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Levels of amyloid-β (Aβ) and tau peptides in brain have been associated with Alzheimer disease (AD). The current study investigated the abilities of plasma Aβ42 and total-tau (t-tau) levels in predicting cognitive decline in subjects with amnestic mild cognitive impairment (MCI). Plasma Aβ42 and t-tau levels were quantified in 22 participants with amnestic MCI through immunomagnetic reduction (IMR) assay at baseline. The cognitive performance of participants was measured through neuropsychological tests at baseline and annual follow-up (average follow-up period of 1.5 years). The predictive value of plasma Aβ42 and t-tau for cognitive status was evaluated. We found that higher levels of Aβ42 and t-tau are associated with lower episodic verbal memory performance at baseline and cognitive decline over the course of follow-up. While Aβ42 or t-tau alone had moderate-to-high discriminatory value in the identification of future cognitive decline, the product of Aβ42 and t-tau offered greater differential value. These preliminary results might suggest that high levels of plasma Aβ42 and t-tau in amnestic MCI are associated with later cognitive decline. A further replication with a larger sample over a longer time period to validate and determine their long-term predictive value is warranted.

Introduction Due to the high cost and high failure rate of ascertaining amyloid positron emission tomography positivity (PET+) in patients with earlier stage Alzheimer’s disease (AD), an effective pre-screening tool for amyloid PET scans is needed. Methods Patients with mild cognitive impairment ( n  = 33, 24.2% PET+, 42% females, age 74.4 ± 7.5, MMSE 26.8 ± 1.9) and mild dementia ( n  = 19, 63.6% PET+, 36.3% females, age 73.0 ± 9.3, MMSE 22.6 ± 2.0) were recruited. Amyloid PET imaging, Apolipoprotein E ( APOE ) genotyping, and plasma amyloid β (Aβ) 1–40 , Aβ 1–42 , and total tau protein quantification by immunomagnetic reduction (IMR) method were performed. Receiver operating characteristics (ROC) analysis and Youden’s index were performed to identify possible cut-off points, clinical sensitivities/specificities, and areas under the curve (AUCs). Results Amyloid PET+ participants had lower plasma Aβ 1–42 levels than amyloid PET-negative (PET−) subjects. APOE ε4 carriers had higher plasma Aβ 1–42 than non-carriers. We developed an algorithm involving the combination of plasma Aβ 1–42 and APOE genotyping. The success rate for detecting amyloid PET+ patients effectively increased from 42.3 to 70.4% among clinically suspected MCI and mild dementia patients. Conclusions Our results demonstrate the possibility of utilizing APOE genotypes in combination with plasma Aβ 1–42 levels as a pre-screening tool for predicting the positivity of amyloid PET findings in early stage dementia patients.

Most previous studies concerning avian adaptation to anthropogenic noise have focused on songbirds, but few have focused on non-songbirds commonly found in urban environments such as doves. We conducted field playback-recording experiments on the perch-coos of five dove species, including four native Taiwan species (the spotted dove, Spilopelia chinensis , the oriental turtle-dove, Streptopelia orientalis , the red collared-dove, Streptopelia tranquebarica and the emerald dove, Chalcophaps indica ) and one species not native to Taiwan (the zebra dove, Geopelia striata ) to evaluate the detection and recognition of dove coos in habitats with differing levels of traffic noise. Our results suggest that traffic noise has selected dominant urban species such as the spotted dove to temporally and spatially adjust cooing to reduce the masking effects of traffic noise and rare urban species such as the emerald dove to avoid areas of high traffic noise. Additionally, although the zebra dove had the highest coo frequency among the study species, its coos showed the highest detection value but not the highest recognition value. We conclude that traffic noise is an important factor in shaping the distribution of rare and dominant dove species in urban environments through its significant effects on coo transmission.

Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Mechanical stimulations affect cell proliferation, differentiation, and migration, as well as determining tissue homeostasis and repair. By using a specially designed skin-stretching device, we discover that hair stem cells proliferate in response to stretch and hair regeneration occurs only when applying proper strain for an appropriate duration. A counterbalance between WNT and BMP-2 and the subsequent two-step mechanism are identified through molecular and genetic analyses. Macrophages are first recruited by chemokines produced by stretch and polarized to M2 phenotype. Growth factors such as HGF and IGF-1, released by M2 macrophages, then activate stem cells and facilitate hair regeneration. A hierarchical control system is revealed, from mechanical and chemical signals to cell behaviors and tissue responses, elucidating avenues of regenerative medicine and disease control by demonstrating the potential to manipulate cellular processes through simple mechanical stimulation. Mechanical stimulation is known to affect cell proliferation, differentiation, and regeneration. Here, the authors demonstrate that stretching mouse skin recruits macrophages and polarizes them into M2 cells that facilitate hair regeneration through the release of growth factors, including HGF and IGF-1

Chronic kidney disease is a progressive condition with limited therapeutic options in its advanced stages. Adipose‐derived stem cell therapy has shown potential in preclinical studies for renal repair. This study evaluated the short‐term stability of renal function in patients with moderate to severe chronic kidney disease who received adipose‐derived stem cell therapy, using a matched control group derived from real‐world clinical data for comparison. A total of 34 treated patients were matched in a one‐to‐five ratio with 170 control patients based on key clinical characteristics. The primary outcomes included the mean percentage change in estimated glomerular filtration rate and the incidence of renal function decline exceeding defined thresholds. To enhance the robustness of treatment effect estimation, real‐world data were utilized to construct an external control group that closely resembled the clinical trial population. This approach allowed indirect treatment comparisons and strengthened the internal validity of findings in the absence of randomization. Results demonstrated that the treated group exhibited a more stable renal function trajectory and a significantly lower risk of deterioration compared to the control group, particularly in patients with more advanced disease. Among dose groups, the low‐dose group showed the greatest stability in renal function. These findings support the feasibility of using real‐world data to construct external comparators and suggest that stem cell therapy may offer a short‐term stabilizing effect on renal function. Further research is needed to validate these findings and explore their long‐term clinical implications. Trial Registration: ClinicalTrials.gov identifier: NCT02933827 (registered October 13, 2016. https://clinicaltrials.gov/study/NCT02933827)

Neoadjuvant immunotherapy and chemotherapy have improved the major pathological response (MPR) in patients with early-stage operable non-small cell lung cancer (NSCLC). This study aimed to assess whether the presence of targetable driver mutations affects the efficacy of the combination of immunotherapy and chemotherapy. We enrolled patients with early-stage operable NSCLC who received preoperative neoadjuvant therapy between January 1, 2017, and December 30, 2020. Neoadjuvant therapy was delivered with platinum-doublet chemotherapy; moreover, pembrolizumab was added at the attending physician’s discretion based on patient’s request. Pathological responses were assessed; moreover, disease-free survival was estimated. Next-generation sequencing was performed in case sufficient preoperative biopsy specimens were obtained. We included 23 patients; among them, 11 received a combination of neoadjuvant immunotherapy and chemotherapy while 12 received neoadjuvant chemotherapy alone. The MPR and pathological complete response rates were 54.5% and 27.3%, respectively, in patients who received a combination of neoadjuvant immunotherapy and chemotherapy. These rates were significantly higher than those in patients who only received neoadjuvant chemotherapy. Three patients in the combination group experienced disease recurrence during the follow-up period even though two of them showed an MPR. These three patients had targetable driver mutations, including an EGFR exon 20 insertion, EGFR exon 21 L858R substitution, and MET exon 14 skipping. Only one patient who remained disease-free had a targetable driver mutation. Among patients with early-stage operable NSCLC requiring neoadjuvant therapy, comprehensive genomic profiling is crucial before the administration of the combination of neoadjuvant immunotherapy and chemotherapy.

Dengue virus (DENV) utilizes the endoplasmic reticulum (ER) for replication and assembling. Accumulation of unfolded proteins in the ER lumen leads to ER stress and unfolded protein response (UPR). Three branches of UPRs temporally modulated DENV infection. Moreover, ER stress can also induce autophagy. DENV infection induces autophagy which plays a promotive role in viral replication has been reported. However, the role of ER stress in DENV-induced autophagy, viral titer, and pathogenesis remain unclear. Here, we reveal that ER stress and its downstream UPRs are indispensable for DENV-induced autophagy in various human cells. We demonstrate that PERK-eIF2α and IRE1α-JNK signaling pathways increased autophagy and viral load after DENV infection. However, ATF6-related pathway showed no effect on autophagy and viral replication. IRE1α-JNK downstream molecule Bcl-2 was phosphorylated by activated JNK and dissociated from Beclin 1, which playing a critical role in autophagy activation. These findings were confirmed as decreased viral titer, attenuated disease symptoms, and prolonged survival rate in the presence of JNK inhibitor in vivo . In summary, we are the first to reveal that DENV2-induced ER stress increases autophagy activity, DENV replication, and pathogenesis through two UPR signaling pathways both in vitro and in vivo .

Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLPro) reportedly inhibits the production of type I interferons (IFNs) and pro-inflammatory cytokines in Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene 1 (RIG-I) pathways. The study investigated the inhibitory effect and its antagonistic mechanism of SARS-CoV PLPro on TLR7-mediated cytokine production. TLR7 agonist (imiquimod (IMQ)) concentration-dependently induced activation of ISRE-, NF-κB- and AP-1-luciferase reporters, as well as the production of IFN-α, IFN-β, TNF-α, IL-6 and IL-8 in human promonocyte cells. However, SARS-CoV PLPro significantly inhibited IMQ-induced cytokine production through suppressing the activation of transcription factors IRF-3, NF-κB and AP-1. Western blot analysis with anti-Lys48 and anti-Lys63 ubiquitin antibodies indicated the SARS-CoV PLPro removed Lys63-linked ubiquitin chains of TRAF3 and TRAF6, but not Lys48-linked ubiquitin chains in un-treated and treated cells. The decrease in the activated state of TRAF3 and TRAF6 correlated with the inactivation of TBK1 in response to IMQ by PLPro. The results revealed that the antagonism of SARS-CoV PLPro on TLR7-mediated innate immunity was associated with the negative regulation of TRAF3/6-TBK1-IRF3/NF-κB/AP1 signals.

Background Despite high vaccination rates, severe and critical illnesses in hospitalized patients with COVID-19 continue to pose significant challenges to healthcare systems. This study aimed to identify factors associated with mortality among hospitalized patients with COVID-19 who had received three vaccine doses during the spread of the SARS-CoV-2 Omicron variant. Methods This retrospective observational study was conducted at the Taipei Veterans General Hospital between April and June 2022. Hospitalized adult patients with confirmed COVID-19 who had received three vaccine doses before diagnosis were included. Demographic data, comorbidities, disease severity indicators, laboratory values, and treatment details were collected from the electronic records. Logistic regression analysis was used to identify the factors associated with 28-day mortality and the need for invasive mechanical ventilation. Results A total of 620 patients with a median age of 75 years were hospitalized for COVID-19, and the 28-day mortality rate was 7.9%. The independent predictors of mortality included a higher comorbidity burden, elevated World Health Organization (WHO) ordinal scale scores, elevated neutrophil-to-lymphocyte ratios (NLR), and thrombocytopenia. Among the 610 initially non-ventilated patients, 6.6% required invasive mechanical ventilation. Hematological malignancy, metastatic cancer, higher WHO ordinal scales, elevated NLR and bacterial secondary infection were significant risk factors for respiratory failure. Conclusion Despite receiving three doses of the COVID-19 vaccines, patients hospitalized with COVID-19 continue to experience notable rates of mortality and respiratory failure. During the current endemic phase of COVID-19, these prognostic indicators can help guide the management and early intervention of high-risk patients.

Resistive random access memory (RRAM) is a leading candidate in the race towards emerging nonvolatile memory technologies. The sneak path current (SPC) problem is one of the main difficulties in crossbar memory configurations. RRAM devices with desirable properties such as a selectorless, 1R-only architecture with self-rectifying behavior are potential SPC solutions. In this work, the intrinsic nonlinear (NL) characteristics and relaxation characteristics of bilayer high-k/low-k stacked RRAMs are presented. The intrinsic nonlinearity reliability of bilayer selectorless 1R-only RRAM without additional switches has been studied for their ability to effectively suppress SPC in RRAM arrays. The relaxation properties with resistive switching identification method by utilizing the activation energy (Ea) extraction methodology is demonstrated, which provides insights and design guidance for non-uniform bilayer selectorless 1R-only RRAM array applications.