Discontinuous instabilities in disordered solids.

Under a sufficiently large load, a solid material will flow via rearrangements, where particles change neighbors. Such plasticity is most easily described in the athermal, quasistatic limit of zero temperature and infinitesimal loading rate, where rearrangements occur only when the system becomes mechanically unstable. For disordered solids, the instabilities marking the onset of rearrangements have long been believed to be fold instabilities, in which an energy barrier disappears and the frequency of a normal mode of vibration vanishes continuously. Here, we report that there exists another, anomalous, type of instability caused by the breaking of a "stabilizing bond," whose removal creates an unstable vibrational mode. For commonly studied systems, such as those with harmonic finite-range interparticle interactions, such "discontinuous instabilities" are not only inevitable, they often dominate the modes of failure. Stabilizing bonds are a subset of all the bonds in the system and are prevalent in disordered solids generally. Although they do not trigger discontinuous instabilities in systems with vanishing stiffness at the interaction cutoff, they are, even in those cases, local indicators of incipient mechanical failure. They therefore provide an accurate structural predictor of instabilities not only of the discontinuous type but of the fold type as well.

Adipokines in atopic dermatitis: the link between obesity and atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin condition with intense pruritus, eczema, and dry skin. The recurrent intense pruritus and numerous complications in patients with AD can profoundly affect their quality of life. Obesity is one of its comorbidities that has been confirmed to be the hazard factor of AD and also worsen its severity. Nevertheless, the specific mechanisms that explain the connection between obesity and AD remain incompletely recognized. Recent studies have built hopes on various adipokines to explain this connection. Adipokines, which are disturbed by an obese state, may lead to immune system imbalances in people with AD and promote the development of the disease. This review focuses on the abnormal expression patterns of adipokines in patients with AD and their potential regulatory molecular mechanisms associated with AD. The connection between AD and obesity is elucidated through the involvement of adipokines. This conduces to the in-depth exploration of AD pathogenesis and provides a new perspective to develop therapeutic targets.

Highly Efficient Depolymerization of Waste Polyesters Enabled by Transesterification/Hydrogenation Relay Under Mild Conditions.

The efficient depolymerization of polyesters under mild conditions remains a significant challenge. Herein, we demonstrate a highly efficient strategy for the degradation of a diverse array of waste polyesters as low to 80 °C, 1 bar H2 . The key to the success of this transformation relied on the initial transesterification of macromolecular polyester into more degradable oligomeric fragments in the presence of CH3 OH and the subsequent hydrogenation by the use of the rationally designed quinaldine-based Ru complex. Controlled experiments and preliminary mechanistic studies disclosed the quinaldine-based catalysts could be hydrogenated to the eventually active species, which has been confirmed by X-ray diffraction analysis and directly used as a catalyst in the hydrogenolysis of polyester. The strong viability and high activity of this new species in protic solvent were explained in detail. Besides, the crucial role of CH3 OH in promoting reaction efficiency during the whole process was also elucidated. The synthetic utility of this method was further illustrated by preparing 1,4-cyclohexanedimethanol (CHDM) from waste polyethylene terephthalate (PET).

One-Pot Synthesis of Cellulose/MXene/PVA Foam for Efficient Methylene Blue Removal.

Ti3C2Tx MXene has attracted considerable interest as a new emerging two-dimensional material for environmental remediation due to its high adsorption capacity. However, its use is greatly limited by its poor mechanical properties, low processability and recyclability, and the low dispersity of such powder materials. In this work, a porous adsorbent (C-CMP) containing cellulose nanocrystals (CNC), Ti3C2Tx MXene and polyvinyl alcohol (PVA) was prepared by a simple and environmentally-friendly foaming method. Glutaraldehyde was used as crosslinker to improve the mechanical properties and boost the adsorption efficiency of methylene blue (MB) molecules. Fourier transform infrared (FT-IR), elemental analysis (EDX) and thermogravimetric analysis (TGA) further confirmed that the preparation of the C-CMP foam and cross-linking reaction were successful. Scanning electron microscope (SEM) indicated that the macropores were distributed homogeneously. The adsorption experiment showed that maximum adsorption capacity of MB can reach 239.92 mg·g-1 which was much higher than anionic dye (methyl orange, 45.25 mg·g-1). The adsorption behavior fitted well with the Langmuir isotherm and pseudo-second-order kinetic models. Thermodynamic analysis indicated that the adsorption process was spontaneous and endothermic. Based on FT-IR, EDX and X-ray photoelectron spectroscopy (XPS) analysis, the adsorption mechanism between C-CMP and MB molecules was attributed to electrostatic interaction.

Contact network changes in ordered and disordered disk packings.

We investigate the mechanical response of packings of purely repulsive, frictionless disks to quasistatic deformations. The deformations include simple shear strain at constant packing fraction and at constant pressure, "polydispersity" strain (in which we change the particle size distribution) at constant packing fraction and at constant pressure, and isotropic compression. For each deformation, we show that there are two classes of changes in the interparticle contact networks: jump changes and point changes. Jump changes occur when a contact network becomes mechanically unstable, particles "rearrange", and the potential energy (when the strain is applied at constant packing fraction) or enthalpy (when the strain is applied at constant pressure) and all derivatives are discontinuous. During point changes, a single contact is either added to or removed from the contact network. For repulsive linear spring interactions, second- and higher-order derivatives of the potential energy/enthalpy are discontinuous at a point change, while for Hertzian interactions, third- and higher-order derivatives of the potential energy/enthalpy are discontinuous. We illustrate the importance of point changes by studying the transition from a hexagonal crystal to a disordered crystal induced by applying polydispersity strain. During this transition, the system only undergoes point changes, with no jump changes. We emphasize that one must understand point changes, as well as jump changes, to predict the mechanical properties of jammed packings.

A resonance Rayleigh scattering and colorimetric dual-channel sensor for sensitive detection of perfluorooctane sulfonate based on toluidine blue.

This work described the use of a basic phenothiazine dye (toluidine blue, TB) as a resonance Rayleigh scattering (RRS) and colorimetric probe for the detection of perfluorooctane sulfonate (PFOS). Owing to the electrostatic interactions between TB and PFOS, TB in the presence of PFOS caused great enhancement of RRS signal at dual-wavelength (I345 nm and I506 nm) and the ratio changes of absorbance (A502 nm/A630 nm). The RRS enhancement was attributed to the absorption-rescattering resonance effect, the increase of the molecular size, and the enhancement of hydrophobicity. The analytical procedure was implemented by physically mixing TB, Britton-Robinson buffer solution, and PFOS solution (or sample solution) all-in-one, avoiding the tedious pre-derivatization or the preparation of nanoparticles. The whole approach was less than 8 min. Under the optimal conditions, the analytical performance was acquired. The linear ranges for RRS and colorimetry were 0.04-8.0 and 1.0-20 µmol/L, with detection limits of 4.2 nmol/L and 112 nmol/L, respectively. The RRS method was applied to the determination of PFOS in environmental water with recoveries of 93.2-106%. The dual-channel sensor is convenient, rapidly responsive, sensitive, and cost-effective, integrating the advantages of RRS and colorimetry. Graphical abstract.

Clinical evaluation of a toothpaste containing lysozyme for removal of extrinsic stains on the tooth surface: An 8-week, double-blind, randomized study.

PURPOSE: To assess the efficacy and safety of application of a toothpaste containing lysozyme to remove extrinsic stains on the tooth surface in an 8-week trial. METHODS: 70 adult participants with extrinsic staining of the tooth surface were recruited to this randomized, parallel-controlled, double-blind clinical trial. Participants were allocated randomly to the test group or the control group and the study procedure and correct usage of the toothpaste were explained to them. Staining, measured by the Lobene stain index, and any side effects, were recorded over the course of the 8 weeks. All data were analyzed using SAS software version 8.0. RESULTS: 69 participants completed the study. The value of the Lobene stain index was significantly reduced (P< 0.05) in the treatment group compared with the control group after both 4 and 8 weeks. No obvious side effects were observed. CLINICAL SIGNIFICANCE: The results of this clinical study showed that the toothpaste containing lysozyme was effective in removing extrinsic staining on the tooth surface.

Predicting detection limits of enzyme-linked immunosorbent assay (ELISA) and bioanalytical techniques in general.

The detection limit is one of the most important performance parameters for bioanalytical techniques. Here we present a generic method to estimate the detection limit of biomolecular assays based on a step-by-step analysis of the assay procedure. Enzyme-linked immunosorbent assay (ELISA) is used here as an example; however, much of the information presented in this article may be applied to other types of biomolecular assays and analytical techniques. A clear understanding of what affects the detection limit can help researchers to evaluate different bio-analytical techniques properly, and to design better strategies to optimize and achieve the best analytical performance.

Reductive Amination of Aldehyde and Ketone with Ammonia and H2 by an In Situ-Generated Cobalt Catalyst under Mild Conditions.

Herein, we present the simplest approach for the synthesis of primary amines via reductive amination using H2 as a reductant and aqueous ammonia as a nitrogen source, catalyzed by amorphous Co particles. The highly active Co particles were prepared in situ by simply mixing commercially available CoCl2 and NaBH4/NaHBEt3 without any ligand or support. This reaction system features mild conditions (80 °C, 1-10 bar), high selectivity (99%), a wide substrate scope, simple operation, and easy separation of the catalyst. The successful large-scale application of this reaction in the production of primary amines suggests its potential industrial interest.

Low-frequency vibrational density of states of ordinary and ultra-stable glasses.

A remarkable feature of disordered solids distinct from crystals is the violation of the Debye scaling law of the low-frequency vibrational density of states. Because the low-frequency vibration is responsible for many properties of solids, it is crucial to elucidate it for disordered solids. Numerous recent studies have suggested power-law scalings of the low-frequency vibrational density of states, but the scaling exponent is currently under intensive debate. Here, by classifying disordered solids into stable and unstable ones, we find two distinct and robust scaling exponents for non-phononic modes at low frequencies. Using the competition of these two scalings, we clarify the variation of the scaling exponent and hence reconcile the debate. Via the study of both ordinary and ultra-stable glasses, our work reveals a comprehensive picture of the low-frequency vibration of disordered solids and sheds light on the low-frequency vibrational features of ultra-stable glasses on approaching the ideal glass.

The application of deep learning in abdominal trauma diagnosis by CT imaging.

BACKGROUND: Abdominal computed tomography (CT) scan is a crucial imaging modality for creating cross-sectional images of the abdominal area, particularly in cases of abdominal trauma, which is commonly encountered in traumatic injuries. However, interpreting CT images is a challenge, especially in emergency. Therefore, we developed a novel deep learning algorithm-based detection method for the initial screening of abdominal internal organ injuries. METHODS: We utilized a dataset provided by the Kaggle competition, comprising 3,147 patients, of which 855 were diagnosed with abdominal trauma, accounting for 27.16% of the total patient population. Following image data pre-processing, we employed a 2D semantic segmentation model to segment the images and constructed a 2.5D classification model to assess the probability of injury for each organ. Subsequently, we evaluated the algorithm's performance using 5k-fold cross-validation. RESULTS: With particularly noteworthy performance in detecting renal injury on abdominal CT scans, we achieved an acceptable accuracy of 0.932 (with a positive predictive value (PPV) of 0.888, negative predictive value (NPV) of 0.943, sensitivity of 0.887, and specificity of 0.944). Furthermore, the accuracy for liver injury detection was 0.873 (with PPV of 0.789, NPV of 0.895, sensitivity of 0.789, and specificity of 0.895), while for spleen injury, it was 0.771 (with PPV of 0.630, NPV of 0.814, sensitivity of 0.626, and specificity of 0.816). CONCLUSIONS: The deep learning model demonstrated the capability to identify multiple organ injuries simultaneously on CT scans and holds potential for application in preliminary screening and adjunctive diagnosis of trauma cases beyond abdominal injuries.

Inhibition of PI3K p110δ rebalanced Th17/Treg and reduced macrophages pyroptosis in LPS-induced sepsis.

Sepsis is a systemic inflammatory response syndrome caused by trauma or infection, which can lead to multiple organ dysfunction. In severe cases, sepsis can also progress to septic shock and even death. Effective treatments for sepsis are still under development. This study aimed to determine if targeting the PI3K/Akt signaling with CAL-101, a PI3K p110δ inhibitor, could alleviate lipopolysaccharide (LPS)-induced sepsis and contribute to immune tolerance. Our findings indicated that CAL-101 treatment improved survival rates and alleviated the progression of LPS-induced sepsis. Compared to antibiotics, CAL-101 not only restored the Th17/regulatory T cells (Treg) balance but also enhanced Treg cell function. Additionally, CAL-101 promoted type 2 macrophage (M2) polarization, inhibited TNF-α secretion, and increased IL-10 secretion. Moreover, CAL-101 treatment reduced pyroptosis in peritoneal macrophages by inhibiting caspase-1/gasdermin D (GSDMD) activation. This study provides a mechanistic basis for future clinical exploration of targeted therapeutics and immunomodulatory strategies in the treatment of sepsis.

Anti-TL1A monoclonal antibody modulates the dysregulation of Th1/Th17 cells and attenuates granuloma formation in sarcoidosis by inhibiting the PI3K/AKT signaling pathway.

Sarcoidosis is a systemic granulomatous disease characterized by non-caseating epithelioid cell granulomas. One of its immunological hallmarks is the differentiation of CD4 + naïve T cells into Th1/Th17 cells, accompanied by the release of numerous pro-inflammatory cytokines. The TL1A/DR3 signaling pathway plays a crucial role in activating effector lymphocytes, thereby triggering pro-inflammatory responses. The primary aim of this investigation was to scrutinize the impact of anti-TL1A monoclonal antibody on the dysregulation of Th1/Th17 cells and granuloma formation in sarcoidosis. Initially, the abnormal activation of the TL1A/DR3 signaling pathway in pulmonary tissues of sarcoidosis patients was confirmed using qPCR and immunohistochemistry techniques. Subsequently, employing a murine model of sarcoidosis, the inhibitory effects of anti-TL1A monoclonal antibody on the TL1A/DR3 signaling pathway in sarcoidosis were investigated through qPCR, immunohistochemistry, and Western blot experiments. The influence of anti-TL1A monoclonal antibody on granulomas was assessed through HE staining, while their effects on sarcoidosis Th1/Th17 cells and associated cytokine mRNA levels were evaluated using flow cytometry and qPCR, respectively. Immunofluorescence and Western blot experiments corroborated the inhibitory effects of anti-TL1A monoclonal antibody on the aberrant activation of the PI3K/AKT signaling pathway in sarcoidosis. The findings of this study indicate that the TL1A/DR3 signaling pathway is excessively activated in sarcoidosis. Anti-TL1A monoclonal antibody effectively inhibit this abnormal activation in sarcoidosis, thereby alleviating the dysregulation of Th1/Th17 cells and reducing the formation of pulmonary granulomas. This effect may be associated with the inhibition of the downstream PI3K/AKT signaling pathway. Anti-TL1A monoclonal antibody hold promise as a potential novel therapeutic intervention for sarcoidosis.

[Label-free monitoring 5-FU induced SW 620 cells apoptosis using FTIR microspectroscopy].

The aim of the present study was to evaluate Fourier transform infrared spectroscopy (FTIR) monitoring of biochemical changes in apoptosis cells. Different concentrations of 5-fluorouracil (5-FU) treated colon cancer cell lines SW620 were used to determine the optimum concentration of 5-FU IC50 by means of MTT assay. Cell starvation and 5-Fu synergistic cell cycle arrest was in G1 and S phase. FTIR combined with flow cytometry was applied to analysis of SW 620 cells and SW620 cells treated with 5-FU for 12h, 24h (early apoptosis) and 48 h (late apoptosis) respectively. The peak position and the intensity of all bands were measured and comparison was made between the SW620 and apoptotic SW620 cells. Apoptosis cells have following characteristics compared with SW620 cells (1) The band at 1 740 cm-1 is an C=O stretching vibration. Changes in these bands can reflect lipid changes, and relative peak intensity ratio 11740/11460 significantly increased (p<0. 05), indicating that the relative contents of lipid in apoptosis cells increased. (2) The band at the 1 410 cm-1 peak represents that C-H stretching related was increased to amino acid residues and shifted to higher wave numbers compared to other groups. I1410o/I 460 at early and late death phase was significantly increased, which suggests that the relative contents of amino acid residues in apoptosis cells increased (p <0. 05). New vibrational bands at 1 120 cm-1 appeared at 24 h and increased at 48 h compared with other groups. The 1 120 cm-1 absorption band is mainly due to ser, serine and threonine C-O(H) stretching vibration, and I1120/I 1460 significantly increased (p<0. 05), indicating that the relative quantity of amino acid residues in apoptosis cells increased due to that DNA unwinds the double helix. (3) 1 240 cm-1 is mainly due to the asymmetric stretching modes of phosphodiester groups shifting to higher wave number, illustrating that nucleic acid conformation was changed in apoptosis cells. (4) The band 1 040 cm-1 associated with polysaccharide appeared at 24 and 48 h, meanwhile shifted to higher wave number, suggesting that polysaccharide decreased in late apoptotic cells, and I 1040/I1400 increased at late stage apoptosis, indicating that the relative content of polysaccharide in apoptosis cells increased. The authors' results suggest that FTIR applied to monitoring SW620 cells apoptosis may be as a potential diagnostic tool for cancer chemotherapy monitoring.

PpBZR1, a BES/BZR transcription factor, enhances cold stress tolerance by suppressing sucrose degradation in peach fruit.

Brassinosteroids (BRs) are phytohormones that play numerous roles in a plant's response to environmental stress. While BES/BZR transcription factors are essential components in BR signaling, their role in regulating postharvest fruit responses to cold stress is largely unknown. In this study, the application of 24-epibrassinolide (EBR) to peaches alleviated chilling injury (CI) during postharvest cold storage. We further characterized a key BES/BZR gene, PpBZR1, which regulates peach cold resistance. Transient expression PpBZR1 in peaches showed that PpBZR1 inhibits PpVIN2 expression and VIN activity, resulting in an elevated level of sucrose, which protects fruit from CI. Arabidopsis thaliana expressing PpBZR1 that had a high germination and seedling survival rate at low temperatures, which may be due to higher level of sucrose and lower oxidative damage. Mechanistically, we confirmed that PpBZR1 directly binds to the PpVIN2 promoter and functions as a negative regulator for sucrose metabolism. In addition, PpCBF1/5/6 were induced by EBR treatment and AtCBFs were upregulated in PpBZR1 transgenic Arabidopsis thaliana. Combined with previous findings, we hypothesize that PpBZR1 regulates PpVIN2 and may also be mediated by CBF. In conclusion, PpBZR1 expression is induced by EBR treatment during cold storage, which futher inhibite sucrose degradation gene PpVIN2 transcription via direct binding its promoter and indirectly regulating PpVIN2, resulting in slower sucrose degradation and higher chilling tolerance of peach.

Risk Factors for Granulomatous Mastitis and Establishment and Validation of a Clinical Prediction Model (Nomogram).

Background: This study aimed to explore the risk factors and clinical characteristics of granulomatous mastitis (GM) using a case-control study and establish and validate a clinical prediction model (nomogram). Methods: This retrospective case-control study was conducted in three hospitals in China from June 2017 to December 2021. A total of 1634 GM patients and 186 healthy women during the same period were included and randomly divided into the modeling and validation groups in a 7:3 ratio. To identify the independent risk factors of GM, univariate and multivariate logistic analyses were conducted and used to develop a nomogram. The prediction model was internally and externally validated using the Bootstrap technique and validation cohort. The receiver operating characteristic (ROC) curve and calibration curve were used to evaluate the discrimination and calibration of the prediction model. Decision curve analysis (DCA) and clinical impact curve (CIC) were used to evaluate the clinical significance of the model. Results: The average age of GM patients was 33.14 years (mainly 20-40). The incidence was high within five years from delivery and mainly occurred in the unilateral breast. The majority of the patients exhibited local skin alterations, while some also presented with systemic symptoms. On multivariate logistic analysis, age, high prolactin level, sex hormone intake, breast trauma, nipple discharge or invagination, and depression were independent risk factors for GM. The mean area under the curve (AUC) in the modeling and validation groups were 0.899 and 0.889. The internal and external validation demonstrated the model's predictive ability and clinical value. Conclusion: Lactation-related factors are the main risk factors of GM, leading to milk stasis or increased ductal secretion. Meanwhile, hormone disorders could affect the secretion and expansion of mammary ducts. All these factors can obstruct or injure the duct, inducing inflammatory reactions and immune responses. Additionally, blunt trauma, depressed mood, and diet preference can accelerate the process. The nomogram can effectively predict the risk of GM.

The Relevance of Serum Macrophage Migration Inhibitory Factor Level and Executive Function in Patients with White Matter Hyperintensity in Cerebral Small Vessel Disease.

(1) Objective: To investigate the relationship between serum macrophage migration inhibitory factor (MIF) level and white matter hyperintensity (WMH) and executive function (EF) in cerebral small vascular disease (CSVD), and assess the impact and predictive value of MIF level and Fazekas scores in CSVD-related cognitive impairment (CI) (CSVD-CI); (2) Methods: A total of 117 patients with WMH admitted to the First Affiliated Hospital of Xinxiang Medical College from January 2022 to August 2022 were enrolled. According to the Montreal cognitive assessment (MoCA) scale, subjects were divided into a normal cognitive group and an impaired group. All subjects required serum MIF level, 3.0 T MRI, and neuropsychological evaluation to investigate the risk factors for CDVD-CI, analyze the correlation between MIF level, WMH, and EF, and to analyze the diagnostic value of MIF and WMH degree in predicting CSVD-CI; (3) Results: 1. Fazekas score and MIF level were the risk factors of CSVD-CI. 2. The Fazekas score was negatively correlated with MoCA score, positively correlated with Stroop C-Time, Stroop C-Mistake, Stroop interference effects (SIE)-Time, SIE-Mistake, and color trails test (CTT) interference effects (CIE) (B-A). 3. The MIF level was positively correlated with Fazekas score, Stroop C-Time, SIE-Time, CTT B-Time, and CIE (B-A), and negatively correlated with MoCA score. 4. Fazekas score and MIF level were significant factors for diagnosing CSVD-CI; (4) Conclusion: The Fazekas score and MIF level may be the risk factors of CSVD-CI, and they are closely correlated to CI, especially the EF, and they have diagnostic value for CSVD-CI.

An Elastic Cross-Linked Binder for Silicon Anodes in Lithium-Ion Batteries with a High Mass Loading.

Due to the urgent demand for lithium-ion batteries (LIBs) with a high energy density, silicon (Si) possessing an ultrahigh capacity has aroused wide attention. However, its practical application is seriously hindered by enormous volume changes of the Si anode during cycling. Developing novel binders suitable for the Si anode has proven to be an effective strategy to improve its electrochemical performance. Herein, we constructed a three-dimensional network binder, in which the polyacrylic acid (PAA) long chains are cross-linked with one kind of amino acid, lysine (Lys). The abundant polar groups in PAA/Lys enable it to tightly adhere to the Si particles via hydrogen bonds, and the cross-linked structure prevents irreversible slipping of the PAA chains upon volume variation of the particles. The Si used was obtained from a sustainable route by recycling photovoltaic waste silicon. With high elasticity and strong adhesion, the PAA/Lys binder can effectively keep the structural integrity of the Si electrode and improve its electrochemical performance. The Si electrode using the PAA/Lys binder exhibits a good cycling stability (1008 mAh g-1 at 2 A g-1 after 250 cycles). Even with a high mass loading of 3.03 mg cm-2, the Si anode can remain stable for 100 cycles at a high fixed areal capacity of 3.03 mAh cm-2. This work gives a practical method to make stable Si electrodes using sustainable Si source and environmentally friendly amino acid-based binders.

Local and global measures of the shear moduli of jammed disk packings.

Strain-controlled isotropic compression gives rise to jammed packings of repulsive, frictionless disks with either positive or negative global shear moduli. We carry out computational studies to understand the contributions of the negative shear moduli to the mechanical response of jammed disk packings. We first decompose the ensemble-averaged, global shear modulus as 〈G〉=(1-F_{-})〈G_{+}〉+F_{-}〈G_{-}〉, where F_{-} is the fraction of jammed packings with negative shear moduli and 〈G_{+}〉 and 〈G_{-}〉 are the average values from packings with positive and negative moduli, respectively. We show that 〈G_{+}〉 and 〈|G_{-}|〉 obey different power-law scaling relations above and below pN^{2}∼1. For pN^{2}>1, both 〈G_{+}〉N and 〈|G_{-}|〉N∼(pN^{2})^{ß}, where ß∼0.5 for repulsive linear spring interactions. Despite this, 〈G〉N∼(pN^{2})^{ß^{'}} with ß^{'}≳0.5 due to the contributions from packings with negative shear moduli. We show further that the probability distribution of global shear moduli P(G) collapses at fixed pN^{2} and different values of p and N. We calculate analytically that P(G) is a Γ distribution in the pN^{2}≪1 limit. As pN^{2} increases, the skewness of P(G) decreases and P(G) becomes a skew-normal distribution with negative skewness in the pN^{2}≫1 limit. We also partition jammed disk packings into subsystems using Delaunay triangulation of the disk centers to calculate local shear moduli. We show that the local shear moduli defined from groups of adjacent triangles can be negative even when G>0. The spatial correlation function of local shear moduli C(r[over ⃗]) displays weak correlations for pn_{sub}^{2}<10^{-2}, where n_{sub} is the number of particles within each subsystem. However, C(r[over ⃗]) begins to develop long-ranged spatial correlations with fourfold angular symmetry for pn_{sub}^{2}≳10^{-2}.

Inhibition of phosphoinositide­3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model.

Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)-related non-caseating granulomas. Phosphoinositide-3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL-101 (PI3Kδ inhibitor) or AS-605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence-activated cell sorting analysis and reverse transcription-quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA-induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4+CD25- T cells and CD4+CD25+ T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL-101/AS-605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL-101 was more effective in immune modulation compared with AS-605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs-mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune-therapeutic principle for sarcoidosis in the future.