CCN1, a Pro-Inflammatory Factor, Aggravates Psoriasis Skin Lesions by Promoting Keratinocyte Activation

Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. The pathogenesis of psoriasis is multifactorial and is not fully understood. Here we demonstrate that CCN1 (also called Cyr61, which is short for cysteine-rich 61), an extracellular matrix protein that is also considered a pro-inflammatory factor, is highly expressed in the lesional skin of psoriasis patients, as well as in that of imiquimod (IMQ)- and IL-23-treated psoriasis-like mice. Then we show that blocking CCN1 function in vivo attenuates epidermal hyperplasia and inflammation in psoriasis-like mice. Further, in primary cultured normal human keratinocytes and HaCaT (human keratinocyte cell line) cells, CCN1 promotes keratinocyte activation, including the proliferation and expression of immune-related molecules. Finally, we observe that integrin α6β1 is the receptor of CCN1 in keratinocytes, and CCN1 stimulation activates the downstream phosphoinositide-3 kinase/Akt/NF-κB signaling pathway. Taken together, our findings reveal that CCN1 has a critical role in psoriasis pathogenesis. Moreover, as CCN1 is a secreted extracellular matrix (ECM) protein, our study also provides evidence that ECM, which is involved in psoriatic pathogenesis, could be a potent target for psoriasis treatment

Small-Molecule Inhibitor of AF9/Enl-DOT1L/AF4/AFF4 Interactions Suppresses Malignant Gene Expression and Tumor Grow

Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis. MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%). The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L. Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia. Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target. Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological activities against MLL-rearranged leukemia and other cancer cells. Results: Compound-1 was identified to be a novel small-molecule inhibitor of the AF9/ENL-DOT1L/AF4/AFF4 interaction with IC50s of 0.9-3.5 µM. Pharmacological inhibition of the PPIs significantly reduced SEC and DOT1L-mediated H3K79 methylation in the leukemia cells. Gene profiling shows compound-1 significantly suppressed the gene signatures related to onco-MLL, DOT1L, HoxA9 and Myc. It selectively inhibited proliferation of onco-MLL- or Myc-driven cancer cells and induced cell differentiation and apoptosis. Compound-1 exhibited strong antitumor activity in a mouse model of MLL-rearranged leukemia. Conclusions: The AF9/ENL-DOT1L/AF4/AFF4 interactions are validated to be an anticancer target and compound-1 is a useful in vivo probe for biological studies as well as a pharmacological lead for further drug development

Gate-Compatible Circuit QED in a Three-Dimensional Cavity Architecture

Semiconductor-based superconducting qubits offer a versatile platform for studying hybrid quantum devices in circuit quantum electrodynamics (cQED) architecture. Most of these cQED experiments utilize coplanar waveguides, where the incorporation of DC gate lines is straightforward. Here, we present a technique for probing gate-tunable hybrid devices using a three-dimensional (3D) microwave cavity. A recess is machined inside the cavity wall for the placement of devices and gate lines. We validate this design using a hybrid device based on an InAs-Al nanowire Josephson junction. The coupling between the device and the cavity is facilitated by a long superconducting strip, the antenna. The Josephson junction and the antenna together form a gatemon qubit. We further demonstrate the gate-tunable cavity shift and two-tone qubit spectroscopy. This technique could be used to probe various quantum devices and materials in a 3D cQED architecture that requires DC gate voltages

High-efficiency single-photon source above the loss-tolerant threshold for efficient linear optical quantum computing

Photon loss is the biggest enemy for scalable photonic quantum information processing. This problem can be tackled by using quantum error correction, provided that the overall photon loss is below a threshold of 1/3. However, all reported on-demand and indistinguishable single-photon sources still fall short of this threshold. Here, by using tailor shaped laser pulse excitation on a high-quantum efficiency single quantum dot deterministically coupled to a tunable open microcavity, we demonstrate a high-performance source with a single-photon purity of 0.9795(6), photon indistinguishability of 0.9856(13), and an overall system efficiency of 0.712(18), simultaneously. This source for the first time reaches the efficiency threshold for scalable photonic quantum computing. With this source, we further demonstrate 1.89(14) dB intensity squeezing, and consecutive 40-photon events with 1.67 mHz count rate

Granulocyte colony-stimulating factor effects on neurological and motor function in animals with spinal cord injury: a systematic review and meta-analysis

BackgroundSpinal cord injury (SCI) is a severe neurological injury for which no effective treatment exists. Granulocyte colony-stimulating factor (G-CSF) is used to treat autologous bone marrow transplantation, chemotherapy-induced granulocytopenia, Acquired Immune Deficiency Syndrome (AIDS), etc. Recent research has revealed the potential application of G-CSF on neuroprotective effectiveness. In central nervous system diseases, G-CSF can be used to alleviate neuronal injury.ObjectiveTo investigate the effects of G-CSF on Basso, Beattie, and Bresnahan (BBB) scale score, inclined plane test, electrophysiologic exam, quantitative analysis of TUNEL-positive cells, and quantitative analysis of glial fibrillary acidic protein (GFAP) immunostaining images in animal models of SCI.MethodsWe searched PubMed, Web of Science, and Embase databases for all articles on G-CSF intervention with animal models of SCI reported before November 2022. A total of 20 studies met the inclusion criteria.ResultsResults revealed that G-CSF intervention could improve the BBB scale score in both groups at 3, 7, 14, 28, and 35 days [at 35  days, weighted mean differences (WMD) = 2.4, 95% CI: 1.92–2.87, p < 0.00001, I2 = 69%]; inclined plane test score; electrophysiologic exam; quantitative analysis of TUNEL-positive cell numbers; quantitative analysis of GFAP immunostaining images in animal models of SCI. Subgroup analysis revealed that treatment with normal saline, phosphate-buffered saline, and no treatment resulted in significantly different neurological function effectiveness compared to the G-CSF therapy. SD rats and Wistar rats with SCI resulted in significant neurological function effectiveness. C57BL/6 mice showed no difference in the final effect. The T9–T10 or T10 segment injury model and the T8–T9 or T9 segment injury model resulted in significant neurological function effectiveness. The BBB score data showed no clear funnel plot asymmetry. We found no bias in the analysis result (Egger’s test, p = 0.42). In our network meta-analysis, the SUCRA ranking showed that 15 mg/kg-20 mg/kg was an optimal dose for long-term efficacy.ConclusionOur meta-analysis suggests that G-CSF therapy may enhance the recovery of motor activity and have a specific neuroprotective effect in SCI animal models.Systematic review registration: PROSPERO, identifier: CRD42023388315

Survey of Photovoltaic Industry and Policy in Germany and China

As building-integrated photovoltaic (PV) solutions can meet around one-third of electricity demand in Germany and China, both countries are interested in exploring this potential. PV technologies have demonstrated significant price reductions, but large-scale global application of PV requires further technology improvements and cost reductions along the value chain. We analyze policies in Germany and China, including deployment support, investment support for manufacturing plants and R&D support measures, and we survey the industrial actors they can encourage to pursue innovation. While deployment support has been successful, investment support for manufacturing in these nations has not been sufficiently tied to innovation incentives, and R&D support has been comparatively weak. The paper concludes with a discussion of the opportunities for global policy coordination

Association between hepatitis B virus infection and metabolic syndrome: a retrospective cohort study in Shanghai, China

Background: Metabolic syndrome (MS) and hepatitis B (HBV) infection are two major public health problems in China. There are few studies about their association, and the results of these studies are contradictory. We conducted a retrospective cohort study to assess the association between MS and HBV in a Shanghai community-based cohort. Methods: Nine hundred seventy-six Shanghai residents were recruited from the Putuo community. 480 HBV infections were in exposed group and 496 non-infections in unexposed group. All metabolic-related parameters and hepatitis B serology were tested with routine biochemical or immunological methods. “Exposed” was defined by HBV infection represented by hepatitis B surface antigen (HBsAg) and without anti-virus treatment. “Unexposed” were subjects who didn’t infect with HBV (Represented by HBsAg) and no MS when they entered the cohort. MS was defined based on the updated National Cholesterol Education Program Adult Treatment Panel III criteria. The Cox proportional hazards model was used to estimate the hazard ratios (HR) and related 95% confidence intervals (95% CI) for the association between HBV infection and MS over a 20-year follow-up period. Results: Of 976 subjects recruited, 480 had latent HBV infection (exposed subjects). After adjusting for age, the crude HR was 2.46 (95% CI: 1.77, 3.41). After adjusting for potential risk factors of MS (age, gender, smoking, passive smoking, alcohol consumption, physical activity, and diet), the HR was 2.27 (95% CI: 1.52, 3.38). Conclusions: This 20-year follow-up retrospective cohort study in Shanghai showed a positive association between HBV infection and MS