External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing‐radiation beams. However, the efficacy of radiotherapy is usually limited by tumor ...hypoxia‐associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core–shell nanoparticles based poly(lactic‐co‐glycolic) acid (PLGA) are fabricate, by encapsulating water‐soluble catalase (Cat), an enzyme that can decompose H2O2 to generate O2, inside the inner core, and loading hydrophobic imiquimod (R837), a Toll‐like‐receptor‐7 agonist, within the PLGA shell. The formed PLGA‐R837@Cat nanoparticles can greatly enhance radiotherapy efficacy by relieving the tumor hypoxia and modulating the immune‐suppressive tumor microenvironment. The tumor‐associated antigens generated postradiotherapy‐induced immunogenic cell death in the presence of such R837‐loaded adjuvant nanoparticles will induce strong antitumor immune responses, which together with cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4) checkpoint blockade will be able to effectively inhibit tumor metastases by a strong abscopal effect. Moreover, a long term immunological memory effect to protect mice from tumor rechallenging is observed post such treatment. This work thus presents a unique nanomedicine approach as a next‐generation radiotherapy strategy to enable synergistic whole‐body therapeutic responses after local treatment, greatly promising for clinical translation.
Radiotherapy with polylactic‐co‐glycolic acid‐R837@Cat nanoparticles is able to induce immunogenic cell death and generate tumor debris as tumor‐associated antigens, which, with the help of those adjuvant nanoparticles, can induce robust antitumor immune responses. With further combination of checkpoint blockade, such treatment effectively targets distant metastatic tumors with a strong abscopal effect, and offers a long‐term immune memory protective effect afterward.
Abnormal H₂O₂ levels are closely related to many diseases, including inflammation and cancers. Herein, we simultaneously load HRP and its substrate, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic ...acid) (ABTS), into liposomal nanoparticles, obtaining a Lipo@HRP&ABTS optical nanoprobe for in vivo H₂O₂-responsive chromogenic assay with great specificity and sensitivity. In the presence of H₂O₂, colorless ABTS would be converted by HRP into the oxidized form with strong near-infrared (NIR) absorbance, enabling photoacoustic detection of H₂O₂ down to submicromolar concentrations. Using Lipo@HRP&ABTS as an H₂O₂-responsive nanoprobe, we could accurately detect the inflammation processes induced by LPS or bacterial infection in which H₂O₂ is generated. Meanwhile, upon systemic administration of this nanoprobe we realize in vivo photoacoustic imaging of small s.c. tumors (∼2 mm in size) as well as orthotopic brain gliomas, by detecting H₂O₂ produced by tumor cells. Interestingly, local injection of Lipo@HRP&ABTS further enables differentiation of metastatic lymph nodes from those nonmetastatic ones, based on their difference in H₂O₂ contents. Moreover, using the H₂O₂-dependent strong NIR absorbance of Lipo@HRP&ABTS, tumor-specific photothermal therapy is also achieved. This work thus develops a sensitive H₂O₂-responsive optical nanoprobe useful not only for in vivo detection of inflammation but also for tumor-specific theranostic applications.
Performance is a critical challenge in mobile image processing. Given a reference imaging pipeline, or even human-adjusted pairs of images, we seek to reproduce the enhancements and enable real-time ...evaluation. For this, we introduce a new neural network architecture inspired by bilateral grid processing and local affine color transforms. Using pairs of input/output images, we train a convolutional neural network to predict the coefficients of a locally-affine model in bilateral space. Our architecture learns to make local, global, and content-dependent decisions to approximate the desired image transformation. At runtime, the neural network consumes a low-resolution version of the input image, produces a set of affine transformations in bilateral space, upsamples those transformations in an edge-preserving fashion using a new
slicing
node, and then applies those upsampled transformations to the full-resolution image. Our algorithm processes high-resolution images on a smartphone in milliseconds, provides a real-time viewfinder at 1080p resolution, and matches the quality of state-of-the-art approximation techniques on a large class of image operators. Unlike previous work, our model is trained off-line from data and therefore does not require access to the original operator at runtime. This allows our model to learn complex, scene-dependent transformations for which no reference implementation is available, such as the photographic edits of a human retoucher.
We address the fundamental challenge of
scalability
for real-time volumetric surface reconstruction methods. We design a memory efficient, hierarchical data structure for commodity graphics hardware, ...which supports live reconstruction of large-scale scenes with fine geometric details. Our sparse data structure fuses overlapping depth maps from a moving depth camera into a single volumetric representation, from which detailed surface models are extracted. Our hierarchy losslessly streams data bidirectionally between GPU and host, allowing for unbounded reconstructions. Our pipeline, comprised of depth map post-processing, camera pose estimation, volumetric fusion, surface extraction, and streaming, runs entirely in real-time. We experimentally demonstrate that a shallow hierarchy with relatively large branching factors yields the best memory/speed tradeoff, consuming an order of magnitude less memory than a regular grid. We compare an implementation of our data structure to existing methods and demonstrate higher-quality reconstructions on a variety of large-scale scenes, all captured in real-time.
The abnormal tumor microenvironment (TME) featured with hypoxia, acidosis, dense extracellular matrix and increased tumor interstitial fluid pressure is closely related with the resistance of tumors ...to various therapies. Herein, a unique type of biocompatible nanoscale delivery system is fabricated by utilizing a chemotherapeutic drug, paclitaxel (PTX), to induce co-assembly of catalase and human serum albumin (HSA), the latter of which is pre-modified with chlorine e6 (Ce6), forming smart multifunctional HSA-Ce6-Cat–PTX nanoparticles via a rather simple one-step method. Upon intravenous injection, HSA-Ce6-Cat–PTX nanoparticles show high tumor accumulation and efficient intra-tumoral diffusion, likely owning to their changeable sizes that can maintain large initial sizes (~100nm) during blood circulation and transform into small protein-drug complexes (<20nm) within the tumor. Meanwhile, catalase within those nanoparticles could trigger decomposition of endogenic TME H2O2 to generate oxygen in-situ so as to relieve tumor hypoxia. This effect together with PTX-induced intra-tumoral perfusion enhancement is able to dramatically modulate TME to favor the anti-tumor effect in the combined photodynamic/chemotherapy with HSA-Ce6-Cat–PTX. Thus, our work presents a simple drug-induced self-assembly strategy to fabricate enzyme-loaded therapeutic albumin nanoparticles for synergistic cancer combination therapy.
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A striking feature of living systems is their ability to produce motility by amplification of collective molecular motion from the nanoscale up to macroscopic dimensions. Some of nature's protein ...motors, such as myosin in muscle tissue, consist of a hierarchical supramolecular assembly of very large proteins, in which mechanical stress induces a coordinated movement. However, artificial molecular muscles have often relied on covalent polymer-based actuators. Here, we describe the macroscopic contractile muscle-like motion of a supramolecular system (comprising 95% water) formed by the hierarchical self-assembly of a photoresponsive amphiphilic molecular motor. The molecular motor first assembles into nanofibres, which further assemble into aligned bundles that make up centimetre-long strings. Irradiation induces rotary motion of the molecular motors, and propagation and accumulation of this motion lead to contraction of the fibres towards the light source. This system supports large-amplitude motion, fast response, precise control over shape, as well as weight-lifting experiments in water and air.
GCaMP8f is a sensitive genetically encoded Ca2+ indicator that enables imaging of neuronal activity. Here, we present a protocol to perform Ca2+ imaging of the Drosophila neuromuscular junction using ...GCaMP8f targeted to pre- or postsynaptic compartments. We describe ratiometric Ca2+ imaging using GCaMP8f fused to mScarlet and synaptotagmin that reveals Ca2+ dynamics at presynaptic terminals. We then detail “quantal” imaging of miniature transmission events using GCaMP8f targeted to postsynaptic compartments by fusion to a PDZ-binding motif.
For complete details on the use and execution of this protocol, please refer to Li et al.,1 Han et al.,2 Perry et al.,3 and Han et al.4
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•Ca2+ imaging to assess single-action-potential presynaptic signals at the fly NMJ•Image and quantify “quantal” postsynaptic Ca2+ signals at the Drosophila NMJ•Sub-synaptically targeted GCaMP8 indicators for ratiometric and quantitative imaging
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
GCaMP8f is a sensitive genetically encoded Ca2+ indicator that enables imaging of neuronal activity. Here, we present a protocol to perform Ca2+ imaging of the Drosophila neuromuscular junction using GCaMP8f targeted to pre- or postsynaptic compartments. We describe ratiometric Ca2+ imaging using GCaMP8f fused to mScarlet and synaptotagmin that reveals Ca2+ dynamics at presynaptic terminals. We then detail “quantal” imaging of miniature transmission events using GCaMP8f targeted to postsynaptic compartments by fusion to a PDZ-binding motif.
Cell phone cameras have small apertures, which limits the number of photons they can gather, leading to noisy images in low light. They also have small sensor pixels, which limits the number of ...electrons each pixel can store, leading to limited dynamic range. We describe a computational photography pipeline that captures, aligns, and merges a burst of frames to reduce noise and increase dynamic range. Our system has several key features that help make it robust and efficient. First, we do not use bracketed exposures. Instead, we capture frames of constant exposure, which makes alignment more robust, and we set this exposure low enough to avoid blowing out highlights. The resulting merged image has clean shadows and high bit depth, allowing us to apply standard HDR tone mapping methods. Second, we begin from Bayer raw frames rather than the demosaicked RGB (or YUV) frames produced by hardware Image Signal Processors (ISPs) common on mobile platforms. This gives us more bits per pixel and allows us to circumvent the ISP's unwanted tone mapping and spatial denoising. Third, we use a novel FFT-based alignment algorithm and a hybrid 2D/3D Wiener filter to denoise and merge the frames in a burst. Our implementation is built atop Android's Camera2 API, which provides per-frame camera control and access to raw imagery, and is written in the Halide domain-specific language (DSL). It runs in 4 seconds on device (for a 12 Mpix image), requires no user intervention, and ships on several mass-produced cell phones.
Bullous pemphigoid (BP) is an autoimmune blistering disorder that predominantly affects the elderly. As the main treatment for BP, systemic corticosteroids are often limited by their side effects. ...Safer treatment modalities are therefore needed. Dupilumab is a biologic agent used to treat BP in recent years.
Medical records of patients with moderate-to-severe BP were retrospectively reviewed. Twenty-four patients were included (follow-up period: 32 weeks), eight of whom received dupilumab in combination with methylprednisolone and azathioprine (dupilumab group) while the other 16 patients received methylprednisolone and azathioprine (conventional group). Response to dupilumab was evaluated by comparison of several parameters (time to stop new blister formation, time to reduce the systemic glucocorticoids to minimal dose, and total amount of methylprednisolone).
The median age of patients in the dupilumab and conventional groups were 64.50 years (range: 22-90 years) and 64.50 years (range: 17-86 years), respectively. The median duration of disease before admission in the dupilumab group was 2 months (range: 1-240 months) and 2.5 months (range: 1-60 months) in the conventional group. The median time to stop new blister formation was 8 days (range: 1-13 days) and 12 days (range: 5-21 days) in patients of the dupilumab and conventional groups, respectively (
= 0.028 by Kaplan-Meier analysis). In addition, the median time to reduce the systemic glucocorticoids to minimal dose (methylprednisolone 0.08 mg/kg/day) was 121.5 and 148.5 days for the dupilumab and conventional therapy groups, respectively (
= 0.0053 by Kaplan-Meier analysis). The median total amount of methylprednisolone (at the time of reaching the minimal dose) used in the dupilumab group was 1,898 mg (range: 1,624-2,932 mg) while the cumulative dose of conventional group was 2,344 mg (range: 1,708-4,744 mg) (
= 0.036 by Mann-Whitney
test). The median total amount of azathioprine (at the time of reaching the minimal dose) used in dupilumab group was 8,300 mg (range: 7,100-10,400 mg) while the total dose of conventional group was 10,300 mg (range: 8,900-14,400 mg) (
= 0.0048 by Mann-Whitney
test). No adverse event related to dupilumab was recorded.
Dupilumab in addition to methylprednisolone and azathioprine seems superior to methylprednisolone/azathioprine alone in controlling disease progression and accelerating the tapering of glucocorticoids.
Transcatheter arterial chemoembolization (TACE) is the primary local treatment for patients with unresectable hepatocellular carcinoma (HCC). Numerous studies have demonstrated the pivotal role of ...circular RNAs (circRNAs) in TACE efficacy. This study aimed to investigate the function of circular RNA DNAH14 (circDNAH14) in TACE for HCC and to elucidate its molecular mechanisms. To simulate hypoxia conditions experienced during TACE, HCC cells were treated with cobalt chloride. The expression levels of circDNAH14, microRNA-508-3p (miR-508-3p), and Prothymosin Alpha (PTMA) were modulated via transfection for knockdown or overexpression. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, flow cytometry, and Transwell assays, along with epithelial-mesenchymal transition (EMT) evaluations, were employed to assess cell proliferation, apoptosis, invasion, migration, and EMT. The results indicated that hypoxia treatment downregulated the expression of circDNAH14 and PTMA while upregulating miR-508-3p. Such treatment suppressed HCC cell proliferation, invasion, migration, and EMT, and induced apoptosis. Knockdown of circDNAH14 or PTMA intensified the suppressive effects of hypoxia on the malignant behaviors of HCC cells. Conversely, upregulation of miR-508-3p or PTMA mitigated the effects of circDNAH14 overexpression and knockdown, respectively. Mechanistically, circDNAH14 was found to competitively bind to miR-508-3p, thereby regulating PTMA expression. In vivo, nude mouse xenograft experiments demonstrated that circDNAH14 knockdown augmented the hypoxia-induced suppression of HCC tumor growth. In conclusion, circDNAH14 mitigates the suppressive effects of hypoxia on HCC, both in vitro and in vivo, by competitively binding to miR-508-3p and regulating PTMA expression.
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