Dedifferentiation-like reprogramming of degenerative nucleus pulposus cells into notochordal-like cells by defined factors.

The extensive degeneration of functional somatic cells and the depletion of endogenous stem/progenitor populations present significant challenges to tissue regeneration in degenerative diseases. Currently, a cellular reprogramming approach enabling directly generating corresponding progenitor populations from degenerative somatic cells remains elusive. The present study focused on intervertebral disc degeneration (IVDD) and identified a three-factor combination (OCT4, FOXA2, TBXT [OFT]) that could induce the dedifferentiation-like reprogramming of degenerative nucleus pulposus cells (dNPCs) toward induced notochordal-like cells (iNCs). Single-cell transcriptomics dissected the transitions of cell identity during reprogramming. Further, OCT4 was found to directly interact with bromodomain PHD-finger transcription factor to remodel the chromatin during the early phases, which was crucial for initiating this dedifferentiation-like reprogramming. In rat models, intradiscal injection of adeno-associated virus carrying OFT generated iNCs from in situ dNPCs and reversed IVDD. These results collectively present a proof-of-concept for dedifferentiation-like reprogramming of degenerated somatic cells into corresponding progenitors through the development of a factor-based strategy, providing a promising approach for regeneration in degenerative disc diseases.

Volitional modulation of neuronal activity in the external globus pallidus by engagement of the cortical-basal ganglia circuit.

Volitional modulation of neural activity is not confined to the cortex but extends to various brain regions. Yet, it remains unclear whether neurons in the basal ganglia structure, the external globus pallidus (GPe), can be volitionally controlled. Here, we employed a volitional conditioning task to compare the volitional modulation of GPe and primary motor cortex (M1) neurons as well as the underlying circuits and control mechanisms. The results revealed that the volitional modulation of GPe neuronal activity engaged both M1 and substantia nigra pars reticulata (SNr) neurons, indicating the involvement of the cortex-GPe-SNr loop. In contrast, the volitional modulation of M1 neurons primarily occurred through the engagement of M1 local circuitry. Furthermore, lesioning M1 neurons did not affect the volitional learning or volitional control signal in GPe, whereas lesioning of GPe neurons impaired the learning process for the volitional modulation of M1 neuronal activity at the intermediate stage. Additionally, lesion of GPe neurons enhanced M1 neuronal activity when performing the volitional control task without reward delivery and a random reward test. Taken together, our findings demonstrated that GPe neurons could be volitionally controlled by engagement of the cortical-basal ganglia circuit and inhibit learning process for the volitional modulation of M1 neuronal activity by regulating M1 neuronal activity. Thus, GPe neurons can be effectively harnessed for independent volitional modulation for neurorehabilitation in patients with cortical damage. KEY POINTS: The cortical-basal ganglia circuit contributes to the volitional modulation of GPe neurons. Volitional modulation of M1 neuronal activity mainly engages M1 local circuitry. Bilateral GPe lesioning impedes volitional learning at the intermediate stages. Lesioning of GPe neurons inhibits volitional learning process by regulating M1 neuronal activity.

An accelerated PETALUTE MRI sequence for in vivo quantification of sodium content in human articular cartilage at 3T.

OBJECTIVE: In this work, we evaluate the sodium magnetic resonance imaging (MRI) capabilities of a three-dimensional (3D) dual-echo ultrashort echo time (UTE) sequence with a novel rosette petal trajectory (PETALUTE), in comparison to the 3D density-adapted (DA) radial spokes UTE sequence in human articular cartilage in the knee. MATERIALS AND METHODS: We scanned five healthy subjects using a 3D dual-echo PETALUTE acquisition and two comparable implementations of 3D DA-radial spokes acquisitions, one matching the number of k-space projections (Radial - Matched Spokes) and the other matching the total number of samples (Radial - Matched Samples) acquired in k-space. RESULTS: The PETALUTE acquisition enabled equivalent sodium quantification in articular cartilage volumes of interest (168.8 ± 29.9 mM, mean ± standard deviation) to those derived from the 3D radial acquisitions (171.62 ± 28.7 mM and 149.8 ± 22.2 mM, respectively). We achieved a 41% shorter scan time of 2:06 for 3D PETALUTE, compared to 3:36 for 3D radial acquisitions. We also evaluated the feasibility of further acceleration of the PETALUTE sequence through retrospective compressed sensing with 2 × and 4 × acceleration of the first echo and showed structural similarity of 0.89 ± 0.03 and 0.87 ± 0.03 when compared to non-retrospectively accelerated reconstruction. CONCLUSION: We demonstrate improved scan time with equivalent performance using a 3D dual-echo PETALUTE sequence compared to the 3D DA-radial sequence for sodium MRI of articular cartilage.

Neural representation and modulation of volitional motivation in response to escalating efforts.

Task-dependent volitional control of the selected neural activity in the cortex is critical to neuroprosthetic learning to achieve reliable and robust control of the external device. The volitional control of neural activity is driven by a motivational factor (volitional motivation), which directly reinforces the target neurons via real-time biofeedback. However, in the absence of motor behaviour, how do we evaluate volitional motivation? Here, we defined the criterion (ΔF/F) of the calcium fluorescence signal in a volitionally controlled neural task, then escalated the efforts by progressively increasing the number of reaching the criterion or holding time after reaching the criterion. We devised calcium-based progressive threshold-crossing events (termed 'Calcium PTE') and calcium-based progressive threshold-crossing holding-time (termed 'Calcium PTH') for quantitative assessment of volitional motivation in response to progressively escalating efforts. Furthermore, we used this novel neural representation of volitional motivation to explore the neural circuit and neuromodulator bases for volitional motivation. As with behavioural motivation, chemogenetic activation and pharmacological blockade of the striatopallidal pathway decreased and increased, respectively, the breakpoints of the 'Calcium PTE' and 'Calcium PTH' in response to escalating efforts. Furthermore, volitional and behavioural motivation shared similar dopamine dynamics in the nucleus accumbens in response to trial-by-trial escalating efforts. In general, the development of a neural representation of volitional motivation may open a new avenue for smooth and effective control of brain-machine interface tasks. KEY POINTS: Volitional motivation is quantitatively evaluated by M1 neural activity in response to progressively escalating volitional efforts. The striatopallidal pathway and adenosine A2A receptor modulate volitional motivation in response to escalating efforts. Dopamine dynamics encode prediction signal for reward in response to repeated escalating efforts during motor and volitional conditioning. Mice learn to modulate neural activity to compensate for repeated escalating efforts in volitional control.

Assessing pulsatile waveforms of paravascular cerebrospinal fluid dynamics within the glymphatic pathways using dynamic diffusion-weighted imaging (dDWI)

Cerebrospinal fluid (CSF) in the paravascular spaces of the surface arteries (sPVS) is a vital pathway in brain waste clearance. Arterial pulsations may be the driving force of the paravascular flow, but its pulsatile pattern remains poorly characterized, and no clinically practical method for measuring its dynamics in the human brain is available. In this work, we introduce an imaging and quantification framework for in-vivo non-invasive assessment of pulsatile fluid dynamics in the sPVS. It used dynamic Diffusion-Weighted Imaging (dDWI) at a lower b-values of 150s/mm2 and retrospective gating to detect the slow flow of CSF while suppressing the fast flow of adjacent arterial blood. The waveform of CSF flow over a cardiac cycle was revealed by synchronizing the measurements with the heartbeat. A data-driven approach was developed to identify sPVS and allow automatic quantification of the whole-brain fluid waveforms. We applied dDWI to twenty-five participants aged 18-82 y/o. Results demonstrated that the fluid waveforms across the brain showed an explicit cardiac-cycle dependency, in good agreement with the vascular pumping hypothesis. Furthermore, the shape of the CSF waveforms closely resembled the pressure waveforms of the artery wall, suggesting that CSF dynamics is tightly related to artery wall mechanics. Finally, the CSF waveforms in aging participants revealed a strong age effect, with a significantly wider systolic peak observed in the older relative to younger participants. The peak widening may be associated with compromised vascular compliance and vessel wall stiffening in the older brain. Overall, the results demonstrate the feasibility, reproducibility, and sensitivity of dDWI for detecting sPVS fluid dynamics of the human brain. Our preliminary data suggest age-related alterations of the paravascular pumping. With an acquisition time of under six minutes, dDWI can be readily applied to study fluid dynamics in normal physiological conditions and cerebrovascular/neurodegenerative diseases.

MDA5 expression is associated with TGF-ß-induced fibrosis: potential mechanism of interstitial lung disease in anti-MDA5 dermatomyositis.

OBJECTIVES: This study aimed to investigate the high-resolution CT (HRCT) characteristics of anti-melanoma differentiation-associated gene 5 (MDA5) antibody positive dermatomyositis-associated interstitial lung disease (anti-MDA5 DM-ILD), and to clarify the underlying mechanisms of the clinical phenomenon. METHODS: Clinical data and HRCT patterns were compared between anti-MDA5 DM-ILD (n = 32) and antisynthetase syndrome-associated ILD (ASS-ILD) (n = 29). RNA sequencing of whole-blood samples from the two groups, and in vitro experiments using human embryonic lung fibroblasts (HELFs) were conducted to explore the potential mechanisms of the clinical findings. RESULTS: The anti-MDA5 DM-ILD subset had a significantly higher incidence of rapidly progressive ILD (RPILD) than ASS-ILD (65.6% vs 37.9%; P = 0.031). The relative percentage of the lung fibrosis HRCT pattern was significantly lower in the anti-MDA5 DM-ILD group, especially the RPILD subgroup (P = 0.013 and 0.003, respectively). RNA sequencing detected the upregulated genes including interferon-induced helicase C domain 1 (encoding MDA5), and a trend towards downregulated expression of TGF-ß signalling components in anti-MDA5 DM-ILD. In vitro culture of HELFs revealed that upregulated expression of MDA5 in HELFs was correlated with the downregulated expression of alpha smooth muscle actin, connective tissue growth factor, collagen I and collagen III by suppressing the TGF-ß signalling pathway. CONCLUSIONS: Anti-MDA5 DM-ILD patients have significantly less lung fibrosis and elevated MDA5 expression. The upregulated expression of MDA5 has relations with the suppression of the pro-fibrotic function of fibroblasts via the TGF-ß signalling pathway, which may partially explain the mechanism of the clinical phenomenon.

Closed-form model and analysis for the enhancement effect of a rectangular plate in the scattering characteristics of multiphoton quantum radar.

A closed-form model of multiphoton quantum radar cross-section (QRCS) in the monostatic scenes is constructed for rectangular flat plates based on quantum interference and uncertainty. The model is justified by the comprehensive analysis of the model parameters in the model building process. Then, we use the model to quantitatively analyze the main lobe enhancement effect of multiphoton QRCS, which means that the more incident photons will enhance the main lobe magnitude of QRCS with other factors being the same. Moreover, we predict that enhancement effects might also exist for the side lobe close to the main lobe. In addition, we present the specific conditions for side lobe enhancement. On this basis, the enhancement angle range is defined to unify the description of the main lobe and side lobe enhancement effects. The influencing factors of the enhancement angle range are clarified. The results exhibit that the angle range of enhancement in multiphoton QRCS fluctuates with the change of target size and incident wavelength. All enhancement effects are exponentially related to the incident photon number. This work brings the description of multiphoton QRCS into the closed-form model analysis stage, which will provide prior information for research in many fields, such as photonic technology, radar technology, and precision metrology.

Retracted: Expression and Mechanism of Interleukin 1 (IL-1), Interleukin 2 (IL-2), Interleukin 8 (IL-8), BMP, Fibroblast Growth Factor 1 (FGF1), and Insulin-Like Growth Factor (IGF-1) in Lumbar Disc Herniation.

This manuscript has been retracted due to concerns regarding the authorship and the credibility of the study.Reference:Zhengkuan Xu, Xiaopeng Zhou, Gang Chen. Expression and Mechanism of Interleukin 1 (IL-1), Interleukin 2 (IL-2), Interleukin 8 (IL-8), BMP, Fibroblast Growth Factor 1 (FGF1), and Insulin-Like Growth Factor (IGF-1) in Lumbar Disc Herniation. Med Sci Monit, 2019; 25:984-990. DOI: 10.12659/MSM.911910.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration.

Exosome therapy is a promising therapeutic approach for intervertebral disc degeneration (IVDD) and achieves its therapeutic effects by regulating metabolic disorders, the microenvironment and cell homeostasis with the sustained release of microRNAs, proteins, and transcription factors. However, the rapid clearance and disruption of exosomes are the two major challenges for the application of exosome therapy in IVDD. Herein, a thermosensitive acellular extracellular matrix (ECM) hydrogel coupled with adipose-derived mesenchymal stem cell (ADSC) exosomes (dECM@exo) that inherits the superior properties of nucleus pulposus tissue and ADSCs was fabricated to ameliorate IVDD. This thermosensitive dECM@exo hydrogel system can provide not only in situ gelation to replenish ECM leakage in nucleus pulposus cells (NPCs) but also an environment for the growth of NPCs. In addition, sustained release of ADSC-derived exosomes from this system regulates matrix synthesis and degradation by regulating matrix metalloproteinases (MMPs) and inhibits pyroptosis by mitigating the inflammatory response in vitro. Animal results demonstrated that the dECM@exo hydrogel system maintained early IVD microenvironment homeostasis and ameliorated IVDD. This functional system can serve as a powerful platform for IVD drug delivery and biotherapy and an alternative therapy for IVDD.

Scar Tissue-Targeting Polymer Micelle for Spinal Cord Injury Treatment.

Spinal cord injury (SCI) is a devastating disorder, leading to permanent motor and sensory deficit. Despite recent advances in neurosciences, the treatment efficacy on SCI patients remains unsatisfactory, mainly due to the poor accumulation, short retention, and lack of controlled release of therapeutics in lesion tissue. Herein, an injured spinal cord targeting prodrug polymer micelle is built. An esterase-responsive bond is used to link apocynin (APO) monomer, because of the enhanced esterase activity found in microglia cells after activation, which ensures a controlled degradation of APO prodrug (Allyloxypolyethyleneglycol-b-poly [2-(((4-acetyl-2-methoxyphenoxy)carbonyl)oxy)ethyl methacrylate], APEG-PAPO or PAPO) by activated microglia cells. A scar tissue-homing peptide (cysteine-alanine-glutamine-lysine, CAQK) is introduced to the PAPO to endow the polymer micelle the lesion tissue-targeting ability. As a result, this CAQK-modified prodrug micelle (cPAM) exhibits an improved accumulation and prolonged retention in lesion tissue compared to the control micelle. The cPAM also leads to superior tissue protection and sustained motor function recovery than the control groups in a mouse model of SCI. In conclusion, the cPAM induces an effective treatment of SCI by the lesion tissue specific delivery of the prodrug polymer via its robust scar binding effect, making the scar tissue a drug releasing platform for sustained treatment of SCI.

Fat-water separation by fast metabolite cycling magnetic resonance spectroscopic imaging at 3 T: A method to generate separate quantitative distribution maps of musculoskeletal lipid components.

PURPOSE: To provide a rapid, noninvasive fat-water separation technique that allows producing quantitative maps of particular lipid components. METHODS: The calf muscles in 5 healthy adolescents (age 12-16 years; body mass index = 20 ± 3 kg/m2 ) were scanned by two different fat fraction measurement methods. A density-weighted concentric-ring trajectory metabolite-cycling MRSI technique was implemented to collect data with a nominal resolution of 0.25 mL within 3 minutes and 16 seconds. For comparative purposes, the standard Dixon technique was performed. The two techniques were compared using structural similarity analysis. Additionally, the difference in the distribution of each lipid over the adolescent calf muscles was assessed based on the MRSI data. RESULTS: The proposed MRSI technique provided individual fat fraction maps for eight musculoskeletal lipid components identified by LCModel analysis (IMC/L [CH3 ], EMCL [CH3 ], IMC/L [CH2 ]n , EMC/L [CH2 ]n , IMC/L [CH2 -CH], EMC/L [CH2 -CH], IMC/L [-CH=CH-], and EMC/L [-CH=CH-]) with mean structural similarity indices of 0.19, 0.04, 0.03, 0.50, 0.45, 0.04, 0.07, and 0.12, respectively, compared with the maps generated by the used Dixon method. Further analysis of voxels with zero structural similarity demonstrated an increased sensitivity of fat fraction lipid maps from the data acquired using this MRSI technique over the standard Dixon technique. The lipid spatial distribution over calf muscles was consistent with previously published findings in adults. CONCLUSION: This MRSI technique can be a useful tool when individual lipid fat fraction maps are desired within a clinically acceptable time and with a nominal spatial resolution of 0.25 mL.

Osmolarity controls the differentiation of adipose-derived stem cells into nucleus pulposus cells via histone demethylase KDM4B.

Adipose-derived stem cells (ADSCs) are an ideal source of cells for intervertebral disc (IVD) regeneration, but the effect of an increased osmotic microenvironment on ADSC differentiation remains unclear. Here, we aimed to elucidate whether hyperosmolarity facilitates ADSC nucleus pulposus (NP)-like differentiation and whether histone demethylase KDM4B is involved in this process. ADSCs were cultured under standard and increased osmolarity conditions for 1-3 weeks, followed by analysis for proliferation and viability. Differentiation was then quantified by gene and protein analysis. Finally, KDM4B knockdown ADSCs were generated using lentiviral vectors. The results showed that increasing the osmolarity of the differentiation medium to 400 mOsm significantly increased NP-like gene expression and the synthesis of extracellular matrix (ECM) components during ADSC differentiation; however, further increasing the osmolarity to 500 mOsm suppressed the NP-like differentiation of ADSCs. KDM4B, as well as the IVD formation regulators forkhead box (Fox)a1/2 and sonic hedgehog (Shh), were found to be significantly upregulated at 400 mOsm. KDM4B knockdown reduced Foxa1/2, Shh, and NP-associated markers' expression, as well as the synthesis of ECM components. The reduction in NP-like differentiation caused by KDM4B knockdown was partially rescued by Purmorphamine, a specific agonist of Shh. Moreover, we found that KDM4B can directly bind to the promoter region of Foxa1/2 and decrease the content of H3K9me3/2. In conclusion, our results indicate that a potential optimal osmolarity window might exist for successful ADSC differentiation. KDM4B plays an essential role in regulating the osmolarity-induced NP-like differentiation of ADSCs by interacting with Foxa1/2-Shh signaling.

Effects of IGFBP3 gene silencing mediated inhibition of ERK/MAPK signaling pathway on proliferation, apoptosis, autophagy, and cell senescence in rats nucleus pulposus cells.

OBJECTIVE: Disc degeneration is the common life-threatening disease characterized by flank pain. The gene expression of insulin-like growth factor binding protein 3 (IGFBP3) is increased in patients with disc degeneration, however, its mechanism is still unknown. This study aimed to investigate the influence of IGFBP3 gene silencing mediated inhibition of extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling on proliferation, apoptosis, autophagy, and cell senescence in rats nucleus pulposus (NP) cells. METHODS: The expression of IGFBP3 in disc NP of patients was assessed by real-time PCR (RT-PCR) and western blot. RT-PCR, transwell assay, immunohistochemical staining, SA-ß-Gal staining, and western blot were performed to explore the molecular mechanism of IGFBP3 in NP cell migration and invasion. RESULTS: In this study, IGFBP3 was highly expressed in disc NP of patients. With RT-PCR, transwell assay, immunohistochemical staining, SA-ß-Gal staining, and western blot, downregulated IGFBP3 could inhibit NP cells' migration and invasion by targeting the ERK/MAPK signaling pathway. CONCLUSION: Our findings revealed that the inhibition of the ERK/MAPK pathway was mediated by IGFBP3 silencing that had effects on proliferation, apoptosis, autophagy, and cell senescence. Furthermore, our findings suggested the underlying mechanism of disc degeneration.

Concentration-dependent, dual roles of IL-10 in the osteogenesis of human BMSCs via P38/MAPK and NF-κB signaling pathways.

Microenvironmental conditions can influence the differentiation and functional roles of mesenchymal stem cells (MSCs). Recent studies have suggested that an inflammatory microenvironment can significantly affect the osteogenic differentiation of MSCs. Here, we show, for the first time, that IL-10 has concentration-dependent, dual roles in the osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs). Low physiologic concentrations of IL-10 (0.01-1.0 ng/ml) activate the p38/MAPK signaling pathway to promote the osteogenesis of hBMSCs, but higher pathologic doses of IL-10 (10-100 ng/ml) inhibit p38/MAPK signaling by activating NF-κB, inhibiting osteogenesis. These results demonstrate that p38/MAPK and NF-κB signaling mediates the double-edged sword effect of IL-10 on hBMSCs. The osteogenic impairment was reversed at higher doses of IL-10 when cells were supplemented with the NF-κB inhibitor BAY11-7082. These data provide important insights into the regulatory effects of IL-10 on the biologic behavior of hBMSCs.-Chen, E., Liu, G., Zhou, X., Zhang, W., Wang, C., Hu, D., Xue, D., Pan, Z. Concentration-dependent, dual roles of IL-10 in the osteogenesis of human BMSCs via P38/MAPK and NF-κB signaling pathways.

FoxA2 regulates the type II collagen-induced nucleus pulposus-like differentiation of adipose-derived stem cells by activation of the Shh signaling pathway.

Adipose tissue-derived stem cell (ADSC)-based therapy is promising for the treatment of intervertebral disc (IVD) degeneration, but the difficulty in inducing nucleus pulposus (NP)-like differentiation limits its clinical applications. Forkhead box (Fox)-A2 is an essential transcription factor for the formation of a normal NP. We demonstrated that type II collagen stimulates NP-like differentiation of ADSCs, partly by increasing the expression of FoxA2. We constructed FoxA2-overexpressing and -knockdown ADSCs by using lentiviral vectors. FoxA2 overexpression significantly enhanced NP-specific gene expression and the synthesis of glycosaminoglycan and collagen, whereas FoxA2 knockdown decreased NP-like differentiation and the expression of aggrecan and collagen II. The enhanced NP-like differentiation related to FoxA2 overexpression was partially rescued by an Shh signaling pathway inhibitor. In addition, FoxA2 inhibited the expression of Itg-α2 and further promoted NP-like differentiation induced by type II collagen. Furthermore, FoxA2-overexpressing ADSCs combined with type II collagen hydrogels promoted regeneration of degenerated NP in vivo. Our findings suggest that FoxA2 plays an essential role in the NP-like differentiation of ADSCs by activating the Shh signaling pathway.-Zhou, X., Ma, C., Hu, B., Tao, Y., Wang, J., Huang, X., Zhao, T., Han, B., Li, H., Liang, C., Chen, Q., Li, F. FoxA2 regulates the type II collagen-induced nucleus pulposus-like differentiation of adipose-derived stem cells by activation of the Shh signaling pathway.

Expression and Mechanism of Interleukin 1 (IL-1), Interleukin 2 (IL-2), Interleukin 8 (IL-8), BMP, Fibroblast Growth Factor 1 (FGF1), and Insulin-Like Growth Factor (IGF-1) in Lumbar Disc Herniation.

BACKGROUND The expression and mechanism of IL-1, IL-2, IL-8, BMP, FGF1, and IGF-1 in Sprague-Dawley (SD) rats with lumbar disc herniation were investigated. MATERIAL AND METHODS Immunohistochemical methods were applied to identify IL-1, IL-2, IL-8, BMP, FGF1, and IGF-1. PI3K, AKT protein, and mRNA expression were detected and analyzed by Western blot analysis. We selected 30 healthy SD rats and divided them into 2 groups to construct an animal model that was validated by immediate CT scanning. Cartilage tissues from the lumbar disc herniation (experimental) group and control group were obtained and compared. RESULTS The expression of BMP was not significantly different between the control group and the experimental group (P>0.05). FGF1: There was no significant difference in the expression of FGF1 (P>0.05) between the control group and the experimental group. Compared with the control group, the expression of IGF-1 in the experimental group was significantly higher (P<0.05); the expression of IL-1 in the experimental group was significantly higher (P<0.05); and the expression of IL-2 in the experimental group was also significantly higher (P<0.05). There was no significant difference in IL-8 between the experimental group and the control group (P>0.05). The expression levels of PI3K and AKT protein and mRNA were significantly higher than those in healthy controls (P<0.05). CONCLUSIONS After lumbar disc herniation occurred, the IGF-1 was first activated; the PI3K/AKT signaling pathway was later activated, which resulted in the expression of IL-1 and IL-2 inflammation-related factors being increased.

Constraining Dark Matter Models with a Light Mediator at the PandaX-II Experiment.

We search for nuclear recoil signals of dark matter models with a light mediator in PandaX-II, a direct detection experiment in the China Jinping underground laboratory. Using data collected in 2016 and 2017 runs, corresponding to a total exposure of 54 ton day, we set upper limits on the zero-momentum dark matter-nucleon cross section. These limits have a strong dependence on the mediator mass when it is comparable to or below the typical momentum transfer. We apply our results to constrain self-interacting dark matter models with a light mediator mixing with standard model particles, and set strong limits on the model parameter space for the dark matter mass ranging from 5 GeV to 10 TeV.

Spin-Dependent Weakly-Interacting-Massive-Particle-Nucleon Cross Section Limits from First Data of PandaX-II Experiment.

New constraints are presented on the spin-dependent weakly-interacting-massive-particle–- (WIMP-)nucleon interaction from the PandaX-II experiment, using a data set corresponding to a total exposure of 3.3×10^{4} kg day. Assuming a standard axial-vector spin-dependent WIMP interaction with ^{129}Xe and ^{131}Xe nuclei, the most stringent upper limits on WIMP-neutron cross sections for WIMPs with masses above 10 GeV/c^{2} are set in all dark matter direct detection experiments. The minimum upper limit of 4.1×10^{-41} cm^{2} at 90% confidence level is obtained for a WIMP mass of 40 GeV/c^{2}. This represents more than a factor of 2 improvement on the best available limits at this and higher masses. These improved cross-section limits provide more stringent constraints on the effective WIMP-proton and WIMP-neutron couplings.

Limits on Axion Couplings from the First 80 Days of Data of the PandaX-II Experiment.

We report new searches for solar axions and galactic axionlike dark matter particles, using the first low-background data from the PandaX-II experiment at China Jinping Underground Laboratory, corresponding to a total exposure of about 2.7×10^{4} kg day. No solar axion or galactic axionlike dark matter particle candidate has been identified. The upper limit on the axion-electron coupling (g_{Ae}) from the solar flux is found to be about 4.35×10^{-12} in the mass range from 10^{-5} to 1 keV/c^{2} with 90% confidence level, similar to the recent LUX result. We also report a new best limit from the ^{57}Fe deexcitation. On the other hand, the upper limit from the galactic axions is on the order of 10^{-13} in the mass range from 1 to 10 keV/c^{2} with 90% confidence level, slightly improved compared with the LUX.