Huntington's disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) ...is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.
As the popularity of dental implants continues to grow at a rate of about 14% per year, so do the risks associated with the procedure. Complications such as sinusitis and nerve damage are not ...uncommon, and inadequate cleaning can lead to peri-implantitis around the implant, jeopardizing its stability and potentially necessitating retreatment. To address this issue, this research proposes a new system for evaluating the degree of periodontal damage around implants using Periapical film (PA). The system utilizes two Convolutional Neural Networks (CNN) models to accurately detect the location of the implant and assess the extent of damage caused by peri-implantitis. One of the CNN models is designed to determine the location of the implant in the PA with an accuracy of up to 89.31%, while the other model is responsible for assessing the degree of Peri-implantitis damage around the implant, achieving an accuracy of 90.45%. The system combines image cropping based on position information obtained from the first CNN with image enhancement techniques such as Histogram Equalization and Adaptive Histogram Equalization (AHE) to improve the visibility of the implant and gums. The result is a more accurate assessment of whether peri-implantitis has eroded to the first thread, a critical indicator of implant stability. To ensure the ethical and regulatory standards of our research, this proposal has been certified by the Institutional Review Board (IRB) under number 202102023B0C503. With no existing technology to evaluate Peri-implantitis damage around dental implants, this CNN-based system has the potential to revolutionize implant dentistry and improve patient outcomes.
Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that ...epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal-epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.
Fluorescence probes emitting in the second near‐infrared (NIR‐II, 1000–1700 nm) window with the ability for deep‐tissue imaging in mammals herald a new era in surgical methodology. However, the ...brightness of these NIR‐II probes is still far from satisfactory due to their low fluorescence quantum yields (QYs), preventing the observation of high‐resolution images such as whole‐organ vascular networks in real time. Described here is the molecular engineering of a series of semiconducting polymer dots (Pdots) incorporated with aggregation‐induced emission moieties to exhibit the QYs as high as 14% in the NIR‐II window. Benefiting from the ultrahigh brightness, a 1400 nm long‐pass filter is utilized to realize in vivo 3D tumor mapping in mice. To further understand how the geometrical and electron structures of the semiconducting polymers affect their optical properties, the in‐depth and thorough density‐functional theory calculations are performed to interpret the experimental results. This study lays the groundwork for further molecular design of highly bright NIR‐II Pdots.
This work reports the design of second near‐infrared fluorescent polymer dots (Pdots) incorporated with AIEgens for deep‐tissue tumor tracking. These Pdots possess ultrahigh fluorescence quantum yield of 14%. Detailed optical characterizations and theoretical density‐functional theory calculations are provided to elucidate the role of AIEgens. 3D fluorescent tumor mapping is performed.
In this study we aimed to identify the predictors of drug survival for biologic and targeted synthetic DMARDs (bDMARDs and tsDMARDs) among patients with rheumatoid arthritis (RA) in a real-world ...setting. Data from RA patients receiving bDMARDs and tsDMARDs between 2007 and 2019 were extracted from the Taiwan Rheumatology Association Clinical Electronic Registry (TRACER). Patients were categorized into tumor necrosis factor-alpha (TNF-α) inhibitors, non-TNF-α inhibitors, and tofacitinib groups. The primary outcome was 3-year drug retention and the causes of bDMARDs and tsDMARDs discontinuation were recorded. Baseline demographic data before the initiation of bDMARDs and tsDMARDs treatment were analyzed to identify the predictors of 3-year drug survival. A total of 1,270 RA patients were recruited (TNF-α inhibitors: 584; non-TNF-α inhibitors: 535; tofacitinib: 151). The independent protective factors for 3-year drug survival were positive rheumatoid factor (RF) (HR: 0.48, 95% CI: 0.27-0.85, p = 0.013) and biologics-naïve RA (HR: 0.61, 95% CI: 0.39-0.94, p = 0.024). In contrast, positive anti-citrullinated protein antibody (ACPA) (HR: 2.24, 95% CI: 1.32-3.79, p = 0.003) and pre-existing latent tuberculosis (HR: 2.90, 95% CI: 2.06-4.09, p<0.001) were associated with drug discontinuation. RA patients treated with TNF-α inhibitors exhibited better drug retention, especially in the biologics-naïve subgroup (p = 0.037). TNF-α inhibitors were associated with lower cumulative incidence of discontinuation due to inefficacy and adverse events (both p<0.001). Baseline RF and ACPA positivity in abatacept-treated patients were associated with a better 3-year drug survival. However, negative ACPA levels predicted superior drug survival of TNF-α inhibitors and tofacitinib. In conclusion, bio-naïve status predicted better drug survival in TNF-α inhibitors-treated RA patients. RF and ACPA positivity predicted better abatacept drug survival. In contrast, ACPA negativity was associated with superior TNF-α inhibitors and tofacitinib survival.
Siglecs are a family of receptor-type glycan recognition proteins (lectins) involved in self-nonself discrimination by the immune system. Identification of Siglec ligands is necessary to understand ...how Siglec-ligand interaction translates into biological outcomes. However, this is challenging because the interaction is weak. To facilitate identification of Siglec ligands, we adopted a proximity labeling method based on the tyramide radicalization principle. Cells that express Siglec ligands were labeled with Siglec-peroxidase complexes and incubated with biotin tyramide and hydrogen peroxide to generate short-lived tyramide radicals that covalently label the proteins near the Siglec-peroxidase complex. A proof-of-principle experiment using CD22 (Siglec-2) probe identified its known ligands on B cells, including CD22 itself, CD45, and IgM, among others, demonstrating the validity of this method. The specificity of labeling was confirmed by sialidase treatment of target cells and using glycan recognition-deficient mutant CD22 probes. Moreover, possible interactions between biotin-labeled proteins were revealed by literature-based protein-protein interaction network analysis, implying the presence of a molecular cluster comprising CD22 ligands. Further application of this method identified CD44 as a hitherto unknown Siglec-15 ligand on RAW264.7-derived osteoclasts. These results demonstrated the utility of proximity labeling for the identification of Siglec ligands, which may extend to other lectins.
Carbodicarbene (CDC), unique carbenic entities bearing two lone pairs of electrons are well‐known for their strong Lewis basicity. We demonstrate herein, upon introducing a weak Brønsted acid benzyl ...alcohol (BnOH) as a co‐modulator, CDC is remolded into a Frustrated Lewis Pair (FLP)‐like reactivity. DFT calculation and experimental evidence show BnOH loosely interacting with the binding pocket of CDC via H‐bonding and π‐π stacking. Four distinct reactions in nature were deployed to demonstrate the viability of proof‐of‐concept as synergistic FLP/Modulator (CDC/BnOH), demonstrating enhanced catalytic reactivity in cyclotrimerization of isocyanate, polymerization process for L‐lactide (LA), methyl methacrylate (MMA) and dehydrosilylation of alcohols. Importantly, the catalytic reactivity of carbodicarbene is uniquely distinct from conventional NHC which relies on only single chemical feature of nucleophilicity. This finding also provides a new spin in diversifying FLP reactivity with co‐modulator or co‐catalyst.
In the presence of co‐modulator alcohol, the putative strong σ donor, CDC is reshaped into frustrated Lewis pair‐like reactivity. The unique synergistic FLP behavior of CDC; unachievable by its counterpart NHCs, is shown to have beneficial and complementary effects on isocyanate cyclotrimerization, LA polymerization, MMA polymerization and dehydrosilylation of alcohols.
Recent studies have shown the evocation of lateral spread response (LSR) due to the compression of the facial nerve in hemifacial spasm (HFS). Intraoperative monitoring (IOM) of LSR could help locate ...neurovascular conflicts and confirm adequate micro-vascular decompression (MVD) while treatment of hemifacial spasm (HFS). However, studies on early LSR loss before decompression in HFS surgery are sparse, indicating the need to understand various perceptions on it. Therefore, we retrospectively analyzed 50 adult HFS patients who underwent MVD during the period of September 2018-June 2021. We employed IOM combining traditional LSR (tLSR) and dual LSR (dLSR). One patient was excluded owing to the lack of LSR induction throughout the surgery, while 49 were divided into groups A (
= 14) and B (
= 35), designated as with or without early LSR loss groups, respectively, and offending vessels were analyzed. The mean age of group A patients was significantly younger (47.8 ± 8.6) than that of group B (53.9 ± 10.6) (
= 0.0393). The significant predominating offending vessel in group A was the anterior inferior cerebellar artery (AICA, 78.57%). However, group B included those with AICA (28.57%), posterior inferior cerebellar artery (PICA, 22.86%), vertebral artery (VA) involved (25.71%), and combined AICA and PICA (22.86%). Group B exhibited poorer clinical outcomes with more complications. Conclusively, early LSR loss might occur in the younger population, possibly due to the AICA offending vessel. The compression severity of offending vessels may determine the occurrence of early LSR loss.
Hepatitis B virus X protein (HBx) and hepatic stellate cells (HSCs) are critical for liver fibrosis development. Anti-fibrosis occurs via reversion to quiescent-type HSCs or clearance of HSCs via ...apoptosis or ferroptosis. We aimed to elucidate the role of chrysophanol in rat HSC-T6 cells expressing HBx and investigate whether chrysophanol (isolated from Rheum palmatum rhizomes) influences cell death via ferroptosis in vitro. Analysis of lipid reactive oxygen species (ROS), Bip, CHOP, p-IRE1α, GPX4, SLC7A11, α-SMA, and CTGF showed that chrysophanol attenuated HBx-repressed cell death. Chrysophanol can impair HBx-induced activation of HSCs via endoplasmic reticulum stress (ER stress) and ferroptosis-dependent and GPX4-independent pathways.
Sprouty2 (SPRY2) is known to inhibit the RAS/MAPK/ERK pathway, and is a potential study target for cancer. The effect of SPRY2 in colorectal cancer (CRC) and whether it is influenced by KRAS mutation ...are not known. We manipulated SPRY2 gene expression and used an activating KRAS‐mutant plasmid to determine its effect on CRC cell function in vitro and/or in vivo. We performed SPRY2 immunohistochemical staining in 143 CRC specimens and analyzed the staining results with various clinicopathological characteristics in relation to KRAS mutation status. SPRY2 knockdown in Caco‐2 cells carrying the wild‐type (WT) KRAS gene upregulated phosphorylated ERK (p‐ERK) levels and increased cell proliferation in vitro, but inhibited cell invasion. However, SPRY2 knockdown in SW480 cells (activating KRAS mutant) or Caco‐2 cells transfected with KRAS‐mutant plasmid did not significantly alter p‐ERK levels, cell proliferation, or invasion. The xenografts of SPRY2‐knockdown Caco‐2 cells were larger with less deep muscle invasion than those of control cells. The clinical cohort study revealed a positive association of SPRY2 protein expression with pT status, lymphovascular invasion, and perineural invasion in KRAS‐WT CRCs. However, the associations were not observed in KRAS‐mutant CRCs. Interestingly, high SPRY2 expression was related to shorter cancer‐specific survival in both KRAS‐WT and KRAS‐mutant CRC patients. Our study demonstrated the dual role of SPRY2 as an inhibitor of RAS/ERK‐driven proliferation and as a promoter of cancer invasion in KRAS‐WT CRC. SPRY2 may promote the invasion and progression of KRAS‐WT CRC, and might also enhance KRAS‐mutant CRC progression through pathways other than invasion.
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