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Psoriasis, an immune-mediated inflammatory skin disorder characterized by a chronically relapsing-remitting course, continues to be primarily managed through topical therapy. While oral administration of tyrosine kinase 2 inhibitors (TYK2i) stands as an effective approach for psoriasis treatment, the potential efficacy of topical application of TYK2i remains unexplored. Herein, the carbomer/alginic acid hydrogel is embedded with borneol (BO) as a new topical carrier of TYK2i for achieving enhanced transdermal permeation and anti-psoriasis efficacy. The hydrogel system, i.e.,TYK2i-BO-gel, exhibits significantly improved preventative and therapeutic effects in mice models of psoriasiform dermatitis, as evidenced by phenotypical images, psoriasis severity score index (PSI), histology, immunohistochemical staining, and PCR analysis. Remarkably, TYK2i-BO-gel outperforms conventional topical corticosteroid therapy by significantly preventing psoriatic lesion recurrence as measured by a nearly 50 % reduction in ear thickness changes (p < 0.0001), PSI (p < 0.0001) and epidermal thickness (p < 0.05). Moreover, a strengthened anti-inflammatory effect caused by TYK2i-BO-gel is seen in a human skin explant model, implying its potential application for human patients. With the addition of BO, the TYK2i-BO-gel not only increases skin permeability but also inhibits the expression of antimicrobial peptides in keratinocytes and facilitates the anti-Th17 response of TYK2i with suppressed activation of STAT3. Therefore, this work represents the accessibility and effectiveness of TYK2i-BO-hydrogel as a new topical formulation for anti-psoriasis management and shows great potential for clinical application.

Background: The involvement of microRNA-668 (miR-668) in the onset and progression of renal fibrosis remains unclear. To this end, we aimed to explore the relevant mechanism of miR-668 in renal fibrosis. Methods: C57BL/6 J male mice were randomly divided into sham-operated, unilateral ureteral obstruction (UUO), and UUO-fenofibrate groups. Based on transfection and drug intervention, HK-2 cells were divided into blank control, TGF-β1, TGF-β1 + fenofibrate (PPARα agonist), mimics-NC, miR-668, mimics-NC + TGF-β1, miR-668 + TGF-β1, miR-668 + TGF-β1 + fenofibrate, miR-668 + TGF-β1 + GW6471 (PPARα inhibitor), mimics-NC + TGF-β1 + fenofibrate, and mimics-NC + TGF-β1 + GW6471 groups. The pathological changes in the renal tissues were observed by hematoxylin–eosin (HE) and Masson staining. The expression of PPARα, PGC-1α, miR-668, E-cadherin, Collagen III (Col III), and α-SMA in the renal tissues or HK-2 cells was detected by western blot, immunohistochemical analyses or real-time quantitative polymerase chain reaction. The regulatory effect of miR-668 on PPARα was verified by dual-luciferase reporter assay. Results: The expression of PPARα and PGC-1α decreased in UUO mice and TGF-β1-induced HK-2 cells, which was improved by fenofibrate. Compared to the non-transfected group, in TGF-β1-stimulated HK-2 cells, the expression of E-cadherin, PPARα and PGC-1α increased and the expression of Col III and α-SMA decreased in the miR-668-transfected group. The dual-luciferase reporter assay indicated the regulatory effect of hsa-mir-668-3p on PPARα. Conclusion: MiR-668 can target PPARα and positively regulate the PPARα/PGC-1α pathway to alleviate renal fibrosis.

Automated parking is a typical function in a self-driving car. The trajectory planning module directly reflects the intelligence level of an automated parking system. Although many competitions have been launched for autonomous driving, most of them focused on on-road driving scenarios. However, driving on a structured road greatly differs from parking in an unstructured environment. In addition, previous competitions typically competed on the overall driving performance instead of the trajectory planning performance. A trajectory planning competition of automated parking (TPCAP) has been recently organized. This event competed on parking-oriented planners without involving other modules, such as localization, perception, or tracking control. This study reports the TPCAP benchmarks, achievements, experiences, and future perspectives.

Replacing traffic signals with roadside vehicle-to-infrastructure systems in the era of connected and autonomous vehicles (CAVs) is promising. Managing CAVs in a signal-free intersection, known as autonomous intersection management (AIM), controls the driving behavior of each intersection-traverse CAV to maximize the throughput. Although AIM improves the gross throughput, the fairness of each individual vehicle in its right of way is not seriously considered. This study sets up an AIM system in the cyber–physical–social space to trade traverse priorities quantitatively and fairly. To that end, one needs an AIM method that is optimal and stable, otherwise no convincing trades of traverse priorities could be made. This study proposes a near-optimal lane-free AIM method based on numerical optimal control, wherein log-exp functions are deployed to convexify nondifferentiable collision-avoidance constraints. Besides that, a parameterized social force model (SFM) is proposed to provide a tunable initial guess for numerical optimal control. By tuning the urgency weights in SFM, one may get cooperative trajectories in different homotopy classes, which are further utilized to decide the amount of virtual currency to reward those CAVs who tend to share their traverse priorities. The overall method improves the traverse throughput with individual fairness respected. In experiencing this system, passengers learn how to behave with politeness when they drive manually. Experiments show the efficiency and robustness of the AIM method and also show the efficacy of the overall priority-sharing system.

Trajectory planning for automated parking has been widely known as more challenging than that for on-road driving due to the nonconvex kinematics, high-dimensional collision-avoidance constraints, and difficulty to determine the global optimum among many local optima. Changes in a dynamic environment easily make a previously planned parking trajectory invalid. Compared with the on-road planners which evade newly emerged obstacles via a nudge or side pass, a parking planner has to replan a completely different trajectory for evasion. A qualified online trajectory replanner should run fast, ensure trajectory continuity, and avoid extra halfway stops. This paper proposes a parallel stitching strategy to fulfill these demands. When the ego vehicle tracks an originally planned parking trajectory online, an evasive trajectory begins to be replanned once a new obstacle is found to block the way. Thereafter, a connective trajectory is planned, the two ends of which are future poses along the original trajectory and the evasive trajectory, respectively. The two ends of the connective trajectory are chosen by greedily evaluating various candidates via parallel computation, which ensures that our replanner runs fast with high solution quality. According to our real-world experiments and simulations, the proposed replanner outperforms the existing ones w.r.t. solution speed and quality. As an interesting feature, our proposed replanner also supports switching to a better homotopy class online.

Acute kidney injury (AKI) is a common complication of sepsis characterized by a rapid degradation of renal function. The effect of vitamin D on AKI remains poorly understood. Here, we showed that vitamin D receptor (VDR) activation protects against lipopolysaccharide (LPS)-induced AKI by blocking renal tubular epithelial cell apoptosis. Mice lacking VDR developed more severe AKI than wild-type (WT) control mice after LPS treatment, which was manifested by marked increases in body weight loss and accumulation of serum blood urea nitrogen and creatinine as well as the magnitude of apoptosis of tubular epithelial cells. In the renal cortex, LPS treatment led to more dramatic downregulation of Bcl-2, more robust induction of p53-upregulated modulator of apoptosis (PUMA) and miR-155, and more severe caspase-3 activation in VDR knockout mice compared with WT control mice. Conversely, paricalcitol pretreatment markedly prevented LPS-induced AKI. Paricalcitol ameliorated body weight loss, attenuated serum blood urea nitrogen and creatinine accumulation, blocked tubular cell apoptosis, prevented the suppression of Bcl-2, and reversed PUMA and miR-155 induction and caspase-3 activation in LPS-treated WT mice. In HK2 cells, LPS induced PUMA and miR-155 by activating NF-κB, whereas 1,25(OH)2D3blocked PUMA and miR-155 induction by repressing NF-κB activation. Both PUMA and miR-155 target Bcl-2 to promote apoptosis; namely, PUMA inhibits Bcl-2 activity, whereas miR-155 promotes Bcl-2 mRNA degradation and inhibits Bcl-2 protein translation. Collectively, these data provide strong evidence that LPS induces tubular cell apoptosis via upregulating PUMA and miR-155, whereas vitamin D/VDR signaling protects against AKI by blocking NF-κB-mediated PUMA and miR-155 upregulation.

In recent years, messenger RNA (mRNA) vaccines have exhibited great potential to replace conventional vaccines owing to their low risk of insertional mutagenesis, safety and efficacy, rapid and scalable production, and low‐cost manufacturing. With the great achievements of chemical modification and sequence optimization methods of mRNA, the key to the success of mRNA vaccines is strictly dependent on safe and efficient gene vectors. Among various delivery platforms, non‐viral mRNA vectors could represent perfect choices for future clinical translation regarding their safety, sufficient packaging capability, low immunogenicity, and versatility. In this review, the recent progress in the development of non‐viral mRNA vectors is focused on. Various organic vectors including lipid nanoparticles (LNPs), polymers, peptides, and exosomes for efficient mRNA delivery are presented and summarized. Furthermore, the latest advances in clinical trials of mRNA vaccines are described. Finally, the current challenges and future possibilities for the clinical translation of these promising mRNA vectors are also discussed. This review has focused on up‐to‐date development of non‐viral vectors for mRNA Vaccine. The advantages and disadvantages of various mRNA vector are commented and discussed. Meanwhile, the ongoing clinical trials of various mRNA vector are also summarized. The prospect of clinical transformation of various mRNA vectors are highlighted.

Objective To investigate the association of the MTHFRC677T gene polymorphism with metabolic syndrome (MetS) in people in Hubei Province, China.Methods A case–control study was conducted with 651 subjects with MetS (MetS group) and 727 healthy controls (control group) at Renmin Hospital of Wuhan University between January and December 2016. The MTHFRC677T genotype was detected by the gene chip technique and clinical data were collected.Results Body mass index, waist circumference, the waist-hip-ratio, systolic and diastolic blood pressure, fasting blood glucose, fasting insulin, triglyceride, total cholesterol, low-density lipoprotein-cholesterol, and homocysteine levels, and the homeostasis model assessment of insulin resistance were higher in the MetS group than in controls. The risk of MetS was higher for the TT genotype and T allele carriers than for the CC genotype and C allele carriers. With MetS, the TT genotype increased the risk of elevated blood pressure, fasting glucose levels, and triglyceride levels. Patients with MetS and the TT genotype showed more severe abdominal obesity, dyslipidaemia, insulin resistance, elevated blood pressure, elevated fasting glucose levels, and hyperhomocysteinaemia compared with those with the CC genotype.Conclusions In this population, MTHFRC677T gene polymorphism may be a risk factor for MetS.

Nifedipine and FPL 64176 (FPL), which block and potentiate L-type voltage-gated Ca2+channels, respectively, modulate Cav1.2 more potently than Cav1.3. To identify potential strategies for developing subtype-selective inhibitors, we investigated the role of divergent amino acid residues in transmembrane domains IIIS5 and the extracellular IIIS5-3P loop region in modulation of these channels by nifedipine and FPL. Insertion of the extracellular IIIS5-3P loop from Cav1.2 into Cav1.3 (Cav1.3+) reduced the IC50of nifedipine from 289 to 101 nM, and substitution of S1100 with an A residue, as in Cav1.2, accounted for this difference. Substituting M1030 in IIIS5 to V in Cav1.3+ (Cav1.3+V) further reduced the IC50of nifedipine to 42 nM. FPL increased current amplitude with an EC50of 854 nM in Cav1.3, 103 nM in Cav1.2, and 99 nM in Cav1.3+V. In contrast to nifedipine block, substitution of M1030 to V in Cav1.3 had no effect on potency of FPL potentiation of current amplitude, but slowed deactivation in the presence and absence of 10 μM FPL. FPL had no effect on deactivation of Cav1.3/dihydropyridine-insensitive (DHPi), a channel with very low sensitivity to nifedipine block (IC50∼93 μM), but did shift the voltage-dependence of activation by ∼−10 mV. We conclude that the M/V variation in IIIS5 and the S/A variation in the IIIS5-3P loop of Cav1.2 and Cav1.3 largely determine the difference in nifedipine potency between these two channels, but the difference in FPL potency is determined by divergent amino acids in the IIIS5-3P loop.

We described a challenge named “Diabetic Retinopathy (DR)—Grading and Image Quality Estimation Challenge” in conjunction with ISBI 2020 to hold three sub-challenges and develop deep learning models for DR image assessment and grading. The scientific community responded positively to the challenge, with 34 submissions from 574 registrations. In the challenge, we provided the DeepDRiD dataset containing 2,000 regular DR images (500 patients) and 256 ultra-widefield images (128 patients), both having DR quality and grading annotations. We discussed details of the top 3 algorithms in each sub-challenges. The weighted kappa for DR grading ranged from 0.93 to 0.82, and the accuracy for image quality evaluation ranged from 0.70 to 0.65. The results showed that image quality assessment can be used as a further target for exploration. We also have released the DeepDRiD dataset on GitHub to help develop automatic systems and improve human judgment in DR screening and diagnosis.