Association Between Fatty Liver Index, Controlled Attenuation Parameter, and Metabolic Syndrome Stages: A Community-Based Study.

BACKGROUND Controlled attenuation parameter (CAP) is a recent ultrasound-based method for measuring hepatic steatosis, which is common in patients with metabolic syndrome (MetS). The fatty liver index (FLI), an algorithm-based method, is frequently used to evaluate hepatic steatosis. This study assessed how FLI and CAP relate to the earlier MetS stage and their ability to identify it. MATERIAL AND METHODS A total of 170 community-based individuals were studied. Demographic information, body mass index, waist circumference, and blood pressures were collected. CAP was assessed by FibroScan. Fasting glucose, lipid tests, and γ-glutamyl transferase were measured. The CAP and FLI results were categorized into quartiles, with the MetS stages as the main outcomes. The odds ratio (OR) of the outcomes was calculated using logistic regression. The area under the curve in receiver operating characteristic analysis (AUC-ROC) was used to detect the stages of MetS. Sensitivity, specificity, and appropriate cut-offs based on ROC analysis are shown. RESULTS The higher the FLI or CAP category, the lower the proportion of non-MetS and the higher the proportion of moderate MetS. Each single-quartile increase in FLI and CAP was associated with an increased likelihood of being in the higher MetS stages - FLI: adjusted OR 3.1 (2.23-4.32); CAP: adjusted OR 1.96 (1.48-2.59). In the ROC analysis, FLI had a higher AUC-ROC than CAP in separating the stages of MetS, although findings were significant (P<0.001). FLI in detecting the stages of mild-to-severe versus non-MetS performed well (AUC-ROC [95% confidence interval]: 0.79 [0.72-0.87]), with high sensitivity (0.86) but low specificity (0.62). CONCLUSIONS FLI and CAP were positively associated with the MetS stage and its components, suggesting that they could be used as a MetS screening tool in community studies.

Identifying potential patients with diabetes-related dementia: a descriptive approach using routinely collected data.

AIMS: Diabetes-related dementia (DRD) is a new dementia subtype associated with type 2 diabetes mellitus, first described in 2013. This study investigated data from a local New Zealand memory service to identify patients that met the criteria for DRD. METHODS: Using routinely collected data from 2013-2021, we selected a sample of people with dementia, diabetes, and no CT evidence of Alzheimer's disease (AD), vascular dementia, or frontotemporal dementia. We compared their socio-demographic, clinical, and cognitive characteristics with a sample of patients with diabetes and Alzheimer's disease. RESULTS: Forty (16%) of 249 patients with diabetes and dementia had "normal" CT scans (DRD subgroup), and 38 (15%) had AD (AD subgroup). Compared to NZ Europeans, disproportionally more Maori and Pacific Islanders (70.2%) were in the DRD subgroup. In the Pacific subgroup (n=31), the DRD subgroup had higher memory subscores than the AD subgroup (p=0.047), and the Kaplan-Meier plot suggested poorer survival (p=0.13). Maori patients with diabetes and dementia were more likely to meet all four criteria for DRD. CONCLUSION: We have replicated the findings of the 2013 DRD research and have demonstrated a higher risk for the DRD subtype of dementia among the Maori and Pacific Islander patients in our sample.

Optical Microphone-Based Speech Reconstruction System With Deep Learning for Individuals With Hearing Loss.

OBJECTIVE: Although many speech enhancement (SE) algorithms have been proposed to promote speech perception in hearing-impaired patients, the conventional SE approaches that perform well under quiet and/or stationary noises fail under nonstationary noises and/or when the speaker is at a considerable distance. Therefore, the objective of this study is to overcome the limitations of the conventional speech enhancement approaches. METHOD: This study proposes a speaker-closed deep learning-based SE method together with an optical microphone to acquire and enhance the speech of a target speaker. RESULTS: The objective evaluation scores achieved by the proposed method outperformed the baseline methods by a margin of 0.21-0.27 and 0.34-0.64 in speech quality (HASQI) and speech comprehension/intelligibility (HASPI), respectively, for seven typical hearing loss types. CONCLUSION: The results suggest that the proposed method can enhance speech perception by cutting off noise from speech signals and mitigating interference caused by distance. SIGNIFICANCE: The results of this study show a potential way that can help improve the listening experience in enhancing speech quality and speech comprehension/intelligibility for hearing-impaired people.

Association of sepsis-induced cardiomyopathy and mortality: a systematic review and meta-analysis.

BACKGROUND: The implication of sepsis-induced cardiomyopathy (SIC) to prognosis is controversial, and its association with mortality at different stages remains unclear. We conducted a systematic review and meta-analysis to understand the association between SIC and mortality in septic patients. METHODS: We searched and appraised observational studies regarding the mortality related to SIC among septic patients in PubMed and Embase from inception until 8 July 2021. Outcomes comprised in-hospital and 1-month mortality. We adopted the random-effects model to examine the mortality risk ratio in patients with and without SIC. Meta-regression, subgroup, and sensitivity analyses were applied to examine the outcome's heterogeneity. RESULTS: Our results, including 20 studies and 4,410 septic patients, demonstrated that SIC was non-statistically associated with increased in-hospital mortality, compared to non-SIC (RR 1.28, [0.96-1.71]; p = 0.09), but the association was statistically significant in patients with the hospital stay lengths longer than 10 days (RR 1.40, [1.02-1.93]; p = 0.04). Besides, SIC was significantly associated with a higher risk of 1-month mortality (RR 1.47, [1.17-1.86]; p < 0.01). Among SIC patients, right ventricular dysfunction was significantly associated with increased 1-month mortality (RR 1.72, [1.27-2.34]; p < 0.01), while left ventricular dysfunction was not (RR 1.33, [0.87-2.02]; p = 0.18). CONCLUSIONS: With higher in-hospital mortality in those hospitalized longer than 10 days and 1-month mortality, our findings imply that SIC might continue influencing the host's system even after recovery from cardiomyopathy. Besides, right ventricular dysfunction might play a crucial role in SIC-related mortality, and timely biventricular assessment is vital in managing septic patients.

[Relationship Between Social Isolation and Health Behaviors and Ulcer Severity in Diabetic Foot Patients].

Objective: To explore the relationship between social isolation and health behaviors and ulcer severity in patients with diabetic foot. Methods: A cross-sectional study was conducted with 160 patients suffering from type 2 diabetes mellitus combined with diabetic foot. The patients received treatment at the Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University between September 2020 and December 2021. Patient information was collected, including the scores for Lubben Social Network Scale and the Wagner classification of foot ulcers. Analysis was conducted to study the characteristics of the patients' health behaviors, including whether they received information and education on diabetic foot, whether there were delays in their attempt to access medical service, the frequency of foot examinations, etc. In addition, patient demographic data were collected, including sex, age, education, and employment status. According to their scores for Lubben Social Network Scale, the patients were divided into a social isolation group ( n=60) and a non-social-isolation group ( n=100). The severity of the foot ulcers and the health behaviors of the two groups were compared to identify differences. Results: The findings suggest that, compared with the non-social-isolation group, the social isolation group had a higher proportion of diabetic foot patients with Wagner grade 3-5 diabetic foot ulcers ( P<0.05). Analysis of the health behaviors showed that the social isolation group had a higher proportion of diabetes foot patients who had never undergone examination of their feet and those who had delayed attempts to access medical service for their condition ( P<0.05). There were no significant differences between the two groups in terms of whether the patients had received information and education concerning diabetic foot, causes of foot injury, self-treatment of wounds, smoking, and drinking. Correlational analysis suggested that the scores of Lubben Social Network Scale were negatively correlated with the delayed attempts to access medical service ( r=-0.353, P=0.001), that is, the higher the degree of social isolation, the longer the delay in patients' attempt to access medical service for their diabetic foot. Conclusions: Social isolation is correlated to health behaviors and ulcer severity in patients with diabetic foot. Giving more attention to the problem of social isolation of diabetic foot patients and increasing their ties with the social environment and the members of their social network may have a positive effect on improving the delays in diabetic foot patients' attempt to access medical service, which is particularly important for follow-up treatment.

Study of optical-based speech acquisition system using vibration signals from speakers' medical masks.

Medical masks have become necessary of late because of the COVID-19 outbreak; however, they tend to attenuate the energy of speech signals and affect speech quality. Therefore, this study proposes an optical-based microphone approach to obtain speech signals from speakers' medical masks. Experimental results showed that the optical-based microphone approach achieved better performance (85.61%) than the two baseline approaches, namely, omnidirectional (24.17%) and directional microphones (31.65%), in the case of long-distance speech and background noise. The results suggest that the optical-based microphone method is a promising approach for acquiring speech from a medical mask.

Third Asia-Pacific consensus recommendations on colorectal cancer screening and postpolypectomy surveillance.

The Asia-Pacific region has the largest number of cases of colorectal cancer (CRC) and one of the highest levels of mortality due to this condition in the world. Since the publishing of two consensus recommendations in 2008 and 2015, significant advancements have been made in our knowledge of epidemiology, pathology and the natural history of the adenoma-carcinoma progression. Based on the most updated epidemiological and clinical studies in this region, considering literature from international studies, and adopting the modified Delphi process, the Asia-Pacific Working Group on Colorectal Cancer Screening has updated and revised their recommendations on (1) screening methods and preferred strategies; (2) age for starting and terminating screening for CRC; (3) screening for individuals with a family history of CRC or advanced adenoma; (4) surveillance for those with adenomas; (5) screening and surveillance for sessile serrated lesions and (6) quality assurance of screening programmes. Thirteen countries/regions in the Asia-Pacific region were represented in this exercise. International advisors from North America and Europe were invited to participate.

Clinical efficacy of SGLT2 inhibitors with different SGLT1/SGLT2 selectivity in cardiovascular outcomes among patients with and without heart failure: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Some sodium-glucose co-transporter-2 (SGLT2) inhibitors showed benefits on heart failure (HF), but different SGLT2/SGLT1 selectivity might influence the treatment effect. This study aimed to meta-analyze the treatment effects of SGLT2 inhibitors and the diversity of receptor selectivity for patients with and without HF. METHODS: Randomized controlled trials were searched in PubMed, Embase, Cochrane databases and ClinicalTrials.gov registry from inception to October 2020. The interest outcomes were analyzed with random-effects models and presented with a risk ratio (RR) and 95% confidence interval (CI). Subgroup analyses examined the treatment effects among SGLT2 inhibitors with different SGLT2/SGLT1 selectivity. RESULTS: The final analyses included 10 trials and 52,607 patients. The RR of total cardiovascular (CV) death or hospitalization for HF (HHF) between SGLT2 inhibitors and placebo was 0.79 (95% CI 0.74-0.84, I2 = 31%). With SGLT2 inhibitors, HF patients had reduced mortality risks (RR 0.89, 95% CI 0.80-0.99, I2 = 0), and non-HF patients had lower risks of major adverse CV events (RR 0.92, 95% CI 0.85-0.99, I2 = 0). The risk reduction of HHF was consistent in groups of HF (RR 0.72, 95% CI 0.64-0.80, I2 = 8%) and non-HF (RR 0.74, 95% CI 0.61-0.89, I2 = 0), but the effect of the low SGLT2/SGLT1 selectivity inhibitor was insignificant in non-HF patients. CONCLUSION: The efficacy of SGLT2 inhibitors on risk reduction of total CV death or HHF is consistent with the previous studies. The regimen is beneficial for reducing mortality in patients with HF and major adverse CV events in those without HF. Different SGLT2/SGLT1 selectivity may differ in the treatment effects in patients with and without HF.

Risk of colonoscopy-related complications in a fecal immunochemical test-based population colorectal cancer screening program.

BACKGROUND: The likelihood of advanced or synchronous neoplasms is significantly higher in fecal immunochemical test (FIT)-positive individuals than in the general population. The magnitude of the colonoscopy-related complication rate in FIT-positive individuals remains unknown. This study aimed to elucidate the colonoscopy-related complication rate after a positive FIT result and compare it with the rate when colonoscopy was performed for other purposes. METHODS: Information regarding colonoscopy-related severe complications after a positive FIT result (FIT-colonoscopy) and ordinary colonoscopy during 2010-2014 was collected from the Taiwanese Colorectal Cancer Screening Program Database and National Health Insurance Research Database. Severe complications included significant bleeding, perforation, and cardiopulmonary events ≤ 14 days after colonoscopy. The number of events per 1000 procedures was used to quantify complication rates. Multivariate analysis was conducted to assess the association of various factors with severe complications associated with FIT-colonoscopy compared with ordinary colonoscopy. RESULTS: 319 114 FIT-colonoscopies (214 955 patients) were identified, 51 242 (16.1 %) of which included biopsy and 94 172 (29.5 %) included polypectomy. Overall, 2125 significant bleedings (6.7 ‰) and 277 perforations (0.9 ‰) occurred ≤ 14 days after FIT-colonoscopy. Polypectomy, antiplatelet use, and anticoagulant use were associated with higher risk of complications (adjusted odds ratio [aOR] 4.41, 95 % confidence interval [CI] 4.05-4.81); aOR 1.35, 95 %CI 1.12-1.53; aOR 1.88, 95 %CI 0.61-5.84, respectively). Compared with ordinary colonoscopy, FIT-colonoscopy involved significantly higher risk of significant bleeding (aOR 3.10, 95 %CI 2.90-3.32). CONCLUSIONS: FIT-colonoscopy was associated with a more than two-fold risk of significant bleeding, especially when polypectomy was performed.

Optimal Lymph Node Yield for Survival Prediction in Rectal Cancer Patients After Neoadjuvant Therapy.

PURPOSE: A lymph node (LN) yield ≥12 is required to for accurate determination of nodal status for colorectal cancer but cannot always be achieved after neoadjuvant therapy. This study aims to determine the difference in LN yield from rectal cancer patients treated with and without neoadjuvant therapy and the effects of specific LN yields on survival. PATIENTS AND METHODS: The study cohort included a total of 4344 rectal cancer patients treated between January 2007 and December 2015, 2260 (52.03%) of whom received neoadjuvant therapy. Data were retrieved from the Taiwan nationwide cancer registry database. The minimum acceptable LN yield below 12 was investigated using the maximum area under the ROC curve. RESULTS: The median LN yield was 12 (8-17) for patients who received neoadjuvant therapy and 17 (13-24) for those who did not. The recommended LN yield ≥12 was achieved in 82.73% of patients without and 57.96% of those with neoadjuvant therapy (p < 0.0001). Patients with LN yield ≥12 had a higher OS probability than did those with LN <12 (OR, 1.33; 95% CI, 1.06-1.66; p = 0.0124). However, the predictive accuracy for survival was greater for LN yield ≥10 (AUC, 0.7767) than cut-offs of 12, 8, or 6, especially in patients with pathologically-negative nodes (AUC, 0.7660). CONCLUSION: Neoadjuvant therapy significantly reduces the LN yield in subsequent surgery. A lower yield (LN ≥ 10) may be adequate for nodal evaluation in rectal cancer patients after neoadjuvant therapy.

Quantification of the Endogenous Adduction Level on Hemoglobin and Correlation with Albumin Adduction via Proteomics: Multiple Exposure Markers of Catechol Estrogen.

Catechol estrogens (CEs) are genotoxic metabolites whose detection is challenging due to their low concentrations and high variability in the blood. By intact protein and free CE measurement of the spiked hemolysate, endogenous CEs were revealed to mainly (>99%) exist as hemoglobin (Hb) adducts in red blood cells. In order to detect endogenous CE-Hb adducts, we developed a two-step method that involved protein precipitation and solid phase extraction to purify Hb from red blood cells, and the method was coupled with proteomics using liquid chromatography-tandem mass spectrometry. Using bottom-up proteomics and standard additions, we identified C93 and C112 of Hb-ß as the main adduction sites of Hb, and this accounted for CE-induced oxidization of adducted peptides by sample preparation. The non-adducted, adducted, and oxidized tryptic peptides that covered the same Hb-ß sequences were targeted by parallel reaction monitoring to determine the adduction level in red blood cells. A quantification limit (S/N < 8) below the endogenous CE-Hb adduction level with relative standard errors that ranged from 5 to 22% was achieved and applied to clinical samples. The human serum albumin (HSA) adduction levels from the same patient were also determined using a previously developed method (Anal. Chem.2019,91, 15922-15931). A positive correlation (R2 = 0.673) between the CE-HSA and CE-Hb adduction level was obtained from all clinical samples, and both levels were significantly (p < 0.005) higher for patients with breast cancer compared to healthy controls. However, double indexes derived from the red blood cell and the serum, respectively, provide higher precision and confidence in predicting cancer risk than the single index. This study reported an efficient sample preparation for proteomics-based Hb adducts and revealed the potential of using multiple blood proteins for developing more reliable and specific markers based on protein adductomics.

Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice.

Compelling evidence supports vascular contributions to cognitive impairment and dementia (VCID) including Alzheimer's disease (AD), but the underlying pathogenic mechanisms and treatments are not fully understood. Cis P-tau is an early driver of neurodegeneration resulting from traumatic brain injury, but its role in VCID remains unclear. Here, we found robust cis P-tau despite no tau tangles in patients with VCID and in mice modeling key aspects of clinical VCID, likely because of the inhibition of its isomerase Pin1 by DAPK1. Elimination of cis P-tau in VCID mice using cis-targeted immunotherapy, brain-specific Pin1 overexpression, or DAPK1 knockout effectively rescues VCID-like neurodegeneration and cognitive impairment in executive function. Cis mAb also prevents and ameliorates progression of AD-like neurodegeneration and memory loss in mice. Furthermore, single-cell RNA sequencing revealed that young VCID mice display diverse cortical cell type-specific transcriptomic changes resembling old patients with AD, and the vast majority of these global changes were recovered by cis-targeted immunotherapy. Moreover, purified soluble cis P-tau was sufficient to induce progressive neurodegeneration and brain dysfunction by causing axonopathy and conserved transcriptomic signature found in VCID mice and patients with AD with early pathology. Thus, cis P-tau might play a major role in mediating VCID and AD, and antibody targeting it may be useful for early diagnosis, prevention, and treatment of cognitive impairment and dementia after neurovascular insults and in AD.

Study on proanthocyanidins crosslinked collagen membrane for guided bone tissue regeneration.

The goal of this study is to understand the ability of a newly developed barrier membrane to enhance bone tissue regeneration. Here in this study we present the in vitro characterization of the barrier membrane made from type I collagen and crosslinked by oligomeric proanthocyanidins (OPCs). The effects of the membrane (P-C film) on cell cycle, proliferation, alkaline phosphatase activity, and mineralization were evaluated using the human osteoblast cell line MG-63, while the barrier ability was examined using MG-63 cells, as well as the human skin fibroblast cell line WS-1. The pore size is one of the factors that plays a key role in tissue regeneration, therefore, we evaluated the pore size of the membrane using a capillary flow porometer. Our results showed that the mean pore size of the P-C film was approximately 7-9 µm, the size known to inhibit cell migration across the membrane. The P-C film also demonstrated excellent cell viability and good biocompatibility, since the cell number increased with time, with MG-63 cells proliferating faster on the P-C film than in the cell culture flask. Furthermore, the P-C film promoted osteoblast differentiation, resulting in higher alkaline phosphatase activity and mineralization. Therefore, our results suggest that this P-C film has a great potential to be used in guided bone regeneration during periodontal regeneration and bone tissue engineering.

Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial.

BACKGROUND: To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1-3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC). METHODS: This phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local-regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS). RESULTS: Total nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months. CONCLUSIONS: Axitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort. Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461.

Visfatin increases ICAM-1 expression and monocyte adhesion in human osteoarthritis synovial fibroblasts by reducing miR-320a expression.

Pathophysiological events that modulate the progression of structural changes in osteoarthritis (OA) include monocyte adhesion and infiltration, and synovial inflammation. In particular, the adhesion protein intercellular adhesion molecule type 1 (ICAM-1) promotes monocyte recruitment into the synovial tissue. Visfatin is an adipocyte hormone that promotes the release of inflammatory cytokines during OA progression. We report that visfatin enhances ICAM-1 expression in human OA synovial fibroblasts (OASFs) and facilitates the adhesion of monocytes with OASFs. AMPK and p38 inhibitors, as well as their respective siRNAs, attenuated the effects of visfatin upon ICAM-1 synthesis and monocyte adhesion. We also describe how miR-320a negatively regulates visfatin-induced promotion of ICAM-1 expression and monocyte adhesion. We detail how visfatin affects ICAM-1 expression and monocyte adhesion with OASFs by inhibiting miR-320a synthesis via the AMPK and p38 signaling pathways.

Protective effects of diallyl trisulfide (DATS) against doxorubicin-induced inflammation and oxidative stress in the brain of rats.

Doxorubicin (DOX) is a widely used antitumor drug that causes severe neurotoxicity in patients. Diallyl trisulfide (DATS) is an organosulfur compound with established potent antioxidant and anti-inflammatory properties. Herein, we investigated the neuroprotective efficacy of DATS in preventing DOX-induced neurotoxicity in a rat model. Specifically, DATS (40 mg/kg) was administered to rats 24 h after DOX treatment, once a week for 8 weeks. Our results showed that DATS treatment led to a decrease in plasma levels of tumor necrosis factor-alpha (TNF-α) induced by DOX. DATS restored cerebral cortex and hippocampus histopathological architecture and neuronal loss. Immunohistochemical staining indicated that DATS decreased the expression of glial fibrillar acidic protein (GFAP) in DOX treated rats. Components of stress-related inflammatory proteins (TNF-α, phospho nuclear factor kappa B (NF-κB), inducible nitricoxide synthase (iNOS) and cyclooxygenase-2 (COX-2)) were all significantly increased in the DOX group, in comparison with the control group, whereas they were decreased after DATS treatment. In addition, the mRNA of antioxidant enzymes (superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1, 4 (GPx1 and GPx4)) and antioxidant proteins (heme oxygenase-1 (HO-1), superoxide dismutase 1, 2 (SOD1 and SOD2), Γ-glutamylcysteine synthase (Γ-GCSc)) were markedly increased in DOX group compared with the control group, which were significantly attenuated by DATS treatment. The upregulation of antioxidants enzymes in DOX group was probably a compensatory effect against elevated oxidative stress induced by DOX. DATS treatment could ameliorate this oxidative stress in brain. Our results suggested that DATS has potential clinical applications in the prevention of DOX-induced neurotoxicity by ameliorating inflammatory insults and oxidative stress.

Reversible Underwater Adhesion: The Unique C-shaped Suckers of Net-winged Midge Larvae (Blepharicera sp.).

Aquatic insects living in fast-flowing streams have developed various types of attachment systems to resist being carried away by strong currents. Combinations of various attachment devices offer aquatic insects advantages in underwater adhesion on substrates with different surface properties. In this study, the net-winged midge (Blepharicera sp.) larvae were investigated to understand micro-/nano-structural attachment mechanisms. The hierarchical structure of insect adhesive surfaces was characterized using Optical Microscopy (OM), Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). Centrifugal measurements were also conducted to measure the critical rotational velocity at which the larvae of Blepharicera sp. can adhere to substrates with varying roughness. Commercial suckers require smooth substrate surface to maintain a pressure that is lower than the surrounding pressure for adhesion under the sucker cup while the suckers of net-winged midge larvae possess hierarchical micro-/nano-structures, which attach closely to rough surfaces underwater. Furthermore, the functions of microstructures observed on the sucker, including wrinkled surface, inward setae, outer fibers, and nick were explored and may contribute to underwater adhesion. The aligned C-shaped suckers can attach and detach effectively by closing or opening the gap. The unique microstructure and adhesion capability of such suckers could shed light on the design and synthesis of novel bio-inspired devices for reversible underwater adhesion.

Targeting Endogenous Adduction Level of Serum Albumin by Parallel Reaction Monitoring via Standard Additions and Intact Protein Measurement: Biological Dosimetry of Catechol Estrogens.

Abundant blood proteins adducted by active electrophiles are excellent markers to predict the risk of electrophile-induced toxicity. However, detecting endogenously adducted proteins by bottom-up selective (or parallel) reaction monitoring (SRM/PRM) is challenging because of the high variability in sample preparation and detection as well as low adduction levels. Here, we reported a new approach in developing PRM methods by combining intact protein measurement with standard additions to target optimal conditions for detecting catechol estrogens (CEs)-adducted human serum albumin (HSA). Blood serum was added with multiple amounts of CEs to obtain serum standards. Intact protein measurement revealed two linear ranges of adduction levels (adducted-CE/HSA): 0.34-0.42 (R2 > 0.94) and 0.81-8.54 (R2 > 0.96) against the amount of added CEs, respectively. Six adduction sites were identified by trypsin (K20, C34, K73, K281, H338, K378) or chymotrypsin (K20, C34, K378) digestion. PRM methods targeting all adducted/nonadducted peptide pairs based on chymotrypsin or trypsin digestion were developed, and the data were compared with those obtained by intact protein measurement. Correlation plots indicated that chymotrypsin-PRM leads to poor sensitivity and largely underestimated protein adduction levels. Trypsin-PRM leads to sensitive and highly correlated (R2 > 0.91) protein adduction levels with a detection limit below the endogenous level and relative standard deviation <25%. As a proof of concept, clinical serum samples were examined by trypsin-PRM, and a slightly higher adduction level was observed for the obesity group when compared with the healthy group. This is the first report on determining adduction levels of blood proteins for long-term exposure to CEs. The standard addition approach can be generally applied to protein adductomics with resolvable mass increments by intact protein measurement to accelerate the development of bottom-up methods close to the inherent limit.

Copper-induced synthesis of palladium/copper popcorn nanoparticles as sensors for differential pulse voltammetric determination of dopamine.

Popcorn nanoparticles (pop-NPs) consisting of a Pd/Cu alloy were synthesized using a seed-mediated growth method. The Cu and Pd atoms were co-deposited on a cubic Pd seed to reduce the energy of fault stacking. The same synthesis method with a reduced volume of the Cu(II) salt leads to Pd/Cu alloy nanoparticles with branches (br-NPs). Large Pd nanocubes (Pd NCs) were prepared via epitaxial deposition and using tetrachloropalladate (PdCl42-) only. The high-resolution TEM analysis results show the pop-NPs and br-NPs to be single crystals with [Formula: see text] and [Formula: see text] planes, respectively. The results of X-ray photoelectron spectroscopy and cyclic voltammetry measurements corroborated that Pd is enriched on both surfaces. The materials were placed on a glassy carbon electrode to obtain a differential pulse voltammetric sensor for dopamine (DA). The electrochemical sensitivities are (a) 1.55 µA µM-1 cm-2 for the Pd/Cu pop-NP sensor in its linear range (15-300 µM), (b) 1.17 µA µM-1 cm-2 for the br-NP sensor in the linear range (15-200 µM), and (c) 0.97 µA µM-1 cm-2 for the Pd NC sensor in its linear range (15-100 µM). The best working potentials are near 0.10 V (vs. SCE) for all three sensors. The pop-NP-based sensor performs particularly well due to it selectivity over ascorbic and uric acid. Graphical abstract Pd/Cu popcorn nanoparticles (pop-NPs), nanoparticles with branches (br-NPs), and Pd nanocubes (NCs) were synthesized using seed-mediated growth methods and directly used on glassy carbon electrodes for non-enzymatic sensing of dopamine.

BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress.

The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin-proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1α-XBP1s-ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1α inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.