Tumor immunogenicity regulates host immune responses, and conventional dendritic cell type 2 uptakes the majority of tumor antigens in an orthotopic lung cancer model.

Human lung cancer carries high genetic alterations, expressing high tumor-specific neoantigens. Although orthotopic murine lung cancer models recapitulate many characteristics of human lung cancers, genetically engineered mouse models have fewer somatic mutations than human lung cancer, resulting in scarce immune cell infiltration and deficient immune responses. The endogenous mouse lung cancer model driven by Kras mutation and Trp53 deletion (KP model) has minimal immune infiltration because of a scarcity of neoantigens. Fine-tuning tumor antigenicity to trigger the appropriate level of antitumor immunity would be key to investigating immune responses against human lung cancer. We engineered the KP model to express antigens of OVA peptides (minOVA) as neoantigens along with ZsGreen, a traceable fluorescent conjugate. The KP model expressing minOVA exhibited stronger immunogenicity with higher immune cell infiltration comprised of CD8+ T cells and CD11c+ dendritic cells (DCs). Consequentially, the KP model expressing minOVA exhibits suppressed tumor growth compared to its origin. We further analyzed tumor-infiltrated DCs. The majority of ZsGreen conjugated with minOVA was observed in the conventional type 2 DCs (cDC2), where cDC1 has minimal. These data indicate that tumor immunogenicity regulates host immune responses, and tumor neoantigen is mostly recognized by cDC2 cells, which may play a critical role in initiating anti-tumor immune responses in an orthotopic murine lung cancer model.

Complement C1q essential for aeroallergen sensitization via CSF1R+ conventional dendritic cells type 2.

BACKGROUND: Dendritic cells (DCs) are heterogeneous, comprising multiple subsets with unique functional specifications. Our previous work has demonstrated that the specific conventional type 2 DC subset, CSF1R+cDC2s, plays a critical role in sensing aeroallergens. OBJECTIVE: It remains to be understood how CSF1R+cDC2s recognize inhaled allergens. We sought to elucidate the transcriptomic programs and receptor-ligand interactions essential for function of this subset in allergen sensitization. METHODS: We applied single-cell RNA sequencing to mouse lung DCs. Conventional DC-selective knockout mouse models were employed, and mice were subjected to inhaled allergen sensitization with multiple readouts of asthma pathology. Under the clinical arm of this work, human lung transcriptomic data were integrated with mouse data, and bronchoalveolar lavage (BAL) specimens were collected from subjects undergoing allergen provocation, with samples assayed for C1q. RESULTS: We found that C1q is selectively enriched in lung CSF1R+cDC2s, but not in other lung cDC2 or cDC1 subsets. Depletion of C1q in conventional DCs significantly attenuates allergen sensing and features of asthma. Additionally, we found that C1q binds directly to human dust mite allergen, and the C1q receptor CD91 (LRP1) is required for lung CSF1R+cDC2s to recognize the C1q-allergen complex and induce allergic lung inflammation. Lastly, C1q is enriched in human BAL samples following subsegmental allergen challenge, and human RNA sequencing data demonstrate close homology between lung IGSF21+DCs and mouse CSF1R+cDC2s. CONCLUSIONS: C1q is secreted from the CSF1R+cDC2 subset among conventional DCs. Our data indicate that the C1q-LRP1 axis represents a candidate for translational therapeutics in the prevention and suppression of allergic lung inflammation.

CX3CR1+ Macrophage Facilitates the Resolution of Allergic Lung Inflammation via Interacting CCL26.

Rationale: The resolution of inflammation is an active process coordinated by mediators and immune cells to restore tissue homeostasis. However, the mechanisms for resolving eosinophilic allergic lung inflammation triggered by inhaled allergens have not been fully elucidated. Objectives: Our objectives were to investigate the cellular mechanism of tissue-resident macrophages involved in the resolution process of eosinophilic lung inflammation. Methods: For the study, we used the institutional review board-approved protocol for human subsegmental bronchoprovocation with allergen, mouse models for allergic lung inflammation, and novel transgenic mice, including a conditional CCL26 knockout. The samples were analyzed using mass cytometry, single-cell RNA sequencing, and biophysical and immunological analyses. Measurements and Main Results: We compared alveolar macrophage (AM) subsets in the BAL before and after allergen provocation. In response to provocation with inhaled allergens, the subsets of AMs are dynamically changed in humans and mice. In the steady state, the AM subset expressing CX3CR1 is a relatively small fraction in bronchoalveolar space and lung tissue but drastically increases after allergen challenges. This subset presents unique patterns of gene expression compared with classical AMs, expressing high C1q family genes. CX3CR1+ macrophages are activated by airway epithelial cell-derived CCL26 via a receptor-ligand interaction. The binding of CCL26 to the CX3CR1+ receptor induces CX3CR1+ macrophages to secrete C1q, subsequently facilitating the clearance of eosinophils. Furthermore, the depletion of CX3CR1 macrophages or CCL26 in airway epithelial cells delays the resolution of allergic lung inflammation displaying prolonged tissue eosinophilia. Conclusions: These findings indicate that the CCL26-CX3CR1 pathway is pivotal in resolving eosinophilic allergic lung inflammation.

Concurrent locomotor adaptation and retention to visual and split-belt perturbations.

Gait asymmetry is a common symptom in groups with neurological disorders and significantly reduces gait efficiency. To develop efficient training for gait rehabilitation, we propose a novel gait rehabilitation paradigm that combines two distinct perturbation strategies: visual feedback distortion (VFD) and split-belt treadmill (SBT) walking. In SBT walking, spatiotemporal gait adaptation can be readily achieved, but it quickly fades after training. Gait adaptation to implicit VFD in an unconscious manner tends to persist longer, potentially due to a greater engagement of implicit learning during training. Thus, we investigated whether the combined strategies would lead to more effective changes in symmetric gait patterns with longer retention periods. We compared the retention of the preserved asymmetric pattern acquired by "implicit VFD+SBT walking" with "SBT-only walking" and with "SBT walking with conscious correction". In the implicit VFD+SBT walking, the speed of the two belts was gradually changed, the visual representation of gait symmetry was implicitly distorted, and no instructions were given to subjects except to watch the visual feedback. In the SBT walking with conscious correction, subjects were instructed to consciously correct their steps with the help of visual feedback while SBT walking. The SBT-only walking consisted of SBT walking with no visual feedback. After the 7-minute adaptation period, we removed the visual feedback and the split-belt perturbations, and we assessed the retention of the preserved asymmetric pattern while subjects continued walking for the 15-minute post-adaptation period. In a group of subjects who spontaneously showed visuomotor adaptation in response to the implicit VFD (16 out of 27 subjects), we found a greater retention rate during the implicit VFD+SBT walking trial than the SBT-only walking or the SBT walking with conscious correction trials. The implicit visual distortion paradigm delivered in an attention-independent (unconscious) manner can be utilized and integrated into SBT walking to improve the efficacy of symmetric gait adaptation by producing longer-lasting effects on the retention of a newly learned motor pattern.

Configuration Analysis of a Lizard Skin-like Pattern Formed by DNA Self-Assembly.

Nature manifests diverse and complicated patterns through efficient physical, chemical, and biological processes. One of the approaches to generate complex patterns, as well as simple patterns, is the use of the cellular automata algorithm. However, there are certain limitations to produce such patterns experimentally due to the difficulty of finding candidate programmable building blocks. Here, we demonstrated the feasibility of generating an ocellated lizard skin-like pattern by simulation considering the probabilistic occurrence of cells and constructed the simulation results on DNA lattices via bottom-up self-assembly. To understand the similarity between the simulated pattern (SP) and the observed pattern (OP) of lizard skin, a unique configuration scheme (unit configuration was composed of 7 cells) was conceived. SPs were generated through a computer with a controlling population of gray and black cells in a given pattern. Experimental patterns (EPs) on DNA lattices, consisting of double-crossover (DX) tiles without and with protruding hairpins, were fabricated and verified through atomic force microscopy (AFM). For analyzing the similarity of the patterns, we introduced deviation of the average configuration occurrence for SP and EP with respect to OP, i.e., σα(SO) and σα(EO). The configuration and deviation provide characteristic information of patterns. We recognized that the minimum values of <σα(SO)> and <σα(EO)> occurred when 50% (55%) of black cells in given SPs (DX tiles with hairpins in given EPs) appeared to be most similar to the OP. Our study provides a novel platform for the applicability of DNA molecules to systematically demonstrate other naturally existing complex patterns or processes with ease.

The roles of autotaxin/lysophosphatidic acid in immune regulation and asthma.

Lysophosphatidic acid (LPA) species are present in almost all organ systems and play diverse roles through its receptors. Asthma is an airway disease characterized by chronic allergic inflammation where various innate and adaptive immune cells participate in establishing Th2 immune response. Here, we will review the contribution of LPA and its receptors to the functions of immune cells that play a key role in establishing allergic airway inflammation and aggravation of allergic asthma.

Colony-stimulating factor 1 and its receptor are new potential therapeutic targets for allergic asthma.

BACKGROUND: A new approach targeting aeroallergen sensing in the early events of mucosal immunity could have greater benefit. The CSF1-CSF1R pathway has a critical role in trafficking allergens to regional lymph nodes through activating dendritic cells. Intervention in this pathway could prevent allergen sensitization and subsequent Th2 allergic inflammation. OBJECTIVE: To examine the therapeutic effectiveness of CSF1 and CSF1R inhibition for blocking the dendritic cell function of sensing aeroallergens. METHODS: We adopted a model of chronic asthma induced by a panel of three naturally occurring allergens and novel delivery system of CSF1R inhibitor encapsulated nanoprobe. RESULTS: Selective depletion of CSF1 in airway epithelial cells abolished the production of allergen-reactive IgE, resulting in prevention of new asthma development as well as reversal of established allergic lung inflammation. CDPL-GW nanoprobe containing GW2580, a selective CSF1R inhibitor, showed favorable pharmacokinetics for inhalational treatment and intranasal insufflation delivery of CDPL-GW nanoprobe ameliorated asthma pathologies including allergen-specific serum IgE production, allergic lung and airway inflammation and airway hyper-responsiveness (AHR) with minimal pulmonary adverse reaction. CONCLUSION: The inhibition of the CSF1-CSF1R signaling pathway effectively suppresses sensitization to aeroallergens and consequent allergic lung inflammation in a murine model of chronic asthma. CSF1R inhibition is a promising new target for the treatment of allergic asthma.

Macrophages are the primary effector cells in IL-7-induced arthritis.

Synovial macrophages are crucial in the development of joint inflammation and bone damage; however, the pathways that control macrophage remodeling in inflammatory M1 cells or bone-eroding osteoclasts are not fully understood. We determined that elevated IL-7R/CD127 expression is the hallmark of rheumatoid arthritis (RA) M1 macrophages and that these cells are highly responsive to interleukin-7 (IL-7)-driven osteoclastogenesis. We established that lipopolysaccharide (LPS), interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα), the classic M1 macrophage mediators, enhance IL-7R expression in RA and murine macrophages. The local expression of IL-7 provokes arthritis, predominantly through escalating the number of F480+iNOS+ cells rather than CD3+ T cells. Ectopic LPS injection stabilizes IL-7-induced arthritis by increasing myeloid IL-7R expression, in part via IFNγ induction. Hence, in RAG-/- mice, IL-7-mediated arthritis is suppressed because of the reduction in myeloid IL-7R expression due to the lack of IFNγ. Moreover, the amelioration of IL-7-induced arthritis by anti-TNF therapy is due to a decrease in the number of cells in the unique F480+iNOS+IL-7R+CCL5+ subset, with no impact on the F480+Arginase+ cell or CD3+ T cell frequency. Consistent with the preclinical findings, the findings of a phase 4 study performed with RA patients following 6 months of anti-TNF therapy revealed that IL-7R expression was reduced without affecting the levels of IL-7. This study shifts the paradigm by discovering that IL-7-induced arthritis is dependent on F480+iNOS+IL-7R+CCL5+ cell function, which activates TH-1 cells to amplify myeloid IL-7R expression and disease severity.

Gait symmetric adaptation: Comparing effects of implicit visual distortion versus split-belt treadmill on aftereffects of adapted step length symmetry.

Understanding gait adaptation is essential for rehabilitation, and visual feedback can be used during gait rehabilitation to develop effective gait training. We have previously shown that subjects can adapt spatial aspects of walking to an implicitly imposed distortion of visual feedback of step length. To further investigate the storage benefit of an implicit process engaged in visual feedback distortion, we compared the robustness of aftereffects acquired by visual feedback distortion, versus split-belt treadmill walking. For the visual distortion trial, we implicitly distorted the visual representation of subjects' gait symmetry, whereas for the split-belt trial, the speed ratio of the two belts was gradually adjusted without visual feedback. After adaptation, the visual feedback or the split-belt perturbation was removed while subjects continued walking, and aftereffects of preserved asymmetric pattern were assessed. We found that subjects trained with visual distortion trial retained aftereffects longest. In response to the larger speed ratio of split-belt walking, the subjects showed an increase in the size of aftereffects compared to the smaller speed ratio, but it steeply decreased over time in all the speed ratios tested. In contrast, the visual distortion group showed much slower decreasing rate of aftereffects, which was evidence of longer storage of an adapted gait pattern. Visual distortion adaptation may involve the interaction and integration of the change in motor strategy and implicit process in sensorimotor adaptation. Although it should be clarified more clearly through further studies, the findings of this study suggest that gait control employs distinct adaptive processes during the visual distortion and split-belt walking and also the level of reliance of an implicit process may be greater in the visual distortion adaptation than the split-belt walking adaptation.

Calculation of π and Classification of Self-avoiding Lattices via DNA Configuration.

Numerical simulation (e.g. Monte Carlo simulation) is an efficient computational algorithm establishing an integral part in science to understand complex physical and biological phenomena related with stochastic problems. Aside from the typical numerical simulation applications, studies calculating numerical constants in mathematics, and estimation of growth behavior via a non-conventional self-assembly in connection with DNA nanotechnology, open a novel perspective to DNA related to computational physics. Here, a method to calculate the numerical value of π, and way to evaluate possible paths of self-avoiding walk with the aid of Monte Carlo simulation, are addressed. Additionally, experimentally obtained variation of the π as functions of DNA concentration and the total number of trials, and the behaviour of self-avoiding random DNA lattice growth evaluated through number of growth steps, are discussed. From observing experimental calculations of π (πexp) obtained by double crossover DNA lattices and DNA rings, fluctuation of πexp tends to decrease as either DNA concentration or the number of trials increases. Based upon experimental data of self-avoiding random lattices grown by the three-point star DNA motifs, various lattice configurations are examined and analyzed. This new kind of study inculcates a novel perspective for DNA nanostructures related to computational physics and provides clues to solve analytically intractable problems.

Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization.

Airway epithelial cells (AECs) secrete innate immune cytokines that regulate adaptive immune effector cells. In allergen-sensitized humans and mice, the airway and alveolar microenvironment is enriched with colony stimulating factor-1 (CSF1) in response to allergen exposure. In this study we found that AEC-derived CSF1 had a critical role in the production of allergen reactive-IgE production. Furthermore, spatiotemporally secreted CSF1 regulated the recruitment of alveolar dendritic cells (DCs) and enhanced the migration of conventional DC2s (cDC2s) to the draining lymph node in an interferon regulatory factor 4 (IRF4)-dependent manner. CSF1 selectively upregulated the expression of the chemokine receptor CCR7 on the CSF1R+ cDC2, but not the cDC1, population in response to allergen stimuli. Our data describe the functional specification of CSF1-dependent DC subsets that link the innate and adaptive immune responses in T helper 2 (Th2) cell-mediated allergic lung inflammation.

Fabrication and Characterization of Finite-Size DNA 2D Ring and 3D Buckyball Structures.

In order to incorporate functionalization into synthesized DNA nanostructures, enhance their production yield, and utilize them in various applications, it is necessary to study their physical stabilities and dynamic characteristics. Although simulation-based analysis used for DNA nanostructures provides important clues to explain their self-assembly mechanism, structural function, and intrinsic dynamic characteristics, few studies have focused on the simulation of DNA supramolecular structures due to the structural complexity and high computational cost. Here, we demonstrated the feasibility of using normal mode analysis for relatively complex DNA structures with larger molecular weights, i.e., finite-size DNA 2D rings and 3D buckyball structures. The normal mode analysis was carried out using the mass-weighted chemical elastic network model (MWCENM) and the symmetry-constrained elastic network model (SCENM), both of which are precise and efficient modeling methodologies. MWCENM considers both the weight of the nucleotides and the chemical bonds between atoms, and SCENM can obtain mode shapes of a whole structure by using only a repeated unit and its connectivity with neighboring units. Our results show the intrinsic vibrational features of DNA ring structures, which experience inner/outer circle and bridge motions, as well as DNA buckyball structures having overall breathing and local breathing motions. These could be used as the fundamental basis for designing and constructing more complicated DNA nanostructures.

Walking Speed Influences the Effects of Implicit Visual Feedback Distortion on Modulation of Gait Symmetry.

The use of visual feedback in gait rehabilitation has been suggested to promote recovery of locomotor function by incorporating interactive visual components. Our prior work demonstrated that visual feedback distortion of changes in step length symmetry entails an implicit or unconscious adaptive process in the subjects' spatial gait patterns. We investigated whether the effect of the implicit visual feedback distortion would persist at three different walking speeds (slow, self-preferred and fast speeds) and how different walking speeds would affect the amount of adaption. In the visual feedback distortion paradigm, visual vertical bars portraying subjects' step lengths were distorted so that subjects perceived their step lengths to be asymmetric during testing. Measuring the adjustments in step length during the experiment showed that healthy subjects made spontaneous modulations away from actual symmetry in response to the implicit visual distortion, no matter the walking speed. In all walking scenarios, the effects of implicit distortion became more significant at higher distortion levels. In addition, the amount of adaptation induced by the visual distortion was significantly greater during walking at preferred or slow speed than at the fast speed. These findings indicate that although a link exists between supraspinal function through visual system and human locomotion, sensory feedback control for locomotion is speed-dependent. Ultimately, our results support the concept that implicit visual feedback can act as a dominant form of feedback in gait modulation, regardless of speed.

IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells.

IL-11 has been detected in inflamed joints; however, its role in the pathogenesis of arthritis is not yet clear. Studies were conducted to characterize the expression and functional significance of IL-11 and IL-11Rα in rheumatoid arthritis (RA). IL-11 levels were elevated in RA synovial fluid (SF) compared to osteoarthritis (OA) SF and plasma from RA, OA and normal individuals (NLs). Morphologic studies established that IL-11 was detected in lining fibroblasts and macrophages in addition to sublining endothelial cells and macrophages at higher levels in RA compared to NL synovial tissues. Since IL-11Rα was exclusively expressed in RA fibroblasts and endothelial cells, macrophages were not involved in IL-11 effector function. Ligation of IL-11 to IL-11Rα strongly provoked fibroblast infiltration into RA joint, while cell proliferation was unaffected by this process. Secretion of IL-8 and VEGF from IL-11 activated RA fibroblasts was responsible for the indirect effect of IL-11 on endothelial cell transmigration and tube formation. Moreover, IL-11 blockade impaired RA SF capacity to elicit endothelial cell transmigration and tube formation. We conclude that IL-11 binding to endothelial IL-11Rα can directly induce RA angiogenesis. In addition, secretion of proangiogenic factors from migrating fibroblasts potentiated by IL-11 can indirectly contribute to RA neovascularization.

Effects of periodic sensory perturbations during electrical stimulation on gait cycle period.

The spinal cord contains the neural circuitry needed to generate rhythmic walking motions, and afferent sensory feedbacks are involved in the control of locomotion. In this study, we examined the influence of periodic electrical stimulation on the change in gait cycle period during treadmill walking. 40 subjects walked on a treadmill while receiving periodic bursts of electrical stimulation at various perturbation periods (-20, -40, -60, +20, +40 milliseconds from their initial gait cycle periods). Eleven subjects received electrical stimulation to the hamstring, and 29 received electrical stimulation to the calf. Each subject completed four trials; two trials were conducted using high amplitude stimulation causing a slight degree of joint motion, and the other two trials were conducted using reduced amplitude stimulation which did not cause observable motion. Through the trials, we sought to answer the following questions: 1) does the amplitude of electrical stimulation have an effect on the level of entrainment? 2) does the stimulation site effect the level of entrainment? Entrainment refers to the synchronization of gait cycle period to the period of electrical stimulation. The results showed that entrainment was observed when the perturbation periods were induced relatively close to the subject's initial gait cycle period. For both stimulation sites, entrainment was shown in 59% of subjects at +/- 20 milliseconds from the initial gait cycle period. With reduced amplitude, entrainment was still observed (51% all stimulation site groups at +/- 20 milliseconds). In addition, after-effects following electrical perturbation were present as seen by changes in the mean gait cycle period. Our results suggest that human locomotor control is organized with a semi-autonomous peripheral oscillator influenced by afferent information, and that electrical stimulation has the potential to be a simpler, and cost-effective tool for locomotion rehabilitation.

The Effects of Visual Feedback Distortion with Unilateral Leg Loading on Gait Symmetry.

Our prior work provides evidence that visual feedback distortion drives an implicit adaptation; a gradual distortion of visual representation of step length modulated subjects' step lengths away from symmetry. To further explore the effect of the visual feedback distortion on unconscious change in step symmetry, we investigated whether such adaptation would occur even in the presence of altered limb mechanics by adding mass to one side of the leg. 26 subjects performed three 8-min trials (weight only, weight plus visual feedback, and weight plus visual feedback distortion) of treadmill walking. During the weight only trial, the subjects wore a 5 lb mass around the right ankle. The modification of limb inertia caused asymmetric gait. The visual feedback showing right and left step length information as bar graphs was displayed on a computer screen. To add visual feedback distortion, we increased the length of one side of the visual bars by 10% above the actual step length, and the visual distortion was implemented for the side that took longer in response to the added mass. We found that even when adjustments were made to unilateral loading, the subjects spontaneously changed their step symmetry in response to the visual distortion, which resulted in a more symmetric gait. This change may be characterized by sensory prediction errors, and our results suggest that visual feedback distortion has a significant impact on gait symmetry regardless of other conditions affecting limb mechanics. A rehabilitation program employing visual feedback distortion may provide an effective way to restore gait symmetry.

Effects of Partial Absence of Visual Feedback Information on Gait Symmetry.

The incorporation of real-time visual feedback during gait rehabilitation can improve the efficacy of training. Our prior work demonstrated that the imposed distortion of simple visual feedback information of step lengths entails an unintentional adaptive process in the subjects' spatial gait pattern, thereby suggesting the important role of implicit learning in the context of gait rehabilitation that employs visual feedback. The purpose of this study was to investigate whether the removal of a portion of visual feedback information-after it had initially been provided-had any impact on gait symmetry. Eighteen healthy subjects walked on a treadmill for 10-min periods at their preferred walking speed and at a slower walking speed (1.3 mph) during the experimental trials, in which two simple vertical bars corresponding to subject's right and left step length were displayed on a computer screen. Halfway through the trial, one of the bars was removed from the visual feedback via random selection. Subjects were instructed to continually walk normally and also look at the visual feedback until the trials were completed. The changes in step length symmetry ratio were computed and analyzed. We found that displaying only one side of visual feedback influenced subjects to spontaneously modulate gait symmetry away from the baseline, and also that the amount of modulated gait symmetry slightly increased when their walking speed decreased. The changes in gait symmetry occurred by producing either longer right steps produced than left steps or vice versa, but we were unable to find any correlation between side of removal (right or left side) and the different types of trend in response. This warrants further investigation in a study with a larger population. Nonetheless, the results of this study demonstrated the effect of partial absence of visual feedback on changes in step symmetry, and that the perturbation of visual information caused implicit (unintentional) motor processes. A gait training procedure involving a novel way of perturbing visual feedback, such as partial absence of visual feedback tested in this study, may be of value in gait rehabilitation by driving more efficient motor adaptations.

Guiding osteogenesis of mesenchymal stem cells using carbon-based nanomaterials.

In the field of regenerative medicine, stem cells are highly promising due to their innate ability to generate multiple types of cells that could replace/repair damaged parts of human organs and tissues. It has been reported that both in vitro and in vivo function/survival of stem cells could significantly be improved by utilizing functional materials such as biodegradable polymers, metal composites, nanopatterns and nanohybrid particles. Of various biocompatible materials available for use in stem cell-based therapy and research, carbon-based materials-including fullerenes graphene/graphene oxide and carbon nanotubes-have been found to possess unique physicochemical characteristics that contribute to the effective guidance of stem cell differentiation into specific lineages. In this review, we discuss a number of previous reports that investigated the use of carbon-based materials to control stem cell behavior, with a particular focus on their immense potential to guide the osteogenesis of mesenchymal stem cells (MSCs). We hope that this review will provide information on the full potential of using various carbon-based materials in stem cell-mediated regenerative therapy, particularly for bone regeneration and repair.

5 nm Silver Nanoparticles Amplify Clinical Features of Atopic Dermatitis in Mice by Activating Mast Cells.

The triggering effect of silver nanoparticles (NPs) on the induction of allergic reactions is evaluated, by studying the activation of mast cells and the clinical features of atopic dermatitis in a mouse model. Granule release is induced in RBL-2H3 mast cells by 5 nm, but not 100 nm silver NPs. Increases in the levels of reactive oxygen species (hydrogen peroxide and mitochondrial superoxide) and intracellular Ca++ in mast cells are induced by 5 nm silver NPs. In a mouse model of atopic dermatitis induced by a mite allergen, the skin lesions are more severe and appear earlier in mice treated simultaneously with 5 nm silver NPs and allergen compared with mice treated with allergen alone or 100 nm silver NPs and allergen. The histological findings reveal that number of tryptase-positive mast cells and total IgE levels in the serum increase in mice treated with 5 nm silver NPs and allergen. The results in this study indicate that cotreatment with 5 nm silver NPs stimulates mast cell degranulation and induces earlier and more severe clinical alterations in allergy-prone individuals.

Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status.

OBJECTIVE: Studies were performed to uncover the significance of obesity in rheumatoid arthritis (RA) and preclinical models. METHODS: Preclinical arthritis models were used to examine the impact of obesity on disease onset and remission. Conditioned media from RA adipose tissues were used to investigate the mechanism contributing to joint neutrophil influx and M1 macrophage differentiation observed in early and remission phases of arthritis. RESULTS: We report that mice fed with high fat diet (HFD) have an earlier onset of collagen-induced arthritis (CIA) compared with mice on regular diet. However, the differences in CIA joint swelling between the two diet groups are lost once disease is established. We found that early arthritis triggered by obesity is due to elevated joint MIP2/interleukin-8 levels detected in CIA as well as in the RA and mouse adipose tissues and the effect of this chemokine on neutrophil recruitment. Although active disease progression is similarly affected in both diet groups, arthritis resolution is accelerated in lean mice while joint inflammation is sustained in obese mice. We document that HFD can prolong toll-like receptor (TLR)4-induced arthritis by increasing joint monocyte migration and further remodelling the recruited cells into M1 macrophages. Consistently, we show that adipose condition media can transform RA and wild-type naïve myeloid cells into M1 macrophages; however, this function is impaired by TLR4 blockade or deficiency. CONCLUSIONS: We conclude that despite established disease being unaffected by obesity, the early and the resolution phases of RA are impacted by obesity through different mechanisms.