A subject-specific unsupervised deep learning method for quantitative susceptibility mapping using implicit neural representation.

Quantitative susceptibility mapping (QSM) is an MRI-based technique that estimates the underlying tissue magnetic susceptibility based on phase signal. Deep learning (DL)-based methods have shown promise in handling the challenging ill-posed inverse problem for QSM reconstruction. However, they require extensive paired training data that are typically unavailable and suffer from generalization problems. Recent model-incorporated DL approaches also overlook the non-local effect of the tissue phase in applying the source-to-field forward model due to patch-based training constraint, resulting in a discrepancy between the prediction and measurement and subsequently suboptimal QSM reconstruction. This study proposes an unsupervised and subject-specific DL method for QSM reconstruction based on implicit neural representation (INR), referred to as INR-QSM. INR has emerged as a powerful framework for learning a high-quality continuous representation of the signal (image) by exploiting its internal information without training labels. In INR-QSM, the desired susceptibility map is represented as a continuous function of the spatial coordinates, parameterized by a fully-connected neural network. The weights are learned by minimizing a loss function that includes a data fidelity term incorporated by the physical model and regularization terms. Additionally, a novel phase compensation strategy is proposed for the first time to account for the non-local effect of tissue phase in data consistency calculation to make the physical model more accurate. Our experiments show that INR-QSM outperforms traditional established QSM reconstruction methods and the compared unsupervised DL method both qualitatively and quantitatively, and is competitive against supervised DL methods under data perturbations.

Comprehensive investigation into the effects of yeast dietary fiber and temperature on konjac glucomannan/kappa-carrageenan for the development of fat analogs.

In this study, yeast dietary fiber (YDF) was incorporated into konjac glucomannan/kappa-carrageenan (KGM/κ-KC) for the development of fat analogs, and the impact of YDF on the gelation properties and behavior of KGM/κ-KC composite gels was assessed. YDF improved the composite gel whiteness value, and affected the mechanical properties of the composite gel, especially enhancing its hardness, and decreasing its chewiness, elasticity, and gel strength, making it more similar to porcine back fat. When the yeast dietary fiber content was 0.033 g/mL and the heating temperature was 80 °C (T80-2), the textural properties of the composite gel were closest to porcine back fat. The frequency sweep results suggested that YDF incorporation led to enhancement of the intermolecular interaction and intermixing and interaction among more easily at higher processing temperatures (80 °C and 90 °C). By scanning electron microscopy, the fatty surface of porcine back fat was flat and covered with a large amount of oil, while KGM/κ-KC/YDF composite gels developed a dense, stacked network structure. YDF caused more fragmented, folded, and uneven structures to emerge. Overall, YDF could influence the gel behavior of KGM/κ-KC composite gels, and change their colors and mechanical properties. This work could serve as a guide for preparing fat analogs with KGM/κ-KC composite gels.

HIV-1 p17 matrix protein enhances type I interferon responses through the p17-OLA1-STING axis.

Stimulator of IFN genes (STING; also known as STING1) is an important adaptor protein for detecting cytosolic double-stranded DNA, which can come from HIV infection. Several HIV proteins, such as p6, Vpx and Vif, can influence STING-mediated innate immunity, but the function of p17 is still unknown. In this study, we find that HIV-1 p17, but not HIV-2 p17 or SIV p17, promotes STING signaling induced by cyclic GMP-AMP (cGAMP) treatment. Mechanistically, HIV-1 p17 binds to Obg-like ATPase 1 (OLA1) and inhibits the regulation of STING by OLA1. Here, OLA1 interacts with STING and inhibits the translocation and phosphorylation of STING upon cGAMP stimulation. Furthermore, compared with HIV-2 and SIV, the ATPase and GTPase activities of OLA1 are only promoted by HIV-1 p17. Our study shows that the p17 of HIV-1, but not HIV-2 or SIV, promotes STING-mediated innate immunity by interfering the interaction between OLA1 and STING, thus providing a new clue for specific immune activation of HIV-1.

Effects of the soy protein to wheat gluten ratio on the physicochemical and structural properties of Alaska pollock surimi-based meat analogs by high moisture extrusion.

Surimi products have attracted much attention and are widely used in the food industry. Currently, the processing and exploitation of surimi products are mostly based on their gel characteristics. However, the abundant protein in surimi can be rearranged and integrated by high-temperature melting to generate a new surimi product with fibrous structures. In this study, meat analogs (new surimi product) were produced by high moisture extrusion (HME) using Alaska pollock surimi and plant protein (8:2), where the plant protein consisted of different ratios of soy protein and wheat gluten (9:1, 7:3, 5:5, 3:7 and 1:9). The product was marked as SSG because it was composed of Alaska pollock surimi, soy protein and wheat gluten. The structure and color results showed that the hardness and ΔE of SSG decreased, while the fibrous degree and lightness increased with increasing WG content. The observation of the macrostructure and microstructure also showed that the skeleton structure of SSG was more obvious with increasing WG addition, but the viscosity reflected a decreasing trend. Furthermore, an increase in the WG content raised the free water ratio and the total content of ß-sheets, whereas the appropriate plant protein ratio reduced the SSG's thermal stability. In conclusion, Alaskan pollock surimi and the appropriate proportion of plant protein can form structurally stable meat analogs by high moisture extrusion.

Yeast protein as a novel dietary protein source: Comparison with four common plant proteins in physicochemical properties.

Currently, with the preference for a healthy diet and increased awareness of reducing the carbon footprint, the demand for protein is becoming more and more diversified. In this study, the physicochemical properties of yeast protein (YP) and four common plant proteins (soy protein isolate, pea protein isolate, wheat gluten, and peanut protein) were compared. The most prevalent secondary structure in YP is the ß-sheet. Furthermore, YP is in an aggregated state, and it has a high surface hydrophobicity. The tryptophan residues are primarily exposed on the polar surface of YP. The results of in vitro digestibility indicated that YP (84.91 ± 0.52%) was a high-quality protein. Moreover, YP has a higher thermal stability and relatively stable low apparent viscosity, which provides ample possibility for its application in food processing and in foods for people with swallowing difficulties. This study provides theoretical basis in the potential of YP as an alternative protein source.

Newly synthesized AIFM1 determines the hypersensitivity of T lymphocytes to STING activation-induced cell apoptosis.

STING is a well-known signaling adaptor essential for sensing cytosolic dsDNA to produce type I interferon. Although the detailed underlying mechanisms remain enigmatic, recent studies show that STING activation can lead to T lymphocyte apoptosis. Here, we report that AIFM1 facilitates STING activation-induced cell apoptosis in T lymphocytes. Mechanistically, AIFM1 is upregulated after STING activation in T cells but not in HEK293T-STING and THP-1 cells, rendering T cells more sensitive to apoptosis. In contrast to the canonical role of AIFM1 in the caspase-independent parthanatos, the function of AIFM1 is operated by the formation of an AIFM1/IRF3/BAX complex and mitochondrial outer membrane permeabilization, which cause cytochrome c release and caspase activation. Furthermore, supplementation with newly synthesized AIFM1 can reconstitute STING activation-induced cell apoptosis in HEK293T-STING and THP-1 cells. Our study identifies AIFM1 as a key regulating factor determining the hypersensitivity of T lymphocytes to STING activation-induced cell apoptosis.

High-moisture extrusion of yeast-pea protein: Effects of different formulations on the fibrous structure formation.

The demand of meat analogues (MAs) is consistently increasing. The protein materials for MAs are primarily soy, pea, and wheat protein which can not completely meet the growing demand. Hence, this study is focused on the preparation of MAs with up to 50 % yeast protein (YP) instead of pea protein isolate (PPI). In the present study, 0 %, 10 %, 30 %, and 50 % YP powder in dry matter basis were combined with PPI; then the mixtures were used to prepare MAs with fibrous structures using high-moisture extrusion (55 % moisture). The involvement of YP significantly enhanced the hardness of MAs (P < 0.05). The optical and microstructural images illustrated that when YP ratio reached 30 %, obvious fibrous structures still were observed in MAs. Furthermore, MAs containing YP became whiter, which is conducive to reprocessing. With an increase in YP, the bound water content, sheet structures, and exposure of tryptophan residues in MAs increased, whereas the free water content, ß-turn, and random coil structures decreased. Analysis of thermal and rheological behaviors indicated that YP lowered the denaturation temperature of MAs and the viscosity of protein dispersions, which was related to the formation of protein aggregates. Overall, YP can be used to prepare MAs and regulate the fibrous structure in MAs by acting on protein conformations.

PITPNC1 promotes the thermogenesis of brown adipose tissue under acute cold exposure.

Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear. Here, we demonstrate that PITPNC1 is a key player in thermogenesis of BAT. While Pitpnc1-/- mice do not differ with wildtype mice in body weight and insulin sensitivity on either chow or high-fat diet, they develop hypothermia when subjected to acute cold exposure at 4°C. The Pitpnc1-/- brown adipocytes exhibit defective ß-oxidation and abnormal thermogenesis-related metabolism pathways in mitochondria. The deficiency of lipid mobilization in Pitpnc1-/- brown adipocytes might be the result of excessive accumulation of phosphatidylcholine and a reduction of phosphatidic acid. Our findings have uncovered significant roles of PITPNC1 in mitochondrial phospholipid homeostasis and BAT thermogenesis.

IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit ß (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB-expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB-targeting approaches for metastasis treatment.

miR-182 targeting reprograms tumor-associated macrophages and limits breast cancer progression.

The protumor roles of alternatively activated (M2) tumor-associated macrophages (TAMs) have been well established, and macrophage reprogramming is an important therapeutic goal. However, the mechanisms of TAM polarization remain incompletely understood, and effective strategies for macrophage targeting are lacking. Here, we show that miR-182 in macrophages mediates tumor-induced M2 polarization and can be targeted for therapeutic macrophage reprogramming. Constitutive miR-182 knockout in host mice and conditional knockout in macrophages impair M2-like TAMs and breast tumor development. Targeted depletion of macrophages in mice blocks the effect of miR-182 deficiency in tumor progression while reconstitution of miR-182-expressing macrophages promotes tumor growth. Mechanistically, cancer cells induce miR-182 expression in macrophages by TGFß signaling, and miR-182 directly suppresses TLR4, leading to NFκb inactivation and M2 polarization of TAMs. Importantly, therapeutic delivery of antagomiR-182 with cationized mannan-modified extracellular vesicles effectively targets macrophages, leading to miR-182 inhibition, macrophage reprogramming, and tumor suppression in multiple breast cancer models of mice. Overall, our findings reveal a crucial TGFß/miR-182/TLR4 axis for TAM polarization and provide rationale for RNA-based therapeutics of TAM targeting in cancer.

TGF-ß1 induces epithelial-to-mesenchymal transition in chronic rhinosinusitis with nasal polyps through microRNA-182.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) in nasal epithelial cells is involved in tissue remodeling of chronic rhinosinusitis with nasal polyps (CRSwNP). Our study investigated the molecular mechanisms that microRNA-182 (miR-182) regulated EMT in eosinophilic (Eos) and non-eosinophilic (non-Eos) CRSwNP. OBJECTIVE: To investigate the mechanism by which miR-182 regulates EMT in human nasal epithelial cells (hNEPCs). METHODS: The expression of EMT markers (E-cadherin, N-cadherin and vimentin), transforming growth factor (TGF)-ß1, and miR-182 were determined by western blotting and reverse transcription-quantitative PCR (RT-qPCR). Fluorescence in situ hybridization (FISH) was used to detect the miR-182 localization. Additionally, EMT markers expression and cell morphology changes were checked upon treatment with TGF-ß1, or TGF-ß1 with miR-182 inhibitor, or miR-182 mimics, or miR-182 inhibitor alone in hNEPCs. RESULTS: In both Eos CRSwNP and non-Eos CRSwNP, the expression levels of E-cadherin were downregulated while the expression levels of N-cadherin, vimentin, TGF-ß1 and miR-182 were significantly upregulated compared with control nasal tissues. Additionally, more significant changes in these EMT markers were observed in the Eos-CRSwNP when compared with the non-Eos CRSwNP. Invitro hNEPCs model, TGF-ß1 upregulated miR-182 expression and promoted EMT in hNEPCs, indicated by changes in cell morphology and EMT markers expression. Furthermore, these upregulations were reversed by miR-182 inhibitor. CONCLUSIONS: This study showed that miR-182-induced EMT in response to TGF-ß1 might promote nasal polypogenesis in both Eos CRSwNP and non-Eos CRSwNP, thus providing potential targets for the future development of novel therapeutic approaches for the management of CRSwNP.

CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis.

Background: Bone metastasis is a frequent symptom of breast cancer and current targeted therapy has limited efficacy. Osteoclasts play critical roles to drive osteolysis and metastatic outgrowth of tumor cells in bone. Previously we identified CST6 as a secretory protein significantly downregulated in bone-metastatic breast cancer cells. Functional analysis showed that CST6 suppresses breast-to-bone metastasis in animal models. However, the functional mechanism and therapeutic potential of CST6 in bone metastasis is unknown. Methods: Using in vitro osteoclastogenesis and in vivo metastasis assays, we studied the effect and mechanism of extracellular CST6 protein in suppressing osteoclastic niches and bone metastasis of breast cancer. A number of peptides containing the functional domain of CST6 were screened to inhibit bone metastasis. The efficacy, stability and toxicity of CST6 recombinant protein and peptides were evaluated in preclinical metastasis models. Results: We show here that CST6 inhibits osteolytic bone metastasis by inhibiting osteoclastogenesis. Cancer cell-derived CST6 enters osteoclasts by endocytosis and suppresses the cysteine protease CTSB, leading to up-regulation of the CTSB hydrolytic substrate SPHK1. SPHK1 suppresses osteoclast maturation by inhibiting the RANKL-induced p38 activation. Importantly, recombinant CST6 protein effectively suppresses bone metastasis in vitro and in vivo. We further identified several peptides mimicking the function of CST6 to suppress cancer cell-induced osteoclastogenesis and bone metastasis. Pre-clinical analyses of CTS6 recombinant protein and peptides demonstrated their potentials in treatment of breast cancer bone metastasis. Conclusion: These findings reveal the CST6-CTSB-SPHK1 signaling axis in osteoclast differentiation and provide a promising approach to treat bone diseases with CST6-based peptides.

Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.

Long non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and ΔNp63.

Disseminated tumor cells often fall into a long term of dormant stage, characterized by decreased proliferation but sustained survival, in distant organs before awakening for metastatic growth. However, the regulatory mechanism of metastatic dormancy and awakening is largely unknown. Here, we show that the epithelial-like and mesenchymal-like subpopulations of breast cancer stem-like cells (BCSCs) demonstrate different levels of dormancy and tumorigenicity in lungs. The long non-coding RNA (lncRNA) NR2F1-AS1 (NAS1) is up-regulated in the dormant mesenchymal-like BCSCs, and functionally promotes tumor dissemination but reduces proliferation in lungs. Mechanistically, NAS1 binds to NR2F1 mRNA and recruits the RNA-binding protein PTBP1 to promote internal ribosome entry site (IRES)-mediated NR2F1 translation, thus leading to suppression of ΔNp63 transcription by NR2F1. Furthermore, ΔNp63 downregulation results in epithelial-mesenchymal transition, reduced tumorigenicity and enhanced dormancy of cancer cells in lungs. Overall, the study links BCSC plasticity with metastatic dormancy, and reveals the lncRNA as an important regulator of both processes.

Source localization of epileptic spikes using Multiple Sparse Priors.

OBJECTIVE: To evaluate epileptic source estimation using multiple sparse priors (MSP) inverse method and high-resolution, individual electrical head models. METHODS: Accurate source localization is dependent on accurate electrical head models and appropriate inverse solvers. Using high-resolution, individual electrical head models in fifteen epilepsy patients, with surgical resection and clinical outcome as criteria for accuracy, performance of MSP method was compared against standardized low-resolution brain electromagnetic tomography (sLORETA) and coherent maximum entropy on the mean (cMEM) methods. RESULTS: The MSP method performed similarly to the sLORETA method and slightly better than the cMEM method in terms of success rate. The MSP and cMEM methods were more focal than sLORETA with the advantage of not requiring an arbitrary selection of a hyperparameter or thresholding of reconstructed current density values to determine focus. MSP and cMEM methods were better than sLORETA in terms of spatial dispersion. CONCLUSIONS: Results suggest that the three methods are complementary and could be used together. In practice, the MSP method will be easier to use and interpret compared to sLORETA, and slightly more accurate and faster than the cMEM method. SIGNIFICANCE: Source localization of interictal spikes from dense-array electroencephalography data has been shown to be a reliable marker of epileptic foci and useful for pre-surgical planning. The advantages of MSP make it a useful complement to other inverse solvers in clinical practice.

QDtbn1 , an F-box gene affecting maize tassel branch number by a dominant model.

Tassel branch number (TBN) is one of the important agronomic traits that directly contribute to grain yield in maize (Zea mays L.), and identification of genes precisely regulating TBN in the parental lines is important for maize hybrid breeding. In this study, a quantitative trait nucleotide (QTN), QDtbn1 , related to tassel branch number was identified using a testcrossing association mapping population through association mapping with the Indels/SNPs in the 5'-UTR (untranslated region) of Zm00001d053358, which encodes a Kelch repeat-containing F-box protein. QDtbn1 was further confirmed to be associated with TBN by a dominant model using an F2 population, and over-expressing of the candidate gene resulted in a decreasing of TBN, implying that QDtbn1 was governed by the candidate gene with a negative model. This makes QDtbn1 very useful in maize hybrid breeding. QDtbn1 could interact with a maize Skp1-like protein and a SnRK1 protein, and the SnRK1 could also interact with a SnRK2.8 protein. In addition, quantitative real-time PCR assay showed that five substrates of SnRK2 were down-regulated in the over-expressed plants. These imply that the SCF (Skp1/Cul1/F-box protein/Roc1) complex and ABA signal pathway might be involved in the modulation of TBN in maize.

Safety of slow-pulsed transcranial electrical stimulation in acute spike suppression.

We examined the effects of slow-pulsed transcranial electrical stimulation (TES) in suppressing epileptiform discharges in seven adults with refractory epilepsy. An MRI-based realistic head model was constructed for each subject and co-registered with 256-channel dense EEG (dEEG). Interictal spikes were localized, and TES targeted the cortical source of each subject's principal spike population. Targeted spikes were suppressed in five subject's (29/35 treatment days overall), and nontargeted spikes were suppressed in four subjects. Epileptiform activity did not worsen. This study suggests that this protocol, designed to induce long-term depression (LTD), is safe and effective in acute suppression of interictal epileptiform discharges.

BRAF V600E, TERT, and IDH2 Mutations in Pleomorphic Xanthoastrocytoma: Observations from a Large Case-Series Study.

BACKGROUND: Anaplastic pleomorphic xanthoastrocytoma (PXA) was added to grade III glial tumors as a distinct entity in the 2016 World Health Organization (WHO) classification of tumors of the central nervous system. We retrospectively reviewed and analyzed 55 pathologically confirmed PXA cases according to the newest WHO classification to better clarify the clinical, molecular, and prognostic features of this rare neoplasm. METHODS: In total, 55 pathologically confirmed PXA cases according to the newest WHO classification were retrospectively reviewed and analyzed. After sequencing for BRAF, TERT, IDH1/2, and H3F3A, survival analysis was performed to determine the factors affecting survival. RESULTS: The patients with BRAF V600E mutations were generally younger than those without it, although not statistically significant (27.9 ± 15.4 years and 37.1 ± 17.0 years, respectively, P = 0.054). TERT promoter mutation frequency in PXA was lower than in patients with anaplastic PXA although not statistically significant (4.4% and 28.6%, P = 0.083). One instance of PXA with IDH2 mutation, and no IDH1 and H3F3A mutations were found. In terms of prognosis, patients with anaplastic PXA had shorter overall survival and progression-free survival compared with patients with PXA. The subgroup with gross total resection had a longer median OS (not reached vs. 60.0 months, P = 0.0221) and PFS (not reached vs. 60.0 months, P = 0.0232) compared with patients with PXA with subtotal resection. CONCLUSIONS: The identification of BRAF V600E, TERT, and IDH2 mutations in PXA expands our molecular understanding of PXA. Patients with PXA with gross total resection achieve good outcomes.

Accurate source imaging based on high resolution scalp electroencephalography and individualized finite difference head models in epilepsy pre-surgical workup.

PURPOSE: High-density electroencephalographic source imaging (HD-ESI) has emerged as a useful tool for pre-surgical epilepsy workup. However, it is not routinely used in clinical evaluations due to several factors, one of which is the challenge associated with creating anatomically accurate head models. Reasonable solutions now exist and the present study aims to evaluate the use of these highly resolved individual head models in pre-surgical epilepsy evaluation. METHODS: Nine patients with intractable epilepsy who were candidates for resective epilepsy surgeries participated in the study. For each patient, 256-channel electroencephalography data were acquired along with individual structural MRI data that was used to construct individual finite difference models (iFDM). Accuracy of HD-ESI based on iFDM (HD-ESI-iFDM) was evaluated using multiple criteria, including concordance with intracranial electroencephalography (icEEG) and location of surgical resection. Performance of HD-ESI-iFDM was also compared against MRI and positron emission tomography (PET) results. RESULTS: In all but one patient resective surgeries resulted in seizure-free outcome. Source locations derived from HD-ESI-iFDM demonstrated concordance with surgical resection and with icEEG data, when available. The HD-ESI-iFDM also contributed to the planning of intracranial electrodes implantation. Compared to MRI or PET, HD-ESI-iFDM provided more accurate localization of the epileptogenic zone. CONCLUSION: When acquired with high-density sensor arrays and source imaging is performed with anatomically accurate head models, electroencephalography can contribute meaningfully to epilepsy pre-surgical workup for localization of the epileptogenic zone. Now that both high-density electroencephalography and individualized FDM models can be routinely obtained, it can be incorporated as part of clinical practice.