Chronic obstructive pulmonary disease (COPD) is a global disease characterised by chronic obstruction of lung airflow interfering with normal breathing. Although the microbiota of respiratory tract ...is established to be associated with COPD, the causality of gut microbiota in COPD development is not yet established. We aimed to address the connection between gut microbiota composition and lung COPD development, and characterise bacteria and their derived active components for COPD amelioration.
A murine cigarette smoking (CS)-based model of COPD and strategies evaluating causal effects of microbiota were performed. Gut microbiota structure was analysed, followed by isolation of target bacterium. Single cell RNA sequencing, together with sera metabolomics analyses were performed to identify host responsive molecules. Bacteria derived active component was isolated, followed by functional assays.
Gut microbiota composition significantly affects CS-induced COPD development, and faecal microbiota transplantation restores COPD pathogenesis. A commensal bacterium
was isolated and shown to ameliorate COPD. Reduction of intestinal inflammation and enhancement of cellular mitochondrial and ribosomal activities in colon, systematic restoration of aberrant host amino acids metabolism in sera, and inhibition of lung inflammations act as the important COPD ameliorative mechanisms. Besides, the lipopolysaccharide derived from
is anti-inflammatory, and significantly ameliorates COPD by acting as an antagonist of toll-like receptor 4 signalling pathway.
The gut microbiota-lung COPD axis was connected. A potentially benefial bacterial strain and its functional component may be developed and used as alternative agents for COPD prevention or treatment.
We combine theory and experiment to demonstrate that a carefully designed gradient meta-surface supports high-efficiency anomalous reflections for near-infrared light following the generalized ...Snell’s law, and the reflected wave becomes a bounded surface wave as the incident angle exceeds a critical value. Compared to previously fabricated gradient meta-surfaces in infrared regime, our samples work in a shorter wavelength regime with a broad bandwidth (750–900 nm), exhibit a much higher conversion efficiency (∼80%) to the anomalous reflection mode at normal incidence, and keep light polarization unchanged after the anomalous reflection. Finite-difference-time-domain (FDTD) simulations are in excellent agreement with experiments. Our findings may lead to many interesting applications, such as antireflection coating, polarization and spectral beam splitters, high-efficiency light absorbers, and surface plasmon couplers.
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IJS, KILJ, NUK, PNG, UL, UM
The exquisite specificity of antibodies and antibody fragments renders them excellent agents for targeted delivery of radionuclides. Radiolabeled antibodies and fragments have been successfully used ...for molecular imaging and radioimmunotherapy (RIT) of cell surface targets in oncology and immunology. Protein engineering has been used for antibody humanization essential for clinical applications, as well as optimization of important characteristics including pharmacokinetics, biodistribution, and clearance. Although intact antibodies have high potential as imaging and therapeutic agents, challenges include long circulation time in blood, which leads to later imaging time points post‐injection and higher blood absorbed dose that may be disadvantageous for RIT. Using engineered fragments may address these challenges, as size reduction and removal of Fc function decreases serum half‐life. Radiolabeled fragments and pretargeting strategies can result in high contrast images within hours to days, and a reduction of RIT toxicity in normal tissues. Additionally, fragments can be engineered to direct hepatic or renal clearance, which may be chosen based on the application and disease setting. This review discusses aligning the physical properties of radionuclides (positron, gamma, beta, alpha, and Auger emitters) with antibodies and fragments and highlights recent advances of engineered antibodies and fragments in preclinical and clinical development for imaging and therapy.
Antibodies and antibody fragments enable highly specific delivery of radionuclides and can target a wide range of cell surface biomarkers, including antigens expressed on cancer cells and immune cells. The high specificity of antibodies is advantageous for noninvasive whole body molecular imaging and radioimmunotherapy. This review discusses protein engineering, radiolabeling strategies, and recent preclinical and clinical development of engineered antibodies and fragments.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
MicroRNAs (miRNAs), i.e. small non-coding RNA molecules (~22 nt), can bind to one or more target sites on a gene transcript to negatively regulate protein expression, subsequently controlling many ...cellular mechanisms. A current and curated collection of miRNA-target interactions (MTIs) with experimental support is essential to thoroughly elucidating miRNA functions under different conditions and in different species. As a database, miRTarBase has accumulated more than 3500 MTIs by manually surveying pertinent literature after data mining of the text systematically to filter research articles related to functional studies of miRNAs. Generally, the collected MTIs are validated experimentally by reporter assays, western blot, or microarray experiments with overexpression or knockdown of miRNAs. miRTarBase curates 3576 experimentally verified MTIs between 657 miRNAs and 2297 target genes among 17 species. miRTarBase contains the largest amount of validated MTIs by comparing with other similar, previously developed databases. The MTIs collected in the miRTarBase can also provide a large amount of positive samples to develop computational methods capable of identifying miRNA-target interactions. miRTarBase is now available on http://miRTarBase.mbc.nctu.edu.tw/, and is updated frequently by continuously surveying research articles.
Abstract
Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains ...that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein. Indeed, targeted protein degradation technologies, including proteolysis-targeting chimeras
1
(PROTACs), have highlighted clinically important advantages of target degradation over inhibition
2
. However, the generation of heterobifunctional compounds binding to two targets with high affinity is complex, particularly when oral bioavailability is required
3
. Here we describe the development of proteolysis-targeting antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. Focusing on zinc- and ring finger 3 (ZNRF3), a Wnt-responsive ligase, we show that this approach can enable colorectal cancer-specific degradation. Notably, by examining a matrix of additional cell-surface E3 ubiquitin ligases and transmembrane receptors, we demonstrate that this technology is amendable for ‘on-demand’ degradation. Furthermore, we offer insights on the ground rules governing target degradation by engineering optimized antibody formats. In summary, this work describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Electronic device versions of the neural functions of the human retina have high potential for use in artificial vision. This study demonstrates halide perovskite artificial human photoreceptors with ...specific photoresponses to red, green, and blue colors, which are consistent with human retinal photoreceiving cones and rods. In contrast to the current programmable spectral‐response technologies, a novel microcavity structure is combined in this study with a perovskite absorber to achieve a targeted spectrum without using external optical filters. The fabricated artificial photoreceptors exhibit excellent performance including a high detectivity of more than 1013 Jones, a large linear dynamic range of 154 dB, and a short response time of 580 ns. These values are equal to or better than those of the natural human retina. These devices can easily be monolithically integrated on a single flexible substrate by using vacuum deposition, and a true proof‐of‐concept full‐color image reconstruction is demonstrated.
Microcavity‐integrated monolithic flexible perovskite artificial human photoreceptors are demonstrated. The artificial cones and rods exhibit a true similarity with the natural human retina and exhibit excellent specific detectivity, large linear dynamic range, short response time, and low noise current. The potential of these versatile structures is manifested by reproducing a realistic full‐color image.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We propose all‐dielectric metasurfaces that can be actively re‐configured using the phase‐change material Ge2Sb2Te5 (GST) alloy. With selectively controlled phase transitions on the composing GST ...elements, metasurfaces can be tailored to exhibit varied functionalities. Using phase‐change GST rod as the basic building block, we have modelled metamolecules with tunable optical response when phase change occurs on select constituent GST rods. Tunable gradient metasurfaces can be realized with variable supercell period consisting of different patterns of the GST rods in their amorphous and crystalline states. Simulation results indicate a range of functions can be delivered, including multilevel signal modulating, near‐field coupling of GST rods, and anomalous reflection angle controlling. This work opens up a new space in exploring active meta‐devices with broader applications that cannot be achieved in their passive counterparts with permanent properties once fabricated.
The all‐dielectric reconfigurable metasurfaces based on switchable phase‐change material Ge2Sb2Te5 with functional diversity for light modulation are shown. The tunability of EIT resonance on phase‐change metamolecule and the steering of gradient metasurface are demonstrated by selectively modifying the phase of selected constituent Ge2Sb2Te5 rods.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This study examined the progression of chronic kidney disease (CKD) by using average annual decline in estimated GFR (eGFR) and its risk factors in a 10-year follow-up CKD cohort.
A prospective, ...observational cohort study, 4600 individuals fulfilled the definition of CKD, with or without proteinuria, were followed for 10 years. The eGFR was estimated by the MDRD equation. Linear regression was used to estimate participants' annual decline rate in eGFR. We defined subjects with annual eGFR decline rate <1 ml/min/1.73 m2 as non-progression and the decline rate over 3 ml/min/1.73 m2 as rapid progression.
During the follow-up period, 2870 (62.4%) individuals had annual eGFR decline rate greater than 1 ml/min/1.73 m2. The eGFR decline rate was slower in individuals with CKD diagnosed over the age of 60 years than those with onset at a younger age. Comparing to subjects with decline rate <1 ml/min/1.73 m2/year, the odds ratio (OR) of developing rapid CKD progression for diabetes, proteinuria and late onset of CKD was 1.72 (95% CI: 1.48-2.00), 1.89(1.63-2.20) and 0.68 (0.56-0.81), respectively. When the model was adjusted for the latest CKD stage, comparing to those with CKD stage 1, patients with stage 4 and stage 5 have significantly higher risks for rapid progression (OR, 5.17 (2.60-10.25), 19.83 (10.05-39.10), respectively). However, such risk was not observed among patients with the latest CKD stage 2 and 3. The risk for incident ESRD was 17% higher for each 1 ml/min/1.73 m2 increasing in annual decline rate.
Not everyone with CKD develops ESRD after a 10-year follow-up. Absolute annual eGFR decline rate can help clinicians to better predict the progression of CKD. Individuals with renal function decline rate over 3 ml/min/1.73 m2/year require intensive CKD care.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dissemination of epithelial cells is a critical step in metastatic spread. Molecular models of dissemination focus on loss of E-cadherin or repression of cell adhesion through an epithelial to ...mesenchymal transition (EMT). We sought to define the minimum molecular events necessary to induce dissemination of cells out of primary murine mammary epithelium. Deletion of E-cadherin disrupted epithelial architecture and morphogenesis but only rarely resulted in dissemination. In contrast, expression of the EMT transcription factor Twist1 induced rapid dissemination of cytokeratin-positive epithelial cells. Twist1 induced dramatic transcriptional changes in extracellular compartment and cell-matrix adhesion genes but not in cell-cell adhesion genes. Surprisingly, we observed disseminating cells with membrane-localized E-cadherin and β-catenin, and E-cadherin knockdown strongly inhibited Twist1-induced single cell dissemination. Dissemination can therefore occur with retention of epithelial cell identity. The spread of cancer cells during metastasis could similarly involve activation of an epithelial motility program without requiring a transition from epithelial to mesenchymal character.
Inflammatory bowel diseases (IBDs) in humans are characterized in part by aberrant CD4-positive (CD4+) T-cell responses. Currently, identification of foci of inflammation within the gut requires ...invasive procedures such as colonoscopy and biopsy. Molecular imaging with antibody fragment probes could be used to noninvasively monitor cell subsets causing intestinal inflammation. Here, GK1.5 cys-diabody (cDb), an antimouse CD4 antibody fragment derived from the GK1.5 hybridoma, was used as a PET probe for CD4+ T cells in the dextran sulfate sodium (DSS) mouse model of IBD.
The DSS mouse model of IBD was validated by assessing changes in CD4+ T cells in the spleen and mesenteric lymph nodes (MLNs) using flow cytometry. Furthermore, CD4+ T cell infiltration in the colons of colitic mice was evaluated using immunohistochemistry.
Zr-labeled GK1.5 cDb was used to image distribution of CD4+ T cells in the abdominal region and lymphoid organs of mice with DSS-induced colitis. Region-of-interest analysis was performed on specific regions of the gut to quantify probe uptake. Colons, ceca, and MLNs were removed and imaged ex vivo by PET. Imaging results were confirmed by ex vivo biodistribution analysis.
An increased number of CD4+ T cells in the colons of colitic mice was confirmed by anti-CD4 immunohistochemistry. Increased uptake of
Zr-maleimide-deferoxamine (malDFO)-GK1.5 cDb in the distal colon of colitic mice was visible in vivo in PET scans, and region-of-interest analysis of the distal colon confirmed increased activity in DSS mice. MLNs from colitic mice were enlarged and visible in PET images. Ex vivo scans and biodistribution confirmed higher uptake in DSS-treated colons (DSS, 1.8 ± 0.40; control, 0.45 ± 0.12 percentage injected dose %ID per organ, respectively), ceca (DSS, 1.1 ± 0.38; control, 0.35 ± 0.09 %ID per organ), and MLNs (DSS, 1.1 ± 0.58; control, 0.37 ± 0.25 %ID per organ).
Zr-malDFO-GK1.5 cDb detected CD4+ T cells in the colons, ceca, and MLNs of colitic mice and may prove useful for further investigations of CD4+ T cells in preclinical models of IBD, with potential to guide development of antibody-based imaging in human IBD.
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