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A bstract We present kinematically forbidden dark matter annihilations into Standard Model leptons. This mechanism precisely selects the dark matter mass that gives the observed relic abundance. This is qualitatively different from existing models of thermal dark matter, where fixing the relic density typically leaves open orders of magnitude of viable dark matter masses. Forbidden annihilations require the dark matter to be close in mass to the particles that dominate its annihilation rate. We show examples where the dark matter mass is close to the muon mass, the tau mass, or the average of the tau and muon masses. We find that most of the relevant parameter space can be covered by the next generation of proposed beam-dump experiments and future high-luminosity electron positron colliders. Forbidden dark matter predicts large couplings to the Standard Model that can explain the observed value of ( g − 2) μ .

A bstract Dark matter may be a thermal relic whose abundance is set by mutual annihilations among multiple species. Traditionally, this coannihilation scenario has been applied to weak scale dark matter that is highly degenerate with other states. We show that coannihilation among states with split masses points to dark matter that is exponentially lighter than the weak scale, down to the keV scale. We highlight the regime where dark matter does not participate in the annihilations that dilute its number density. In this “sterile coannihilation” limit, the dark matter relic density is independent of its couplings, implying a broad parameter space of thermal relic targets for future experiments. Light dark matter from coannihilation evades stringent bounds from the cosmic microwave background, but will be tested by future direct detection, fixed target, and long-lived particle experiments.

Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer diagnosed in Asian countries, with its incidence on the rise. Cancer stem cell (CSC; also known as tumor-initiating cells, TIC) is inherently resistant to cytotoxic chemotherapy and radiation and associates with poor prognosis and therapy failure. Targeting therapy against cancer stem cell has emerged as a potential therapeutic approach to develop effective regimens. However, the suitable CSC marker of ESCC for identification and targeting is still limited. In this study, we screened the novel CSC membrane protein markers using two distinct stemness characteristics of cancer cell lines by a comparative approach. After the validation of RT-PCR, qPCR and western blot analyses, intercellular adhesion molecule 1 (ICAM1) was identified as a potential CSC marker of ESCC. ICAM1 promotes cancer cell migration, invasion as well as increasing mesenchymal marker expression and attenuating epithelial marker expression. In addition, ICAM1 contributes to CSC properties, including sphere formation, drug resistance, and tumorigenesis in mouse xenotransplantation model. Based on the analysis of ICAM1-regulated proteins, we speculated that ICAM1 regulates CSC properties partly through an ICAM1-PTTG1IP-p53-DNMT1 pathway. Moreover, we observed that ICAM1 and CD44 could have a compensation effect on maintaining the stemness characteristics of ESCC, suggesting that the combination of multi-targeting therapies should be under serious consideration to acquire a more potent therapeutic effect on CSC of ESCC.

To enhance the energy density, hybrid supercapacitors were fabricated, and their electrochemical features were investigated using a two-electrode configuration. By assembling nitrogen-doped graphene/magnetite (NG/Fe3O4) on indium tin oxide-coated (ITO) glass as a cathode and NG/carbon dots(Cdots)/Fe3O4 on ITO glass as an anode, a much higher gravimetric specific capacitance of 252.2 F/g, at a current density of 0.5 A/g, was obtained from this asymmetric supercapacitor compared with that (212.0 F/g) of a symmetric supercapacitor (NG/Cdots/Fe3O4)//(NG/Cdots/Fe3O4). A gravimetric energy density of 90.1 Wh/kg was obtained for an asymmetric ITO glass device at a specific power density of 400.0 W/kg. On the other hand, when an asymmetric two-electrode cell was fabricated with a Cdots/polypyrrole (PPy)/Fe3O4/TEMPO-oxidized cellulose nanofiber (TOCNF)-film electrode and a Cdots/PPy/TOCNF-film electrode, the specific capacitance (107.1 F/g) at a current density of 0.8 A/g was lower than that (456.4 F/g) of a symmetric (Cdots/PPy/Fe3O4/TOCNF)//(Cdots/PPy/Fe3O4/TOCNF)-film cell. Subsequently, a gravimetric energy density of 40.6 Wh/kg was achieved for a symmetric-film device at a specific power density of 320 W/kg. These results suggest that our method offers an efficient approach to developing symmetric and asymmetric devices consisting of hybrid materials for meeting the ever-increasing demands on energy-storage devices.

Oral squamous cell carcinoma (OSCC) remains difficult to treat with current modalities. miR-30c-5p, a tumor-suppressive microRNA frequently downregulated in OSCC, inhibits cancer cell proliferation and migration. However, its clinical application is limited by poor stability and inefficient uptake. To address these issues, miR-30c-5p was encapsulated into chitosan nanoparticles (CS-NPs) using ionic gelation to enhance delivery and protect against degradation. miR-30c-5p-loaded CS-NPs were characterized for particle size, zeta potential, morphology, and encapsulation efficiency. HSC-3 and OEC-M1 cells were treated with free miRNA, CS-NPs, or CS-miRNA-NPs at final concentrations of 5%, 10%, 25%, and 50% (v/v) in culture medium. Cellular uptake was assessed by confocal microscopy. Ex vivo porcine buccal membrane studies evaluated mucosal penetration. Cytotoxicity was determined using MTT assays, while gene regulation was analyzed via quantitative polymerase chain reaction and Western blotting. The prepared CS-NPs had particle sizes ranging from 434 to 452 nm and encapsulation efficiencies between 79% and 87%. Confocal imaging revealed significantly greater cytoplasmic uptake of CS-miRNA-FAM NPs versus free miRNA. Ex vivo studies showed that CS-miR-30c-5p-FAM NPs penetrated mucosa up to 80-160 μm with a 5.42-fold higher fluorescence intensity than free miR-30c-5p-FAM. Cytotoxicity testing showed high cell viability (>93%) for all treatments at concentrations ≤25% (v/v). At 50% (v/v) nanoparticle suspension, viability significantly decreased in OEC-M1 cells (84.41% for naked miRNA, 54.52% for CS-NPs, 61.10% for CS-miRNA-NPs; P < 0.001). After 48 h, greater reductions were observed at 50% (v/v), with cell viability in HSC-3 cells decreasing to 85.55% (free miRNA), 42.72% (CS-NPs), and 51.82% (CS-miRNA-NPs), and in OEC-M1 cells to 73.98%, 33.00%, and 39.89%, respectively. Functional assays showed vimentin mRNA reductions of 85% in HSC-3 and 30% in OEC-M1, with protein decreases confirmed by Western blot. CS-NPs enhance miRNA delivery and gene-silencing efficacy in OSCC cells. These findings support CS-based systems for miRNA therapeutics in oral cancer.

In kidney collecting duct cells, filamentous actin (F-actin) depolymerization is a critical step in vasopressin-induced trafficking of aquaporin-2 to the apical plasma membrane. However, the molecular components of this response are largely unknown. Using stable isotope-based quantitative protein mass spectrometry and surface biotinylation, we identified 100 proteins that showed significant abundance changes in the apical plasma membrane of mouse cortical collecting duct cells in response to vasopressin. Fourteen of these proteins are involved in actin cytoskeleton regulation, including actin itself, 10 actin-associated proteins, and 3 regulatory proteins. Identified were two integral membrane proteins (Clmn, Nckap1) and one actin-binding protein (Mpp5) that link F-actin to the plasma membrane, five F-actin end-binding proteins (Arpc2, Arpc4, Gsn, Scin, and Capzb) involved in F-actin reorganization, and two actin adaptor proteins (Dbn1, Lasp1) that regulate actin cytoskeleton organization. There were also protease (Capn1), protein kinase (Cdc42bpb), and Rho guanine nucleotide exchange factor 2 (Arhgef2) that mediate signal-induced F-actin changes. Based on these findings, we devised a live-cell imaging method to observe vasopressin-induced F-actin dynamics in polarized mouse cortical collecting duct cells. In response to vasopressin, F-actin gradually disappeared near the center of the apical plasma membrane while consolidating laterally near the tight junction. This F-actin peripheralization was blocked by calcium ion chelation. Vasopressin-induced apical aquaporin-2 trafficking and forskolin-induced water permeability increase were blocked by F-actin disruption. In conclusion, we identified a vasopressin-regulated actin network potentially responsible for vasopressin-induced apical F-actin dynamics that could explain regulation of apical aquaporin-2 trafficking and water permeability increase.

To assess the frequent consumption of symptomatic medications in migraineurs, we consecutively recruited 536 migraineurs from a headache clinic. Among them, 194 (36.2%) had chronic migraine and 342 had episodic migraine. When grouped according to duration of headache, the proportion of patients with chronic migraine increased from 25.5% to 50.9% as headache history increased from less than 1 to greater than 20 years. The percentage of patients with frequent analgesics consumption also increased with the duration of headache, in patients with both chronic migraine (from 25.0% to 85.7%) and episodic migraine (from 20.0% to 59.3%). Nonetheless, patients with chronic migraine had a higher prevalence of frequent consumption of abortive medications than patients with episodic migraine regardless of duration of headache history, and the common odds ratio across strata of headache duration was 2.8 (95% confidence interval, 1.9-4.1). However, we found that a long headache history is an important risk factor for frequent consumption of symptomatic medications in migraineurs in patients with both episodic migraine and chronic migraine. [PUBLICATION ABSTRACT]

Background and Aims: Tumor necrosis factor-α (TNF-α) is a cytokine that may act as an endogenous tumor promoter. A genetic polymorphism of TNF-α at position -308 of the promoter region, which includes TNF1 (-308G) and TNF2 (-308A) alleles, has been found to be associated with susceptibility to various types of cancer. We conducted a study to evaluate the association between this polymorphism and hepatocellular carcinoma (HCC). Methods: We recruited 74 HCC patients and 289 healthy controls, and determined their -308 TNF-α promoter genotypes through polymerase chain reaction followed by electrophoresis. Results: Carriage of the TNF2 allele was associated with an increased risk of HCC (odds ratio [OR] = 3.5; 95% confidence interval [CI]:[2.1, 6.0]), and a trend toward a significant increase in the risk of developing HCC was observed from TNF1/TNF1, TNF1/TNF2, to TNF2/TNF2 genotypes (p < 0.01). After adjustment for gender, age, and markers of hepatitis B and C, the OR of developing HCC associated with TNF2 allele carriage was 5.3 (95% CI: [2.3, 12.1]; p < 0.01). Conclusions: Carriage of the TNF2 allele is a significant predictor of HCC independent of hepatitis B and C, and therefore it may be used as a biomarker for susceptibility to HCC.

We present kinematically forbidden dark matter annihilations into Standard Model leptons. This mechanism precisely selects the dark matter mass that gives the observed relic abundance. This is qualitatively different from existing models of thermal dark matter, where fixing the relic density typically leaves open orders of magnitude of viable dark matter masses. Forbidden annihilations require the dark matter to be close in mass to the particles that dominate its annihilation rate. We show examples where the dark matter mass is close to the muon mass, the tau mass, or the average of the tau and muon masses. We find that most of the relevant parameter space can be covered by the next generation of proposed beam-dump experiments and future high-luminosity electron positron colliders. Forbidden dark matter predicts large couplings to the Standard Model that can explain the observed value of \\((g-2)_\\mu\\).

If dark matter was produced in the early Universe by the decoupling of its annihilations into known particles, there is a sharp experimental target for the size of its coupling. We show that if dark matter was produced by inelastic scattering against a lighter particle from the thermal bath, then its coupling can be exponentially smaller than the coupling required for its production from annihilations. As an application, we demonstrate that dark matter produced by inelastic scattering against electrons provides new thermal relic targets for direct detection and fixed target experiments.