Dynamically aggregating MLPs and CNNs for skin lesion segmentation with geometry regularization.

BACKGROUND AND OBJECTIVE: Melanoma is a highly malignant skin tumor. Accurate segmentation of skin lesions from dermoscopy images is pivotal for computer-aided diagnosis of melanoma. However, blurred lesion boundaries, variable lesion shapes, and other interference factors pose a challenge in this regard. METHODS: This work proposes a novel framework called CFF-Net (Cross Feature Fusion Network) for supervised skin lesion segmentation. The encoder of the network includes dual branches, where the CNNs branch aims to extract rich local features while MLPs branch is used to establish both the global-spatial-dependencies and global-channel-dependencies for precise delineation of skin lesions. Besides, a feature-interaction module between two branches is designed for strengthening the feature representation by allowing dynamic exchange of spatial and channel information, so as to retain more spatial details and inhibit irrelevant noise. Moreover, an auxiliary prediction task is introduced to learn the global geometric information, highlighting the boundary of the skin lesion. RESULTS: Comprehensive experiments using four publicly available skin lesion datasets (i.e., ISIC 2018, ISIC 2017, ISIC 2016, and PH2) indicated that CFF-Net outperformed the state-of-the-art models. In particular, CFF-Net greatly increased the average Jaccard Index score from 79.71% to 81.86% in ISIC 2018, from 78.03% to 80.21% in ISIC 2017, from 82.58% to 85.38% in ISIC 2016, and from 84.18% to 89.71% in PH2 compared with U-Net. Ablation studies demonstrated the effectiveness of each proposed component. Cross-validation experiments in ISIC 2018 and PH2 datasets verified the generalizability of CFF-Net under different skin lesion data distributions. Finally, comparison experiments using three public datasets demonstrated the superior performance of our model. CONCLUSION: The proposed CFF-Net performed well in four public skin lesion datasets, especially for challenging cases with blurred edges of skin lesions and low contrast between skin lesions and background. CFF-Net can be employed for other segmentation tasks with better prediction and more accurate delineation of boundaries.

Lipid droplets and autophagosomes together with chaperones fine-tune expression of SGK1.

Serum-glucocorticoid-induced kinase-1 (SGK1) regulates ion homeostasis and promotes survival under stress conditions. The expression of SGK1 is under transcriptional and post-translational regulations that are frequently altered in cancer and immune disorders. We report that an N-terminal amphipathic alpha-helix determines SGK1 expression levels through two distinct mechanisms. It tethers SGK1 to intracellular organelles generating a large pool of membrane-bound SGK1, which is differentially stabilized in lipid droplets (LD) in fed conditions or degraded in the endoplasmic reticulum by ER-phagy in starvation. Association of the α-helix to organelles does not depend on dedicated receptors or special phospholipids rather, it is intrinsic to its physicochemical properties and depends on the presence of bulky hydrophobic residues for attachment to LDs. The second mechanism is recruitment of protein-chaperones that recognize the α-helix as an unfolded protein promoting survival of the cytosolic SGK1 fraction. Together, the findings unveil an unexpected link between levels of energy storage and abundance of SGK1 and how changes in calorie intake could be used to modulate SGK1 expression, whereas the inhibition of molecular chaperones could serve as an additional enhancer in the treatment of malignancies and autoimmune disorders with high levels of SGK1 expression.

A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels.

Proton-gated ion channels conduct mainly Na+ to induce postsynaptic membrane depolarization. Finding the determinants of ion selectivity requires knowledge of the pore structure in the open conformation, but such information is not yet available. Here, the open conformation of the hASIC1a channel was computationally modeled, and functional effects of pore mutations were analyzed in light of the predicted structures. The open pore structure shows two constrictions of similar diameter formed by the backbone of the GAS belt and, right beneath it, by the side chains of H28 from the reentrant loop. Models of nonselective mutant channels, but not those that maintain ion selectivity, predict enlargement of the GAS belt, suggesting that this motif is quite flexible and that the loss of stabilizing interactions in the central pore leads to changes in size/shape of the belt. Our results are consistent with the "close-fit" mechanism governing selectivity of hASIC1a, wherein the backbone of the GAS substitutes at least part of the hydration shell of a permeant ion to enable crossing the pore constriction.

Specific capture and intact release of breast cancer cells using a twin-layer vein-shaped microchip with a self-assembled surface.

Breast cancer is the most fatal disease among female cancers yet its detection still relies on needle biopsy. The unique physical and immune characteristics of breast cancer cells different from blood cells make them suitable to be employed as excellent biomarkers in liquid biopsy, through which breast cancer cells are collected from peripheral blood for further cancer diagnosis, medical treatment monitoring, and drug screening. Although the separation and enrichment of breast cancer cells from peripheral blood have been studied for years, there are still two problems to be solved in these methods: the low efficiency of on-chip immunologic capture in the flow state and the influence of the conjugated antibodies for the following analyses during cell release. In this paper, a vein-shaped microchip with self-assembled surface was developed for the specific and robust capture (91.2%) of breast cancer cells in the flow state. A protein-recovery process was proposed, in which trypsin served as a mild release reagent, releasing 92% of cells with high viability (96%), normal adherent proliferation, and complete proteins on the cell membrane, avoiding disturbance of the conjugated chemical molecules in the following clinical study. The excellent performance demonstrated in isolating free breast cancer cells from real peripheral blood sample, originating from the orthotopic 4T1 breast cancer metastatic models, suggest the microchip could be utilized as a multiple circulating tumor cell capture and release platform that could allow providing more reliable information in liquid biopsies.

Structure and analysis of nanobody binding to the human ASIC1a ion channel.

ASIC1a is a proton-gated sodium channel involved in modulation of pain, fear, addiction, and ischemia-induced neuronal injury. We report isolation and characterization of alpaca-derived nanobodies (Nbs) that specifically target human ASIC1a. Cryo-electron microscopy of the human ASIC1a channel at pH 7.4 in complex with one of these, Nb.C1, yielded a structure at 2.9 Å resolution. It is revealed that Nb.C1 binds to a site overlapping with that of the Texas coral snake toxin (MitTx1) and the black mamba venom Mambalgin-1; however, the Nb.C1-binding site does not overlap with that of the inhibitory tarantula toxin psalmotoxin-1 (PcTx1). Fusion of Nb.C1 with PcTx1 in a single polypeptide markedly enhances the potency of PcTx1, whereas competition of Nb.C1 and MitTx1 for binding reduces channel activation by the toxin. Thus, Nb.C1 is a molecular tool for biochemical and structural studies of hASIC1a; a potential antidote to the pain-inducing component of coral snake bite; and a candidate to potentiate PcTx1-mediated inhibition of hASIC1a in vivo for therapeutic applications.

An arginine residue in the outer segment of hASIC1a TM1 affects both proton affinity and channel desensitization.

Acid-sensing ion channels (ASICs) respond to changes in pH in the central and peripheral nervous systems and participate in synaptic plasticity and pain perception. Understanding the proton-mediated gating mechanism remains elusive despite the of their structures in various conformational states. We report here that R64, an arginine located in the outer segment of the first transmembrane domain of all three isoforms of mammalian ASICs, markedly impacts the apparent proton affinity of activation and the degree of desensitization from the open and preopen states. Rosetta calculations of free energy changes predict that substitutions of R64 in hASIC1a by aromatic residues destabilize the closed conformation while stabilizing the open conformation. Accordingly, F64 enhances the efficacy of proton-mediated gating of hASIC1a, which increases the apparent pH50 and facilitates channel opening when only one or two subunits are activated. F64 also lengthens the duration of opening events, thus keeping channels open for extended periods of time and diminishing low pH-induced desensitization. Our results indicate that activation of a proton sensor(s) with pH50 equal to or greater than pH 7.2-7.1 opens F64hASIC1a, whereas it induces steady-state desensitization in wildtype channels due to the high energy of activation imposed by R64, which prevents opening of the pore. Together, these findings suggest that activation of a high-affinity proton-sensor(s) and a common gating mechanism may mediate the processes of activation and steady-state desensitization of hASIC1a.

A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels.

ASICs are proton-gated sodium channels expressed in neurons. Structures of chicken ASIC1 in three conformations have advanced understanding of proton-mediated gating; however, a molecular mechanism describing desensitization from open and pre-open states (steady-state desensitization or SSD) remains elusive. A distinct feature of the desensitized state is an 180o rotation of residues L415 and N416 in the ß11- ß12 linker that was proposed to mediate desensitization; whether and how it translates into desensitization has not been explored yet. Using electrophysiological measurements of injected Xenopus oocytes, we show that Q276 in ß9 strand works with L415 and N416 to mediate both types of desensitization in ASIC1a, ASIC2a and ASIC3. Q276 functions as a valve that enables or restricts rotation of L415 and N416 to keep the linker compressed, its relaxation lengthens openings and leads to sustained currents. At low proton concentrations, the proposed mechanism working in only one of three subunits of the channel is sufficient to induce SSD.

[The prophylactic effect of BCG polysaccharides nucleic acid on the acute attack of chronic obstructive pulmonary disease].

OBJECTIVE: To investigate the prophylactic effect of BCG polysaccharides nucleic acid (BCG-PSN) on patients with chronic obstructive pulmonary disease and inquire about the mechanism thereof. METHODS: Sixty patients with chronic obstructive pulmonary disease were divided into two groups. In the treatment group, 36 patients received BCG-PSN 0.5 mg intramuscular injection, quaque die alterna, for 18 times. All patients revisited the hospital every 2 weeks and were followed up for 6 months. The number and days of patients with acute attack in 3 and 6 months were assessed. In the treatment group, the blood samples were collected before treatment and 3 and 6 months after treatment for the measurement of the blood IgA, IgG, IgM, CD3, CD4 and CD8. RESULTS: The number and days of patients with acute attack in the treatment group were significantly lower than those in the control group. After the treatment by BCG-PSN, blood CD4 and CD4/CD8 were significantly increased. CONCLUSION: BCG-PSN increases the patient's cellular immunocompetence and thus serves as a good protection against the acute attack of chronic obstructive pulmonary disease.