Self-Supervised Deep Equilibrium Models for Inverse Problems with Theoretical Guarantees

Deep equilibrium models (DEQ) have emerged as a powerful alternative to deep unfolding (DU) for image reconstruction. DEQ models-implicit neural networks with effectively infinite number of layers-were shown to achieve state-of-the-art image reconstruction without the memory complexity associated with DU. While the performance of DEQ has been widely investigated, the existing work has primarily focused on the settings where groundtruth data is available for training. We present self-supervised deep equilibrium model (SelfDEQ) as the first self-supervised reconstruction framework for training model-based implicit networks from undersampled and noisy MRI measurements. Our theoretical results show that SelfDEQ can compensate for unbalanced sampling across multiple acquisitions and match the performance of fully supervised DEQ. Our numerical results on in-vivo MRI data show that SelfDEQ leads to state-of-the-art performance using only undersampled and noisy training data

28. Intravenous Administration of Lentiviral Vectors Expressing Hyperactive Factor IX Converts Severe Into Mild Hemophilia B in a Canine Model

Lentiviral vectors (LVs) are attractive vehicles for liver-directed gene therapy by virtue of their ability to stably integrate in the genome of target cells and the lack of pre-existing immunity against vector components in most humans. Over the past years, we have developed a LV platform that can achieve stable transgene expression in the liver, induce transgene-specific immune tolerance and establish correction of hemophilia in mouse models upon systemic administration. This LV is designed to stringently target transgene expression to hepatocytes through transcriptional and microRNA-mediated regulation. We then investigated the efficacy and safety profile of portal vein administration of LVs expressing wild-type, codon-optimized (c.o.) or c.o. and hyperactive factor IX (FIX) in a canine model of hemophilia B. We produced large-scale batches of LVs qualified for in vivo administration and treated adult hemophilia B dog by portal vein administration. We observed long-term stable reconstitution of canine FIX activity up to 1% of normal and significant amelioration of the clinical phenotype in 3 treated dogs (>9 years cumulative follow up). LV infusion was associated with transient signs of inflammation and mild hepatotoxicity, which could be abrogated by pretreatment with anti-inflammatory drugs. There was no detectable long-term toxicity or development of FIX inhibitors. In the perspective of clinical translation and to increase therapeutic efficacy, we next treated an 11-kg, hemophilia B dog by peripheral vein administration of LVs expressing the c.o. and hyperactive canine FIX at a 5-fold higher dose than those previously administered. At the current follow-up (3 months after gene therapy) FIX activity is 6-9% of normal. Intravenous LV administration, coupled with a 1-day anti-inflammatory and anti-histamine pre-treatment, induced mild and selflimiting leukopenia and elevation of aminotransferases. Treatment of more hemophilia B dogs is underway to confirm and extend these results. Overall, our studies, which suggest comparable efficacy of LV by both portal and peripheral vein administration, position LV-mediated liver gene therapy for further pre-clinical development and clinical translation. LVs may thus complement other available vectors to address some of the outstanding challenges posed by liver gene therapy of hemophilia and conceivably other diseases

756 stable amelioration of hemophilia b in dogs by intravenous administration of lentiviral vectors expressing hyper functional factor ix

Lentiviral vectors (LVs) are attractive vehicles for liver-directed gene therapy by virtue of their ability to stably integrate in the genome of target cells and the low prevalence of pre-existing immunity against HIV in humans. Over the past years, we have developed a LV platform that can achieve stable transgene expression in the liver, induce transgene-specific immune tolerance and establish correction of hemophilia in mouse models upon systemic administration. This LV is designed to stringently target transgene expression to hepatocytes through transcriptional and microRNA-mediated regulation. We then investigated the efficacy and safety profile of portal vein administration of LVs expressing canine factor IX (FIX) in a canine model of hemophilia B. We produced large-scale batches of LVs qualified for in vivo administration and treated adult hemophilia B dog by portal vein administration. We observed long-term stable reconstitution of canine FIX activity up to 1% of normal and significant amelioration of the clinical phenotype in 3 treated dogs with 6, 3.5 and 2.5 years of follow up. LV infusion was associated with transient signs of inflammatory response and mild hepatotoxicity, which could be abrogated by pretreatment with anti-inflammatory drugs. There was no detectable long-term toxicity or development of FIX inhibitors. In the perspective of clinical translation and to increase therapeutic efficacy, we next treated two 10-kg hemophilia B dogs by peripheral vein administration of LVs expressing a codon-optimized and hyperfunctional canine FIX at a 5-fold higher dose than those previously administered. Intravenous LV administration was well tolerated with mild and self-limiting elevation of aminotransferases in one dog. In the dog that reached more than 1 year of follow up FIX activity ranged between 4-8% of normal. Treatment of two more dogs at a higher dose is underway. Overall, our studies position LV-mediated liver gene therapy for further pre-clinical development and clinical translation. LVs may thus complement other available vectors to address some of the outstanding challenges posed by liver gene therapy of hemophilia and conceivably other diseases

Ginkgo biloba extract EGb 761® improves cognition and overall condition after ischemic stroke: Results from a pilot randomized trial

Background: Patients who experienced an ischemic stroke are at risk for cognitive impairment. Quantified Ginkgo biloba extract EGb 761® has been used to treat cognitive dysfunction, functional impairment and neuropsychiatric symptoms in mild cognitive impairment and dementia.Objectives: To assess the cognitive-related effects of EGb 761® treatment in patients after acute ischemic stroke, as well as the feasibility of patient selection and outcome measures.Methods: We conducted a randomized, multicentric, open-label trial at 7 centers in China. Patients scoring 20 or lower on the National Institutes of Health Stroke Scale were enrolled between 7 and 14 days after stroke onset and randomly assigned to receive 240 mg per day of EGb 761® or no additional therapy for 24 weeks in a 1:1 ratio. Both groups received standard treatments for the prevention of recurrent stroke during the trial. General cognitive function and a battery of cognitive tests for sub-domains were evaluated at 24 weeks. All patients were monitored for adverse events.Results: 201 patients ≥50 years old were included, with 100 assigned to the EGb 761® group and 101 to the reference group. The mean change from baseline on the global cognitive function as assessed by the Montreal Cognitive Assessment score was 2.92 in the EGb 761® group and 1.33 in the reference group (between-group difference: 1.59 points; 95% confidence interval [CI], 0.51 to 2.67; p < 0.005). For cognitive domains, EGb 761® showed greater effects on the Hopkins Verbal Learning Test Total Recall (EGb 761® change 1.40 vs. reference −0.49) and Form 1 of the Shape Trail Test (EGb 761® change −38.2 vs. reference −15.6). Potentially EGb 761®-related adverse events occurred in no more than 3% of patients.Conclusion: Over the 24-week period, EGb 761® treatment improved overall cognitive performance among patients with mild to moderate ischemic stroke. Our findings provide valuable recommendations for the design of future trials, including the criteria for patient selection.Clinical Trial Registration:www.isrctn.com, identifier ISRCTN11815543

Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates

: Liver gene therapy with adeno-associated viral (AAV) vectors delivering clotting factor transgenes into hepatocytes has shown multiyear therapeutic benefit in adults with hemophilia. However, the mostly episomal nature of AAV vectors challenges their application to young pediatric patients. We developed lentiviral vectors, which integrate in the host cell genome, that achieve efficient liver gene transfer in mice, dogs and non-human primates, by intravenous delivery. Here we first compare engineered coagulation factor VIII transgenes and show that codon-usage optimization improved expression 10-20-fold in hemophilia A mice and that inclusion of an unstructured XTEN peptide, known to increase the half-life of the payload protein, provided an additional >10-fold increase in overall factor VIII output in mice and non-human primates. Stable nearly life-long normal and above-normal factor VIII activity was achieved in hemophilia A mouse models. Overall, we show long-term factor VIII activity and restoration of hemostasis, by lentiviral gene therapy to hemophilia A mice and normal-range factor VIII activity in non-human primate, paving the way for potential clinical application

Room temperature 2D ferromagnetism in few-layered 1TT-CrTe2_{2}

Spin-related electronics using two dimensional (2D) van der Waals (vdW) materials as a platform are believed to hold great promise for revolutionizing the next generation spintronics. Although many emerging new phenomena have been unravelled in 2D electronic systems with spin long-range orderings, the scarcely reported room temperature magnetic vdW material has thus far hindered the related applications. Here, we show that intrinsic ferromagnetically aligned spin polarization can hold up to 316 K in a metallic phase of 1$T$-CrTe$_{2}$ in the few-layer limit. This room temperature 2D long range spin interaction may be beneficial from an itinerant enhancement. Spin transport measurements indicate an in-plane room temperature negative anisotropic magnetoresistance (AMR) in few-layered CrTe$_{2}$, but a sign change in the AMR at lower temperature, with -0.6$\%$ at 300 K and +5$\%$ at 10 K, respectively. This behavior may originate from the specific spin polarized band structure of CrTe$_{2}$. Our findings provide insights into magnetism in few-layered CrTe$_{2}$, suggesting potential for future room temperature spintronic applications of such 2D vdW magnets.Comment: 9 Pages, 4 Figure

A Fully Coupled Tribocorrosion Simulation Method for Anchor Chain Considering Mechano-Electrochemical Interaction

This study aims at proposing a fully coupled numerical simulation method of tribocorrosion development on anchor chains during service life, where the mechano-electrochemical interaction is considered in a simplified way. The damage evolution can be realized by a user-defined UMESHMOTION FORTRAN subroutine, where both stress-accelerated corrosion and corrosion-accelerated wear can be considered. Based on this numerical method, the time-variant damage morphology of mooring chain can be obtained. Simulation results obtained by different damage evolution models are shown and compared, and some discussions on the simplified simulation method of reciprocating tribocorrosion are also presented. A systematic parametric study is carried out, and the key factors affecting the tribocorrosion of chain link are revealed. Finally, a modified design method is proposed, and it can be used for optimization of the design of marine anchor chains

Short-Duration Transient Temperature Distribution Prediction Model along Chip Vertical Path Applicable to Multi-Timescale Simulation

Based on extremely uneven temperature distribution along the insulated gate bipolar transistor (IGBT) chip vertical path during switching transients, a short-duration transient microsecond-scale prediction model applicable to multi-timescale simulation is presented in this paper. Traditional thermal models often take the chip active area as a uniform heat source to obtain a victual junction temperature (Tvj). In this paper, a discrete distributed heat source model combined with a thermal network model based on the sublayer division strategy is proposed to achieve an accurate temperature distribution description along the chip vertical path. Taking a 1700 V/3600 A IGBT module as an example, the proposed model can evaluate the short-duration transient temperature distribution along the chip vertical path and the error is less than 2 °C compared with the finite element model. Meanwhile, the model is applied to a single short-duration transient timescale and multi-timescale systems separately, and the simulation speed is increased by more than 80 times and 297 times, which verifies its validity and accuracy

Protective Effects of Polydatin from Grapes and Reynoutria japonica Houtt. on Damaged Macrophages Treated with Acetaminophen

The unregulated use of acetaminophen (APAP), an antipyretic and analgesic drug, harms hepatocytes and kidney cells, leading to liver failure and acute kidney injury. Herein, we investigate whether APAP damages macrophages in the immune system by observing its effects on macrophage proliferation and apoptosis. Using proteomics, we analyzed the effects of APAP on macrophage protein expression profiles and evaluated whether polydatin, the active ingredient in grapes and wine, can repair the damaged cells. The results showed that APAP alters the morphology and physiological processes of macrophages, inhibits macrophage proliferation, and promotes apoptosis. We observed 528 differentially expressed proteins when 500 µg/mL APAP was administered to the cells. These proteins are involved in biological processes including cell division, apoptosis, and acute phase response. Overall, our findings demonstrate that APAP harms the immune system by damaging macrophages and that polydatin can repair this damage