Adaptive Two-Stream Consensus Network for Weakly-Supervised Temporal Action Localization.

Weakly-supervised temporal action localization (W-TAL) aims to classify and localize all action instances in untrimmed videos under only video-level supervision. Without frame-level annotations, it is challenging for W-TAL methods to clearly distinguish actions and background, which severely degrades the action boundary localization and action proposal scoring. In this paper, we present an adaptive two-stream consensus network (A-TSCN) to address this problem. Our A-TSCN features an iterative refinement training scheme: a frame-level pseudo ground truth is generated and iteratively updated from a late-fusion activation sequence, and used to provide frame-level supervision for improved model training. Besides, we introduce an adaptive attention normalization loss, which adaptively selects action and background snippets according to video attention distribution. By differentiating the attention values of the selected action snippets and background snippets, it forces the predicted attention to act as a binary selection and promotes the precise localization of action boundaries. Furthermore, we propose a video-level and a snippet-level uncertainty estimator, and they can mitigate the adverse effect caused by learning from noisy pseudo ground truth. Experiments conducted on the THUMOS14, ActivityNet v1.2, ActivityNet v1.3, and HACS datasets show that our A-TSCN outperforms current state-of-the-art methods, and even achieves comparable performance with several fully-supervised methods.

Giant Panda Identification.

The lack of automatic tools to identify giant panda makes it hard to keep track of and manage giant pandas in wildlife conservation missions. In this paper, we introduce a new Giant Panda Identification (GPID) task, which aims to identify each individual panda based on an image. Though related to the human re-identification and animal classification problem, GPID is extraordinarily challenging due to subtle visual differences between pandas and cluttered global information. In this paper, we propose a new benchmark dataset iPanda-50 for GPID. The iPanda-50 consists of 6, 874 images from 50 giant panda individuals, and is collected from panda streaming videos. We also introduce a new Feature-Fusion Network with Patch Detector (FFN-PD) for GPID. The proposed FFN-PD exploits the patch detector to detect discriminative local patches without using any part annotations or extra location sub-networks, and builds a hierarchical representation by fusing both global and local features to enhance the inter-layer patch feature interactions. Specifically, an attentional cross-channel pooling is embedded in the proposed FFN-PD to improve the identify-specific patch detectors. Experiments performed on the iPanda-50 datasets demonstrate the proposed FFN-PD significantly outperforms competing methods. Besides, experiments on other fine-grained recognition datasets (i.e., CUB-200-2011, Stanford Cars, and FGVC-Aircraft) demonstrate that the proposed FFN-PD outperforms existing state-of-the-art methods.

Layered dissolving microneedles as a need-based delivery system to simultaneously alleviate skin and joint lesions in psoriatic arthritis.

Psoriatic arthritis (PsA) is a complicated psoriasis comorbidity with manifestations of psoriatic skin and arthritic joints, and tailoring specific treatment strategies for simultaneously delivering different drugs to different action sites in PsA remains challenging. We developed a need-based layered dissolving microneedle (MN) system loading immunosuppressant tacrolimus (TAC) and anti-inflammatory diclofenac (DIC) in different layers of MNs, i.e., TD-MN, which aims to specifically deliver TAC and DIC to skin and articular cavity, achieving simultaneous alleviation of psoriatic skin and arthritic joint lesions in PsA. In vitro and in vivo skin permeation demonstrated that the inter-layer retained TAC within the skin of ∼100 µm, while the tip-layer delivered DIC up to ∼300 µm into the articular cavity. TD-MN not only efficiently decreased the psoriasis area and severity index scores and recovered the thickened epidermis of imiquimod-induced psoriasis but also alleviated carrageenan/kaolin-induced arthritis even better than DIC injection through reducing joint swelling, muscle atrophy, and cartilage destruction. Importantly, TD-MN significantly inhibited the serum TNF-α and IL-17A in psoriatic and arthritic rats. The results support that this approach represents a promising alternative to multi-administration of different drugs for comorbidity, providing a convenient and effective strategy for meeting the requirements of PsA treatment.

Integrating tacrolimus into eutectic oil-based microemulsion for atopic dermatitis: simultaneously enhancing percutaneous delivery and treatment efficacy with relieving side effects.

Background: Topical application of tacrolimus (FK506) was effective in treating atopic dermatitis (AD); however, the therapeutic efficiency is hampered by its poor penetration into the skin and local side effects of transient irritation symptoms with a burning sensation, a feeling of warmth or heat. Menthol and camphor have been widely used in topical compound formulations for adjunctive pharmacotherapy for antipruritics and analgesics owing to their cool nature, and both present skin penetration enhancing effects. Moreover, they can form a liquid eutectic oil to solubilize hydrophobic drugs. Purpose: Taking advantages of menthol/camphor eutectic (MCE), this work aims to integrate FK506 into MCE to construct a microemulsion system, i.e., FK506 MCE ME, which simultaneously enhances the percutaneous delivery and treatment efficacy, while reduces the side effects of FK506. Methods: The formulation of FK506 MCE ME was optimized and characterized. Different formulations containing FK506 were topically administered to treat 1-chloro-2, 4-dinitrobenzene (DNCB)-induced murine AD. Results: MCE solubilized FK506. FK506 in MCE ME penetrated skin in vitro more than in the commercial ointment, and MCE predominantly exerted the enhancing effects in MCE ME. FK506 MCE ME or FK506 MCE ME gel had greater effects on clinical symptoms, histological analysis, and IgE than did commercial FK506. The anti-pruritic and down-regulation of substance P effects of MCE ME vehicle mitigated the side effects of FK506 application. Conclusion: MCE ME presented the excellent properties of simultaneously enhancing the percutaneous delivery and treatment efficacy, while reducing the side effects of FK506 for AD. Therefore, MCE ME is a promising nanoscale system for FK506 to effectively treating AD with low irritation and high medication adherence. Chemical compounds studied in this article: Tacrolimus (PubChem CID: 445643); menthol (PubChem CID: 1254); camphor (PubChem CID: 2537).

Coated microneedles mediated intradermal delivery of octaarginine/BRAF siRNA nanocomplexes for anti-melanoma treatment.

BRAF is the most frequently mutated gene in skin melanoma. Applying BRAF siRNA (siBraf) to silencing BRAF gene is a current frontline therapy for melanoma. However, delivery of macromolecular siRNA into the tumor site and introduction of siRNA into the tumor cells remain as challenges. In this study, we for the first time developed a siBraf delivery system based on cell penetrating peptide octaarginine (R8) nanocomplexes combined with coated microneedles (MNs), i.e. R8/siBraf coated MNs, for targeted anti-melanoma treatment. The R8/siBraf nanocomplexes were optimized based on the internalization of siBraf by A375 cells. In vitro A375 cell experiments presented that R8/siBraf can enhance siBraf transfection, silence BRAF gene, and inhibit tumor cells growth, comparable to polyethylenimine (PEI)/siBraf. R8/siBraf coated MNs can effectively deliver R8/siBraf into the disease site. In vivo anti-melanoma experiments indicated that R8/siBraf coated MNs can significantly inhibit the melanoma development, induce the tumor cells apoptosis, and suppress their proliferation. The BRAF gene in tumor were also significantly silenced in vivo. SiBraf intradermal delivery via combining MNs and R8 nanocomplexes is a promising approach for skin melanoma treatment, which exploited both virtues of MNs and cell penetrating peptide to obtain the targeting inhibition efficacy on skin melanoma.

Tacrolimus nanoparticles based on chitosan combined with nicotinamide: enhancing percutaneous delivery and treatment efficacy for atopic dermatitis and reducing dose.

BACKGROUND: Topical application of tacrolimus (FK506) was effective in the treatment of atopic dermatitis (AD); however, adverse effects frequently occurred with the increase of FK506 dose during long-term treatment. OBJECTIVE: The objective of this project was to develop a hybrid skin targeting system encapsulating FK506 based on nicotinamide (NIC) and chitosan nanoparticles (CS-NPs), ie, FK506-NIC-CS-NPs, which took advantages of both of NIC and CS-NPs to obtain the synergetic effects of percutaneous delivery and treatment efficacy enhancement along with dose reduction. METHODS: The formulation of FK506-NIC-CS-NPs was optimized and characterized. In vitro and in vivo skin permeation studies were performed. AD-like skin lesions were constructed with BALB/c mice by 1-chloro-2, 4-dinitrobenzene (DNCB)-induced, and FK506-NIC-CS-NPs containing different dose of FK506 were topically administered to treat AD-like skin lesions in comparison with Protopic. RESULTS: NIC was found to significantly increase the FK506 EE to 92.2% by CS-NPs. In comparison with commercial FK506 ointment (Protopic), in vitro and in vivo skin permeation studies demonstrated that NIC-CS-NPs system significantly enhanced FK506 permeation through and into the skin, and deposited more FK506 into the skin. The treatment efficacy on clinical symptoms, histological analysis, and molecular biology of the AD-mice demonstrated that NIC-CS-NPs with ~1/3 dose of FK506 of Protopic was superior to that of Protopic, and NIC-CS-NPs vehicle exhibited the adjuvant therapy and moderate anti-AD effects. CONCLUSION: The system of NIC-CS-NPs enhances the permeability of FK506, plays an adjuvant role in anti-AD, reduces the dose of FK506 in treating AD, and is therefore a promising nanoscale system of FK506 for the effective treatment of AD.

Intradermal delivery of STAT3 siRNA to treat melanoma via dissolving microneedles.

Hyperactivity of signal transducer and activity of transcription 3 (STAT3) plays a crucial role in melanoma invasion and metastasis. Gene therapy applying siRNA targeting STAT3 is a potential therapeutic strategy for melanoma. In this article, we first fabricated safe and novel dissolving microneedles (MNs) for topical application of STAT3 siRNA to enhance the skin penetration of siRNA and used polyethylenimine (PEI, 25 kDa) as carrier to improve cellular uptake of siRNA. The results showed that MNs can effectively penetrate skin and rapidly dissolve in the skin. In vitro B16F10 cell experiments presented that STAT3 siRNA PEI complex can enhance cellular uptake and transfection of siRNA, correspondingly enhance gene silencing efficiency and inhibit tumor cells growth. In vivo experiments indicated that topical application of STAT3 siRNA PEI complex delivered by dissolving MNs into skin can effectively suppress the development of melanoma through silencing STAT3 gene, and the inhibition effect is dose-dependent. STAT3 siRNA delivery via dissolving MNs is a promising approach for skin melanoma treatment with targeting inhibition efficacy and minimal adverse effects.