Additional file 2 of Identification of potential susceptibility genes in patients with primary Sjögren’s syndrome-associated pulmonary arterial hypertension through whole exome sequencing

Additional file 2: Supplementary Figure 1. Variants found in FLG, BCR, GIGYF2, ITK, and SLC26A4 verified by Sanger sequencing

Additional file 1 of Identification of potential susceptibility genes in patients with primary Sjögren’s syndrome-associated pulmonary arterial hypertension through whole exome sequencing

Additional file 1: Supplementary Table 1. Susceptibility genes of primary Sjögren’s syndrome-associated pulmonary arterial hypertension identified by whole genome sequencing

<i>Htr2a</i> Expression Responds Rapidly to Environmental Stimuli in an <i>Egr3</i>-Dependent Manner

Pharmacologic and genetic findings have implicated the serotonin 2A receptor (5-HT_2AR) in the etiology of schizophrenia. Recent studies have shown reduced 5-HT_2AR levels in schizophrenia patients, yet the cause of this difference is unknown. Environmental factors, such as stress, also influence schizophrenia risk, yet little is known about how environment may affect this receptor. To determine if acute stress alters 5-HT_2AR expression, we examined the effect of sleep deprivation on cortical <i>Htr2a</i> mRNA in mice. We found that 6 h of sleep deprivation induces a twofold increase in <i>Htr2a</i> mRNA, a more rapid effect than has been previously reported. This effect requires the immediate early gene early growth response 3 (<i>Egr3</i>), as sleep deprivation failed to induce <i>Htr2a</i> expression in <i>Egr3</i>–/– mice. These findings provide a functional link between two schizophrenia candidate genes and an explanation of how environment may influence a genetic predisposition for schizophrenia

Supplementary figures and tables -Supplemental material for Novel <i>NTRK1</i> mutations in Chinese patients with congenital insensitivity to pain with anhidrosis

<p>Supplemental material, Supplementary figures and tables for Novel <i>NTRK1</i> mutations in Chinese patients with congenital insensitivity to pain with anhidrosis by Xingzhu Geng, Yanshan Liu, XiuZhi Ren, Yun Guan, Yanzhou Wang, Bin Mao, Xiuli Zhao and Xue Zhang in Molecular Pain</p

Synthetic Polymeric Mixed Micelles Targeting Lymph Nodes Trigger Enhanced Cellular and Humoral Immune Responses

It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines because antigen presentation and initiation of T-cell-mediated immune responses occur primarily at these locations. In this study, amphiphilic diblock copolymer poly­(2-ethyl-2-oxazoline)-poly­(d,l-lactide) (PEOz-PLA) combined with carboxylterminated-Pluronic F127 was used to construct mixed micelles [carboxylated-nanoparticles (NPs)] for codelivery of antigen ovalbumin (OVA) and Toll-like receptor-7 agonist CL264 (carboxylated-NPs/OVA/CL264) to the LN-resident dendritic cells (DCs). The results showed that the small, sub-60 nm size of the self-assembled mixed micelles enables them to rapidly penetrate into lymphatic vessels and reach draining lymph nodes after subcutaneous injection. Furthermore, the surface modification with carboxylic groups imparted the carboxylated-NPs with endocytic receptor-targeting ability, allowing for DC internalization of carboxylated-NPs/OVA/CL264 via the scavenger receptor-mediated pathway. Because stimulation of CL264 in early endosomes will lead to a more effective immune response than that in late endo/lysosomes, the mass ratio of PEOz-PLA to carboxylated-Pluronic F127 in the mixed micelles was adjusted to release the encapsulated CL264 to the early endosome, resulting in increased expression of costimulatory molecules and secretion of stimulated cytokines by DCs. Moreover, the incorporation of PEOz outside the micellar shell effectively augmented MHC I antigen presentation through facilitating endosome escape and cytosolic release of antigens. This in turn evoked potent immune responses in vivo, including activation of antigen-specific T-cell responses, production of antigen-specific IgG antibodies, and generation of cytotoxic T-lymphocyte responses. Finally, immunization with the codelivery system in E.G7-OVA tumor-bearing mice could not only significantly inhibit tumor growth but also markedly prolong the survival of tumor-bearing mice. Taken together, carboxylated-NPs/OVA/CL264 have demonstrated great potential for clinical applications as an effective antitumor vaccine for further immunotherapy

Poly(l‑histidine) Based Triblock Copolymers: pH Induced Reassembly of Copolymer Micelles and Mechanism Underlying Endolysosomal Escape for Intracellular Delivery

Various poly­(l-histidine) based amphiphilic copolymers have been developed for intracellular drug delivery due to the pH responsive properties and the escape from endolysosomal pathway. However, the pH induced reassembly of copolymer micelles and the assumed endolysosome membrane rupture during the copolymer facilitated endolysosomal escape have never been elucidated. To address these issues, a series of poly­(ethylene glycol)-poly­(d,l-lactide)-poly­(l-histidine) (mPEG-PLA-PHis) with different degrees of polymerization of PLA and PHis block were synthesized. The self-assembly and reassembly behaviors of the copolymers were characterized using transmission electron microscopy (TEM), ¹H NMR, fluorescence probe technique, and dynamic light scattering (DLS). The copolymers self-assembled into micelles with PLA and unprotonated PHis blocks as hydrophobic core and PEG as hydrophilic shell at neutral pH. The changes in TEM images, ¹H NMR spectrum of PHis peak, pyrene fluorescene spectrum, and particle size as well as size distribution over the pH range from pH 8.5 to 4.5 suggest that the copolymer micelles reassembled into micelles with PLA as hydrophobic core and protonated PHis and PEG as hydrophilic shell under acidic environment. The pH induced reassembly triggered the incoporated doxorubicin (DOX) release, as indicated by the in vitro accelerated drug release and enhanced cytotoxicity. The integrity of endolysosome membrane during the copolymer facilitated DOX endolysosomal escape was observed by confocal laser scan microscopy (CLSM) and further evaluated by hemolysis test and calculation of the critical size of endolysosomal membrane. The results indicate that the endolysosomal membrane remained intact during the copolymer facilitated endolysosomal escape of DOX. It is more reasonable to ascribe the PHis based copolymer facilitation endolysosomal escape to the “proton sponge” hypothesis without rupturing the endolysosomal membrane