NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer.

Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-κB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.

A mouse model of Salmonella typhi infection.

Salmonella spp. are gram-negative flagellated bacteria that can cause food- and waterborne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. Typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. Typhimurium, S. Typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice, but not in humans, and remarkably, we find that tlr11(-/-) mice are efficiently infected with orally administered S. Typhi. We also find that tlr11(-/-) mice can be immunized against S. Typhi. Therefore, tlr11(-/-) mice represent a small-animal model for the study of the immune response to S. Typhi and for the development of vaccines against this important human pathogen.

An NF-κB Transcription-Factor-Dependent Lineage-Specific Transcriptional Program Promotes Regulatory T Cell Identity and Function.

Both conventional T (Tconv) cells and regulatory T (Treg) cells are activated through ligation of the T cell receptor (TCR) complex, leading to the induction of the transcription factor NF-κB. In Tconv cells, NF-κB regulates expression of genes essential for T cell activation, proliferation, and function. However the role of NF-κB in Treg function remains unclear. We conditionally deleted canonical NF-κB members p65 and c-Rel in developing and mature Treg cells and found they have unique but partially redundant roles. c-Rel was critical for thymic Treg development while p65 was essential for mature Treg identity and maintenance of immune tolerance. Transcriptome and NF-κB p65 binding analyses demonstrated a lineage specific, NF-κB-dependent transcriptional program, enabled by enhanced chromatin accessibility. These dual roles of canonical NF-κB in Tconv and Treg cells highlight the functional plasticity of the NF-κB signaling pathway and underscores the need for more selective strategies to therapeutically target NF-κB.

A mathematical model of invasion and control of coconut rhinoceros beetle Oryctes rhinoceros (L.) in Guam.

The coconut rhinoceros beetle (CRB), is one of the most damaging pests to coconut palms causing severe economic harm. Its expansion from Asia to the Pacific in the early 20th century has been stopped by virus control. However, a new haplotype CRB-Guam has recently escaped this control and invaded Guam, other Pacific islands, and has even established itself in the Western Hemisphere. In this paper, we present a compartmental ODE model of CRB population and control. We carefully consider CRB life stages and its interplay with coconut palms as well as "the green waste", the organic matters used by CRB for breeding sites. We calibrate and validate the model based on data count of CRBs trapped in Guam between 2008 and 2014. We derive the basic reproduction number determining the CRB population growth without any control measures. We also identify control levels required to eliminate CRBs. We show that, in the absence of viable virus control, the sanitation, i.e., the removal of the green waste is the most efficient way to control the population. Our model predicts that the sanitation efforts need to roughly double from the current levels to eliminate CRB from Guam. Furthermore, we demonstrate that a rare event like Typhoon Dolphin that hit Guam in 2015 can lead to a quick rise of the CRB population.

PDK1 Is Required for Maintenance of CD4+ Foxp3+ Regulatory T Cell Function.

Regulatory T (Treg) cells have an essential role in maintaining immune homeostasis, in part by suppressing effector T cell functions. Phosphoinositide-dependent kinase 1 (PDK1) is a pleiotropic kinase that acts as a key effector downstream of PI3K in many cell types. In T cells, PDK1 has been shown to be critical for activation of NF-κB and AKT signaling upon TCR ligation and is therefore essential for effector T cell activation, proliferation, and cytokine production. Using Treg cell-specific conditional deletion, we now demonstrate that PDK1 is also essential for Treg cell suppressive activity in vivo. Ablation of Pdk1 specifically in Treg cells led to systemic, lethal, scurfy-like inflammation in mice. Genome-wide analysis confirmed that PDK1 is essential for the regulation of key Treg cell signature gene expression and, further, suggested that PDK1 acts primarily to control Treg cell gene expression through regulation of the canonical NF-κB pathway. Consistent with these results, the scurfy-like phenotype of mice lacking PDK1 in Treg cells was rescued by enforced activation of NF-κB downstream of PDK1. Therefore, PDK1-mediated activation of the NF-κB signaling pathway is essential for regulation of Treg cell signature gene expression and suppressor function.

Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii.

Toll-like receptor 11 (TLR11) recognizes T. gondii profilin (TgPRF) and is required for interleukin-12 production and induction of immune responses that limit cyst burden in Toxoplasma gondii-infected mice. However, TLR11 only modestly affects survival of T. gondii-challenged mice. We report that TLR12, a previously uncharacterized TLR, also recognized TgPRF. TLR12 was sufficient for recognition of TgPRF by plasmacytoid dendritic cells (pDCs), whereas TLR11 and TLR12 were both required in macrophages and conventional DCs. In contrast to TLR11, TLR12-deficient mice succumb rapidly to T. gondii infection. TLR12-dependent induction of IL-12 and IFN-α in pDCs led to production of IFN-γ by NK cells. Consistent with this observation, the partial resistance of Tlr11(-/-) mice is lost upon pDC or NK cell depletion. Thus, TLR12 is critical for the innate immune response to T. gondii, and this TLR may promote host resistance by triggering pDC and NK cell function.

A game-theoretic model of rabies in domestic dogs with multiple voluntary preventive measures.

Game theory is now routinely applied to quantitatively model the decision making of individuals presented with various voluntary actions that can prevent a given disease. Most models consider only a single preventive strategy and the case where multiple preventative actions are available is severely understudied. In our paper, we consider a very simple SI compartmental model of rabies in the domestic dog population. We study two choices of the dog owners: to vaccinate their dogs or to restrict the movements of unvaccinated dogs. We analyze the relatively rich patterns of Nash equilibria (NE). We show that there is always at least one NE at which the owners utilize only one form of prevention. However, there can be up to three different NEs at the same time: two NEs at which the owners use exclusively only the vaccination or movement restriction, and the third NE when the owners use both forms of prevention simultaneously. However, we also show that, unlike the first two types of NEs, the third kind of NE is not convergent stable.

The effects of visual feedback balance training on the pain and physical function of patients with chronic degenerative knee arthritis.

[Purpose] This study aimed to investigate the effects of visual feedback balance training on the pain and dysfunction of patients with chronic degenerative knee arthritis. [Participants and Methods] Twenty-six patients with chronic degenerative knee arthritis participated in this study; the control group (n=13) performed muscle strength training and the experimental group (n=13) performed visual feedback balance training. General physical therapy was applied to both groups three times a week for eight weeks. The visual analog scale was used to measure the patient's pain scale, and the K-WOMAC (Korean Western Ontario and McMaster Universities Osteoarthritis Index) was used as a tool to evaluate their physical function. [Results] In the intra-group comparisons, significant decreases in the visual analog scale and the K-WOMAC were observed for the control group and the experimental group. No significant difference was found in the inter-group comparisons after treatment. [Conclusion] Visual feedback balance training is considered to be an effective intervention method for improving pain and dysfunction in patients with chronic degenerative knee arthritis.

Effects of resistance exercise using the elastic band on the pain and function of patients with degenerative knee arthritis.

[Purpose] This study examined the effects of resistance exercise using the elastic band on the pain and function of patients with degenerative knee arthritis. [Participants and Methods] Thirty patients with degenerative knee arthritis were classified into an experimental group of 15 patients on whom resistance exercise using the elastic band was applied and a control group of 15 patients on whom conservative physical therapy was applied. Both groups received treatments three times a week for four weeks. Pain was measured by the visual analogue scale and function was evaluated by the Korean Western Ontario and McMaster Universities Osteoarthritis Index (K-WOMAC). [Results] The intragroup comparison showed significant decreases in the visual analogue scale and the K-WOMAC in both the experimental and control groups. In the intergroup comparison after treatment, the experimental group showed significantly lower visual analogue scale and K-WOMAC values than the control group. [Conclusion] The results suggest that resistance exercise using the elastic band is an effective intervention for the pain and function of patients with degenerative knee arthritis.

The effects of manual manipulation therapy on pain and dysfunction in patients with lumbar spinal stenosis.

[Purpose] This study investigated the effects of manual manipulation therapy on the pain and dysfunction of patients with lumbar spinal stenosis. [Participants and Methods] In this study, 30 patients with chronic back pain were evenly divided into an experimental group, who received manual traction therapy, and a control group, who received intermittent traction therapy. Both groups received therapy three times a week for eight weeks. A visual analogue scale was used to measure participants' back pain, and the Oswestry disability index (ODI) was used to check the functional impediment they experienced as a result. [Results] The intragroup comparison showed that the visual analog scale and the ODI significantly decreased in the control group and the experimental group, respectively. The intergroup comparison after treatment showed that the visual analog scale and the ODI of the experimental group were significantly lower than in the control group. [Conclusion] The results of this study suggest that manual manipulation therapy is an effective intervention for treating pain and dysfunction in patients with lumbar spinal stenosis.

Effects of the flexion-distraction technique and drop technique on straight leg raising angle and intervertebral disc height of patients with an intervertebral disc herniation.

[Purpose] The purpose of this study was to determine the effects of the flexion-distraction technique and drop technique on the straight leg raising angle and intervertebral disc height of patients with an intervertebral disc herniation. [Participants and Methods] Thirty patients with herniated intervertebral discs were divided into either an experimental group (n=15), who underwent flexion-distraction and drop techniques, or a control group (n=15), who obtained spinal decompression therapy. Both groups were treated three times per week for eight weeks. [Results] An intragroup comparison showed that the straight leg raising angle and the intervertebral disc height significantly increased in both groups. But it was not significantly difference in the intergroup comparison. [Conclusion] The flexion-distraction technique and the drop technique may serve as effective interventions for the straight leg raising angle and intervertebral disc height in patients with intervertebral disc herniations.

Effects of Silicone Oil on Electrowetting to Actuate a Digital Microfluidic Drop on Paper.

The effects of an immiscible, lubricating polydimethylsiloxane fluid, referred to as silicone oil, on the static deformation and on the dynamic motion of a water drop on paper induced by electrowetting were investigated. The deformation of a drop on a hydrophobic film of amorphous fluoropolymers top-coated with less hydrophobic silicone oil was much more predictable, reversible and reproducible than on the uncoated surface. In the dynamic tribological experiment for a sliding drop along an inclined surface, a significant decrease in the friction coefficient, with an unexpected dependency of the contact area, was observed. Based on the curve fitting analysis, the shear stress and the net friction force were estimated quantitatively. Because of the tribological effect and the reduced shear friction force of the oil film, the static and the dynamic electrowetting states of the water drop were enhanced.

The impact of manual spinal traction therapy on the pain and Oswestry disability index of patients with chronic back pain.

[Purpose] The purpose of this study was to examine the effect of manual spinal traction therapy on the pain and Oswestry disability index of patients with chronic back pain. [Participants and Methods] In this study, 30 patients with chronic back pain were evenly divided into an experimental group 1, who received manual traction therapy, and an experimental group 2, who received intermittent traction therapy. Both groups received therapy three times a week for eight weeks. A visual analogue scale was used to measure participants' back pain, and the Oswestry disability index was used to check the functional impediment they experienced as a result. [Results] In a within-group comparison, visual analogue scale and Oswestry disability index significantly decreased in both the experimental 1 and experimental 2. In a between-group comparison after treatment, there was a significantly greater decrease in visual analogue scale and Oswestry disability index in the experimental group 1 compared to the experimental 2. [Conclusion] The manual spinal traction therapy was an effective intervention scheme for the treatment of pain and disorder in patients with chronic back pain.

The effects of flexion-distraction and drop techniques on disorders and Ferguson's angle in female patients with lumbar intervertebral disc herniation.

[Purpose] This study examines the effects of the flexion-distraction technique and the drop technique on disorders and on Ferguson's angle in female patients with lumbar intervertebral disc herniation. [Subjects and Methods] Thirty female patients with lumbar intervertebral disc herniation were divided into an experimental group (n=15) treated with flexion-distraction and drop techniques and a control group (n=15) treated with spinal decompression therapy. Both groups were treated three times a week over an eight-week period. [Results] In the comparison of changes within each group after treatment, both groups showed statistically significant decreases in disorders and in Ferguson's angle. [Conclusion] Flexion-distraction and drop techniques may be an effective intervention to improve disorders and Ferguson's angle in female patients with lumbar intervertebral disc herniation.

Cutting edge: NF-κB p65 and c-Rel control epidermal development and immune homeostasis in the skin.

Psoriasis is an inflammatory skin disease in which activated immune cells and the proinflammatory cytokine TNF are well-known mediators of pathogenesis. The transcription factor NF-κB is a key regulator of TNF production and TNF-induced proinflammatory gene expression, and both the psoriatic transcriptome and genetic susceptibility further implicate NF-κB in psoriasis etiopathology. However, the role of NF-κB in psoriasis remains controversial. We analyzed the function of canonical NF-κB in the epidermis using CRE-mediated deletion of p65 and c-Rel in keratinocytes. In contrast to animals lacking p65 or c-Rel alone, mice lacking both subunits developed severe dermatitis after birth. Consistent with its partial histological similarity to human psoriasis, this condition could be prevented by anti-TNF treatment. Moreover, regulatory T cells in lesional skin played an important role in disease remission. Our results demonstrate that canonical NF-κB in keratinocytes is essential for the maintenance of skin immune homeostasis and is protective against spontaneous dermatitis.

NF-κB: roles and regulation in different CD4(+) T-cell subsets.

The nuclear factor-κB (NF-κB) family of transcription factors plays important roles in various biological processes including apoptosis, stress response, immunity, and inflammation. NF-κB signaling is involved in both immune cell development and function, and it is critical in modulation of the immune response through the transcriptional regulation of cytokine and chemokine expression. An area of great interest in T-cell-mediated adaptive immunity is the ability of naive CD4(+) T cells generated in the thymus to differentiate into various subsets including T-helper 1 (Th1), Th2, Th17, Th9, follicular helper T (Tfh), Th22, and regulatory T (Treg) cells, upon encountering different pathogens and microenvironments. In this review, we discuss the role of NF-κB pathway in the development and functional divergence of the different helper T-cell subsets as well as in regulatory T cells.

The effects of extracorporeal shock wave therapy on pain and range of motion in patients with adhesive capsulitis.

[Purpose] This study examined the effects of extracorporeal shock wave therapy on pain and range of motion in patients with adhesive capsulitis. [Subjects and Methods] Thirty patients with adhesive capsulitis were divided into an experimental group (n=15) that would be treated with extracorporeal shock wave therapy and a control group (n=15) that would be treated only with conservative physical therapy. Both groups were treated three times a week over a four-week period. [Results] An intra-group comparison before and after the treatment showed that both groups experienced a decline in pain and an increase in their range of motion that were statistically significant. An inter-group comparison after the treatment showed that the experimental group had a lower level of pain and a higher range of motion than the control group that were statistically significant. [Conclusion] Extracorporeal shock wave therapy may be an effective intervention for reducing pain and improving the range of motion in patients with adhesive capsulitis.

Optimal Repellent Usage to Combat Dengue Fever.

Dengue fever is one of the most important vector-borne diseases. It is transmitted by Aedes Stegomyia aegypti, and one of the most effective strategies to combat the disease is the reduction of exposure to bites of these mosquitoes. In this paper, we present a game-theoretical model in which individuals choose their own level of protection against mosquito bites in order to maximize their own benefits, effectively balancing the cost of protection and the risk of contracting the dengue fever. We find that even when the usage of protection is strictly voluntary, as soon as the cost of protection is about 10,000 times less than the cost of contracting dengue fever, the optimal level of protection will be within 5 % of the level needed for herd immunity.

Effects of neurofeedback training on the cervical movement of adults with forward head posture.

[Purpose] The purpose of the present study was to examine the effects of neurofeedback training on postural changes in the cervical spine and changes in the range of motion of the neck and in the Neck Disability Index in adults with forward head posture. [Subjects and Methods] The subjects of the study were 40 college students with forward head posture, randomly divided into a neurofeedback training group (NFTG, n=20) and a control group (CG, n=20). The neurofeedback training group received six sessions of pottery and archery games, each for two minutes, three times per week for four weeks, using the neurofeedback system. [Results] There were no significant effects within and between groups in terms of the absolute rotation angle, anterior weight bearing, and range of extension and flexion by x-ray imaging. There were significant effects in the neurofeedback training group pre- intervention and post-intervention in Neck Disability Index. There were significant effects between groups in Neck Disability Index. [Conclusion] It is thought that neurofeedback training, a training approach to self-regulate brain waves, enhances concentration and is therefore an effective intervention method to improve neck pain and daily activities.