings of previous studies on orexin and its receptors in the induction of drug addiction. In addition, cellular and molecular mechanisms of the possible role of orexin in drug tolerance and dependence are discussed. The findings indicate that the administration of OXR antagonists reduces drug dependence. OXR blockers seem to counteract the addictive effects of drugs through multiple mechanisms, such as preventing neuronal adaptation. This review proposes the potential clinical use of OXR antagonists in the treatment of drug dependence.

Abstract 3130: Effect Of Fatty Acids And Berberine On Macrophages Lipids Metabolism And Inflammation

Dietary fatty acids play a significant role in cardiometabolic health. Recent research indicates that genetic alterations of unsaturated fatty acid metabolism, linked to modulated macrophage function contribute to the pathogenesis of atherosclerosis. Numerous studies have explored the dietary effects of fatty acids supplementation on macrophage functions. Berberine (BBR) is an isoquinoline alkaloid found in various medicinal herbs. Aims and objectives: The current study is designed to determine the effect of Palmitic acid (PA) and Linoleic acid (LA) supplementation on the macrophage’s lipids metabolism and inflammation. Additionally, this study determines the effect of BBR on the fatty acid’s supplementation on macrophage modulation. Method: Mouse macrophages J774 were cultured using media made of DMEM, 10%FBS and 1% PNS. PA, LA and berberine were dissolved in ethanol separately. Three different concentrations 5ug/ul, 25ug/ul and 50ug/ul of PA and LA were used. Macrophages were first treated with three different concentrations of PA LA each in 6 well plates and then 5uM of berberine was introduced in another set of PA and LA treated cells. Cells and the media were collected after 12hrs and 24hrs for GCMS analysis to determine the uptake of fatty acids and the effect of BBR on the PA and LA metabolism in macrophages. The media and cell samples of only fatty acid treated samples and cells treated with both fatty acids and BBR were processed in a Shimadzu GCMS-QP2010 SE. RNA was isolated from lysed cells and Real Time - qPCR analysis was processed in Bio-Rad RT-PCR to determine the effect of saturated (PA) and polyunsaturated fatty acids on lipids packaging and signaling as well as the resultant inflammation associated with these fatty acids’ uptake and metabolism. Results and Conclusion: BBR differentially inhibited fatty acids uptake by macrophages. The GCMS analysis has shown that BBR aggressively inhibited PA uptake compared to LA uptake by macrophages indicating a selective and preferential mode of action for BBR towards saturated fatty acids linked to atherosclerosis compared to unsaturated fatty acids.

Penalizing the Hard Example But Not Too Much: A Strong Baseline for Fine-Grained Visual Classification.

Though significant progress has been achieved on fine-grained visual classification (FGVC), severe overfitting still hinders model generalization. A recent study shows that hard samples in the training set can be easily fit, but most existing FGVC methods fail to classify some hard examples in the test set. The reason is that the model overfits those hard examples in the training set, but does not learn to generalize to unseen examples in the test set. In this article, we propose a moderate hard example modulation (MHEM) strategy to properly modulate the hard examples. MHEM encourages the model to not overfit hard examples and offers better generalization and discrimination. First, we introduce three conditions and formulate a general form of a modulated loss function. Second, we instantiate the loss function and provide a strong baseline for FGVC, where the performance of a naive backbone can be boosted and be comparable with recent methods. Moreover, we demonstrate that our baseline can be readily incorporated into the existing methods and empower these methods to be more discriminative. Equipped with our strong baseline, we achieve consistent improvements on three typical FGVC datasets, i.e., CUB-200-2011, Stanford Cars, and FGVC-Aircraft. We hope the idea of moderate hard example modulation will inspire future research work toward more effective fine-grained visual recognition.