Nutrient deficiency patterns and all-cause and cardiovascular mortality in older adults with hypertension: a latent class analysis.

BACKGROUND: Previous researches examining the impact of dietary nutrition on mortality risk have mainly focused on individual nutrients, however the interaction of these nutrients has not been considered. The purpose of this study was to identify of nutrient deficiencies patterns and analyze their potential impact on mortality risk in older adults with hypertension. METHODS: We included participants from the National Health and Nutrition Examination Survey (NHANES) study. The latent class analysis (LCA) was applied to uncover specific malnutrition profiles within the sample. Risk of the end points across the phenogroups was compared using Kaplan-Meier analysis and Cox proportional hazard regression model. Multinomial logistic regression was used to determine the influencing factors of specific malnutrition profiles. RESULTS: A total of 6924 participants aged 60 years or older with hypertension from NHANES 2003-2014 was followed until December 31, 2019 with a median follow-up of 8.7 years. Various nutrients included vitamin A, vitamin B1, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, fiber, folate, calcium, magnesium, zinc, copper, iron, and selenium, and LCA revealed 4 classes of malnutrition. Regarding all-cause mortality, "Nutrient Deprived" group showed the strongest hazard ratio (1.42 from 1.19 to 1.70) compared with "Adequate Nutrient" group, followed by "Inadequate Nutrient" group (1.29 from 1.10 to 1.50), and "Low Fiber, Magnesium, and Vit E" group (1.17 from 1.02 to 1.35). For cardiovascular mortality, "Nutrient Deprived" group showed the strongest hazard ratio (1.61 from 1.19 to 2.16) compared with "Adequate Nutrient" group, followed by "Low Fiber, Magnesium, and Vit E" group (1.51 from 1.04 to 2.20), and "Inadequate Nutrient" group (1.37 from 1.03 to 1.83). CONCLUSIONS: The study revealed a significant association between nutrients deficiency patterns and the risk of all-cause and cardiovascular mortality in older adults with hypertension. The findings suggested that nutrients deficiency pattern may be an important risk factor for mortality in older adults with hypertension.

Toxicity Characterization of Environment-Related Pollutants Using a Biospectroscopy-Bioreporter-Coupling Approach: Potential for Real-World Toxicity Determination and Source Apportionment of Multiple Pollutants.

Exposure to environmental pollutants occurs ubiquitously and poses many risks to human health and the ecosystem. Although many analytical methods have been developed to assess such jeopardies, the circumstances applying these means are restricted to linking the toxicities to compositions in the pollutant mixtures. The present study proposes a novel analytical approach, namely, biospectroscopy-bioreporter-coupling (BBC), to quantify and apportion the toxicities of metal ions and organic pollutants. Using a toxicity bioreporter ADPWH_recA and Raman spectroscopy, both bioluminescent signals and spectral alterations had similar dosage- and time-response behavior to the toxic compounds, validating the possibility of coupling these two methods from practical aspects. Raman spectral alterations successfully distinguished the biomarkers for different toxicity mechanisms of individual pollutants, such as ring breathing mode of DNA/RNA bases (1373 cm-1) by Cr, reactive oxygen species-induced peaks of proteins (1243 cm-1), collagen (813 cm-1), and lipids (1255 cm-1) by most metal ions, and indicative fingerprints of organic toxins. The support vector machine model had a satisfactory performance in distinguishing and apportioning toxicities of individual toxins from all input data, achieving a sensitivity of 88.54% and a specificity of 97.80%. This work set a preliminary database for Raman spectral alterations of whole-cell bioreporter response to multiple pollutants. It proved the state-of-the-art concept that the BBC approach is feasible to rapidly quantify and precisely apportion toxicities of numerous pollutant mixtures.

Symmetrical dual-sideband oppositely chirped differential FMCW LiDAR.

A differential FMCW LiDAR for high-precision distance measurements of remote non-stationary targets is proposed and demonstrated experimentally. The required positive and negative symmetrically oppositely chirped laser beams are generated synchronously through a fixed-frequency laser by employing externally unified broadband optical phase modulation and symmetrical dual-sideband optical filtering. After coaxial transmission and reception, orthogonally polarized optical beat signals containing target distance and vector velocity data are de-chirped separately by optical in-phase and quadrature demodulations and then synchronously received by four-channel photoelectric balance detectors. After differential processing of the received beat signals and a fast Fourier transform, it is possible to implement real-time simultaneous range and vector velocity measurements. The inherent symmetrically oppositely chirped optical frequency make it possible to measure the target distance immune to the internal random phase noise introduced by the spectral linewidth of the frequency-swept laser and the external random phase noise introduced by atmospheric turbulence, speckle, and vibration. Meanwhile, the measurement of the target velocity is immune to the nonlinearity of the frequency-swept laser. These results encourage an approach to overcome the barriers of coherence length, nonlinearity, and external noise, and implement simultaneous real-time ranging and velocimetry of long-range, rapid-moving targets.

Discovery of small molecule ß-catenin suppressors that enhance immunotherapy.

Small molecules directly downregulating ß-catenin could potentially offer a more effective therapeutic approach for combating against cancer stem cells, as compared to targeting the downstream components of the Wnt/ß-catenin pathway. The challenge, however, lies in the fact that very few ß-catenin suppressors have proven clinically effective, leaving a significant gap in medical solutions. Given that E-cadherin has a natural affinity for ß-catenin, it stands to reason that agents designed to increase E-cadherin expression might provide an alternative method of regulating ß-catenin levels. In this study, we report our discovery of DSS-C12 and DSS-B8, specific ester-based drugs derived from Dan-Shen-Su (DSS) extracted from the herb Salvia miltiorrhiza. Remarkably, these compounds display a potent ability to downregulate ß-catenin, while also improving overall survival in post-surgery mice. Additionally, when these drugs are used in combination with PD-L1 checkpoint blockade, they stimulate enhanced systemic immune responses leading to significant suppression of primary tumor growth. In-depth mechanistic studies revealed that DSS-B8 functions as a vitamin D receptor agonist without inducing hypercalcemic effects. Collectively, our findings indicate that DSS-derived small molecules have considerable potential as clinically viable therapeutic strategies for ß-catenin deactivation.

Removal of pollutants and accumulation of high-value cell inclusions in a batch reactor containing Rhodopseudomonas for treating real heavy oil refinery wastewater.

Treating wastewater using purple non-sulfur bacteria (PNSB) is an environmentally friendly technique that can simultaneously remove pollutants and lead to the accumulation of high-value cell inclusions. However, no PNSB system for treating heavy oil refinery wastewater (HORW) and recovering high-value cell inclusions has yet been developed. In this study, five batch PNSB systems dominated by Rhodopseudomonas were used to treat real HORW for 186 d. The effects of using different hydraulic retention times (HRT), sludge retention times (SRT), trace element solutions, phosphate loads, and influent loads were investigated, and the bacteriochlorophyll, carotenoid, and coenzyme Q10 concentrations were determined. The community structure and quantity of Rhodopseudomonas in the systems were determined using a high-sequencing technique and quantitative polymerase chain reaction technique. The long-term results indicated that phosphate was the limiting factor for treating HORW in the PNSB reactor. The soluble chemical oxygen demand (SCOD) removal rates were 67.03% and 85.26% without and with phosphate added, respectively, and the NH4+-N removal rates were 32.18% and 89.22%, respectively. The NO3--N concentration in the effluent was stable at 0-3 mg/L with or without phosphate added. Adding phosphate increased the Rhodopseudomonas relative abundance and number by 13.21% and 41.61%, respectively, to 57.35% and 8.52 × 106 gene copies/µL, respectively. The SRT was the limiting factor for SCOD removal, and the bacteria concentration was the limiting factor for nitrogen removal. Once the inflow load had been increased, the total nitrogen (TN) removal rate increased as the HRT increased. Maximum TN removal rates of 64.46%, 68.06%, 73.89%, 82.15%, and 89.73% were found at HRT of 7, 10, 13, 16, and 19 d, respectively. The highest bacteriochlorophyll, carotenoid, and coenzyme Q10 concentrations were 2.92, 4.99, and 4.53 mg/L, respectively. This study provided a simple and efficient method for treating HORW and reutilizing resources, providing theoretical support and parameter guidance for the application of Rhodopseudomonas in treating HORW.

Amoxicillin degradation in the heat, light, or heterogeneous catalyst activated persulfate systems: Comparison of kinetics, mechanisms and toxicities.

Various activated persulfate (PS) technologies have been investigated and implemented to eliminate antibiotic contaminants from water. The investigation and evaluation of different activation systems are essential for the application of PS techniques. The degradation of amoxicillin (AMX) by heat, light, or heterogeneous catalyst of Fe-AC composite activated PS was investigated, and the kinetics, mechanisms and toxicities were compared in this work. The apparent activation energy of the Fe-AC system was lower than that of the heat system. Hydroxyl and sulfate radicals were demonstrated by electron paramagnetic resonance (EPR) spectroscopy and quenching tests. There were 22, 21 and 13 types of degradation intermediates detected in heat, light and Fe-AC system, respectively. Six pathways of AMX degradation were proposed and compared in the three activated PS systems. The toxicity prediction of degradation intermediates under different treatment processes was estimated by ecological structure-activity relationship model and toxicity estimation software tool. The genotoxicity of the AMX degradation solution was tested by Acinetobacter baylyi ADP1_recA, which indicated that the AMX solution after treatment in the Fe-AC system had almost no genotoxicity. The Fe-AC/PS system shows apparent advantages over the heat or light activated PS system in most cases, demonstrating that the Fe-AC/PS system is suitable for AMX-contaminated remediation in aqueous solution.

Low Ruthenium Content Confined on Boron Carbon Nitride as an Efficient and Stable Electrocatalyst for Acidic Oxygen Evolution Reaction.

To date, only a few noble metal oxides exhibit the required efficiency and stability as oxygen evolution reaction (OER) catalysts under the acidic, high-voltage conditions that exist during proton exchange membrane water electrolysis (PEMWE). The high cost and scarcity of these catalysts hinder the large-scale application of PEMWE. Here, we report a novel OER electrocatalyst for OER comprised of uniformly dispersed Ru clusters confined on boron carbon nitride (BCN) support. Compared to RuO2 , our BCN-supported catalyst shows enhanced charge transfer. It displays a low overpotential of 164 mV at a current density of 10 mA cm-2 , suggesting its excellent OER catalytic activity. This catalyst was able to operate continuously for over 12 h under acidic conditions, whereas RuO2 without any support fails in 1 h. Density functional theory (DFT) calculations confirm that the interaction between the N on BCN support and Ru clusters changes the adsorption capacity and reduces the OER energy barrier, which increases the electrocatalytic activity of Ru.

Online Pharmacy Accessibility of Imatinib, An Oral Chemotherapy Medication.

BACKGROUND: Since prices of imatinib (Gleevec) remain high, patients on oral chemotherapy are looking for alternative methods to access this life-saving medication. We assessed the accessibility of imatinib through online pharmacies and analyzed each website for medication safety, price, and marketing tactics. METHODS: We searched the term "buy imatinib online" using 4 commonly used internet search engines (Google, Bing, Yahoo!, and DuckDuckGo) and screened web pages displayed in the first 10 pages. Websites were included if they were published in English, sold imatinib, were free to access, and offered shipping in the United States. Websites were classified using LegitScript's categorization as "certified," "unclassified," "unapproved," or "rogue." We analyzed information on websites' patient safety characteristics, marketing techniques, pricing, domain registration information, and IP addresses. RESULTS: Of the 44 online pharmacies identified, only 3 (7%) were certified, and the remainder were classified as rogue (52%; n=23), unapproved (30%; n=13), or unclassified (11%; n=5). Thirteen online pharmacies (30%; 9 rogue, 4 unclassified) sold imatinib without a prescription. Nearly one-quarter (n=10) of online pharmacies selling imatinib did not include drug-related warnings on their websites, and nearly half (n=21) did not limit the purchasable quantity. More than three-quarters (n=34) of online pharmacies selling imatinib did not offer pharmacist consultations, even though nearly all websites extended offers to speak with sales associates (91%; n=40). Most online pharmacies selling imatinib claimed price discounts (95%; n=42), but fewer provided bulk discounts (23%; n=10) or coupons (34%; n=15). One-third of rogue pharmacies selling imatinib (n=7) claimed to be registered or accredited on their websites. CONCLUSIONS: The lack of safety measures taken by illegitimate online pharmacies endangers patient safety because they allow patients to purchase imatinib without appropriate evaluation for response, drug interactions, and adverse effects. Healthcare providers need to be aware of this practice and should assure patient access to imatinib through safe and legitimate pharmacies.

Seasonal Variations in the Characteristics of Microbial Community Structure and Diversity in Atmospheric Particulate Matter from Clean Days and Smoggy Days in Beijing.

Microorganisms are an important part of atmospheric particulate matter and are closely related to human health. In this paper, the variations in the characteristics of the chemical components and bacterial communities in PM10 and PM2.5 grouped according to season, pollution degree, particle size, and winter heating stage were studied. The influence of environmental factors on community structure was also analyzed. The results showed that seasonal variations were significant. NO3- contributed the most to the formation of particulate matter in spring and winter, while SO42- contributed the most in summer and autumn. The community structures in summer and autumn were similar, while the community structure in spring was significantly different. The dominant phyla were similar among seasons, but their proportions were different. The dominant genera were no-rank_c_Cyanobacteria, Acidovorax, Escherichia-Shigella and Sphingomonas in spring; Massilia, Bacillus, Acinetobacter, Rhodococcus, and Brevibacillus in summer and autumn; and Rhodococcus in winter. The atmospheric microorganisms in Beijing mainly came from soil, water, and plants. The few pathogens detected were mainly affected by the microbial source on the sampling day, regardless of pollution level. RDA (redundancy analysis) showed that the bacterial community was positively correlated with the concentration of particulate matter and that the wind speed in spring was positively correlated with NO3- levels, NH4+ levels, temperature, and relative humidity in summer and autumn, but there was no clear consistency among winter samples. This study comprehensively analyzed the variations in the characteristics of the airborne bacterial community in Beijing over one year and provided a reference for understanding the source, mechanism, and assessment of the health effects of different air qualities.

Dietary fiber and prevalence of abdominal aortic calcification in the United States (from the national health and nutrition examination survey data [2013-2014]).

BACKGROUND: Abdominal aortic calcification (AAC) is recognized as a valuable predictor of cardiovascular diseases (CVDs). Dietary fiber is strongly correlated with CVDs. However, the effect of dietary fiber on AAC in the population is not well understood. OBJECTIVE: To assess the relationship between dietary fiber intake and AAC in the US adult population. METHODS: A total of 2671 individuals with both dietary fiber intake and AAC score data were enrolled from the 2013-2014 National Health and Nutrition Examination Survey (NHANES), a cross-sectional health examination in the US. Multinomial logistic regression was used to calculate the odds ratio (OR), with 95% confidence interval (CI). To reveal the relationship between dietary fiber intake and AAC, restricted cubic spline was also applied. RESULTS: Out of the total participants, 241 (9%) had severe AAC and 550 (20%) had mild-moderate AAC. Multinomial logistic regression indicated that higher intake of dietary fiber was associated with lower risk of severe AAC, but not with lower risk of mild-moderate AAC. For every one standard deviation increase (9.4 g/day) in dietary fiber intake, the odds of severe AAC were reduced by 28% [OR 0.72 (95% CI, 0.57-0.90), p = 0.004], after adjusting for confounding factors. Dose-response relationship revealed that dietary fiber intake was negatively correlated with severe AAC (p for linear < 0.001, p for nonlinear = 0.695). CONCLUSIONS: Dietary fiber intake was negatively associated with severe AAC, and showed a dose-response relationship in US adults.

Development, validation, and visualization of a web-based nomogram to predict 5-year mortality risk in older adults with hypertension.

BACKGROUND: Hypertension-related mortality has been increasing in older adults, resulting in serious burden to society and individual. However, how to identify older adults with hypertension at high-risk mortality remains a great challenge. The purpose of this study is to develop and validate the prediction nomogram for 5-year all-cause mortality in older adults with hypertension. METHODS: Data were extracted from National Health and Nutrition Examination Survey (NHANES). We recruited 2691 participants aged 65 years and over with hypertension in the NHANES 1999-2006 cycles (training cohort) and 1737 participants in the NHANES 2007-2010 cycles (validation cohort). The cohorts were selected to provide at least 5 years follow-up for evaluating all-cause mortality by linking National Death Index through December 31, 2015. We developed a web-based dynamic nomogram for predicting 5-year risk of all-cause mortality based on a logistic regression model in training cohort. We conducted internal validation by 1000 bootstrapping resamples and external validation in validation cohort. The discrimination and calibration of nomogram were evaluated using concordance index (C-index) and calibration curves. RESULTS: The final model included eleven independent predictors: age, sex, diabetes, cardiovascular disease, body mass index, smoking, lipid-lowering drugs, systolic blood pressure, hemoglobin, albumin, and blood urea nitrogen. The C-index of model in training and validation cohort were 0.759 (bootstrap-corrected C-index 0.750) and 0.740, respectively. The calibration curves also indicated that the model had satisfactory consistence in two cohorts. A web-based nomogram was established ( https://hrzhang1993.shinyapps.io/dynnomapp ). CONCLUSIONS: The novel developed nomogram is a useful tool to accurately predict 5-year all-cause mortality in older adults with hypertension, and can provide valuable information to make individualized intervention.

Experience-dependent structural plasticity at pre- and postsynaptic sites of layer 2/3 cells in developing visual cortex.

The developing brain can respond quickly to altered sensory experience by circuit reorganization. During a critical period in early life, neurons in the primary visual cortex rapidly lose responsiveness to an occluded eye and come to respond better to the open eye. While physiological and some of the molecular mechanisms of this process have been characterized, its structural basis, except for the well-known changes in the thalamocortical projection, remains obscure. To elucidate the relationship between synaptic remodeling and functional changes during this experience-dependent process, we used 2-photon microscopy to image synaptic structures of sparsely labeled layer 2/3 neurons in the binocular zone of mouse primary visual cortex. Anatomical changes at presynaptic and postsynaptic sites in mice undergoing monocular visual deprivation (MD) were compared to those in control mice with normal visual experience. We found that postsynaptic spines remodeled quickly in response to MD, with neurons more strongly dominated by the deprived eye losing more spines. These postsynaptic changes parallel changes in visual responses during MD and their recovery after restoration of binocular vision. In control animals with normal visual experience, the formation of presynaptic boutons increased during the critical period and then declined. MD affected bouton formation, but with a delay, blocking it after 3 d. These findings reveal intracortical anatomical changes in cellular layers of the cortex that can account for rapid activity-dependent plasticity.

COVID-19 Treatments Sold Online Without Prescription Requirements in the United States: Cross-sectional Study Evaluating Availability, Safety and Marketing of Medications.

BACKGROUND: The COVID-19 pandemic has increased online purchases and heightened interest in existing treatments. Dexamethasone, hydroxychloroquine, and lopinavir-ritonavir have been touted as potential COVID-19 treatments. OBJECTIVE: This study assessed the availability of 3 potential COVID-19 treatments online and evaluated the safety and marketing characteristics of websites selling these products during the pandemic. METHODS: A cross-sectional study was conducted in the months of June 2020 to August 2020, by searching the first 100 results on Google, Bing, and Yahoo! mimicking a US consumer. Unique websites were included if they sold targeted medicines, were in English, offered US shipping, and were free to access. Identified online pharmacies were categorized as rogue, unclassified, or legitimate based on LegitScript classifications. Patient safety characteristics, marketing techniques, price, legitimacy, IP addresses, and COVID-19 mentions were recorded. RESULTS: We found 117 websites: 30 selling dexamethasone (19/30, 63% rogue), 39 selling hydroxychloroquine (22/39, 56% rogue), and 48 selling lopinavir-ritonavir (33/48, 69% rogue). This included 89 unique online pharmacies: 70% were rogue (n=62), 22% were unapproved (n=20), and 8% were considered legitimate (n=7). Prescriptions were not required among 100% (19/19), 61% (20/33), and 50% (11/22) of rogue websites selling dexamethasone, lopinavir-ritonavir, and hydroxychloroquine, respectively. Overall, only 32% (24/74) of rogue websites required prescriptions to buy these medications compared with 94% (31/33) of unapproved and 100% (10/10) of legitimate websites (P<.001). Rogue sites rarely offered pharmacist counseling (1/33, 3% for lopinavir-ritonavir to 2/22, 9% for hydroxychloroquine). Drug warnings were unavailable in 86% (6/7) of unapproved dexamethasone sites. It was difficult to distinguish between rogue, unapproved, and legitimate online pharmacies solely based on website marketing characteristics. Illegitimate pharmacies were more likely to offer bulk discounts and claim price discounts, yet dexamethasone and hydroxychloroquine were more expensive online. An inexpensive generic version of lopinavir-ritonavir that is not authorized for use in the United States was available online offering US shipping. Some websites claimed hydroxychloroquine and lopinavir-ritonavir were effective COVID-19 treatments despite lack of scientific evidence. In comparing IP addresses to locations claimed on the websites, only 8.5% (7/82) matched their claimed locations. CONCLUSIONS: The lack of safety measures by illegitimate online pharmacies endanger patients, facilitating access to medications without appropriate oversight by health care providers to monitor clinical response, drug interactions, and adverse effects. We demonstrated how easy it is to go online to buy medications that are touted to treat COVID-19 even when current clinical evidence does not support their use for self-treatment. We documented that illegitimate online pharmacies sidestep prescription requirements, skirt pharmacist counseling, and make false claims regarding efficacy for COVID-19 treatment. Health care professionals must urgently educate the public of the dangers of purchasing drugs from illegitimate websites and highlight the importance of seeking treatment through authentic avenues of care.

Fast Noninvasive Morphometric Characterization of Free Human Sperms Using Deep Learning.

The selection of high-quality sperms is critical to intracytoplasmic sperm injection, which accounts for 70­80% of in vitro fertilization (IVF) treatments. So far, sperm screening is usually performed manually by clinicians. However, the performance of manual screening is limited in its objectivity, consistency, and efficiency. To overcome these limitations, we have developed a fast and noninvasive three-stage method to characterize morphology of freely swimming human sperms in bright-field microscopy images using deep learning models. Specifically, we use an object detection model to identify sperm heads, a classification model to select in-focus images, and a segmentation model to extract geometry of sperm heads and vacuoles. The models achieve an F1-score of 0.951 in sperm head detection, a z-position estimation error within ±1.5 µm in in-focus image selection, and a Dice score of 0.948 in sperm head segmentation, respectively. Customized lightweight architectures are used for the models to achieve real-time analysis of 200 frames per second. Comprehensive morphological parameters are calculated from sperm head geometry extracted by image segmentation. Overall, our method provides a reliable and efficient tool to assist clinicians in selecting high-quality sperms for successful IVF. It also demonstrates the effectiveness of deep learning in real-time analysis of live bright-field microscopy images.

New insights into metabolomics profile generation in fermented tea: the relevance of bacteria and metabolites in Fuzhuan brick tea.

BACKGROUND: The contribution of bacteria to fermented tea is not clear and the associated research is relatively limited. To reveal the role of microorganisms in fermented tea processing, the microbial community and metabolites of Fuzhuan brick tea (FBT), a Chinese traditional fermented tea, were revealed via high-throughput sequencing and liquid chromatography-mass spectrometry (LC-MS). RESULTS: In FBT, bacterial communities had a higher abundance and diversity, Lactococcus and Bacillus were the main bacteria, and Eurotium was the predominant fungus. The predictive metabolic function indicated the pathways of cellular growth, environmental information, genetics and material metabolism of bacterial communities were abundant, whereas the fungal community predictive metabolic function was almost saprotroph. Using LC-MS, 1143 and 536 metabolites were defined in positive and negative ion mode, respectively. There were essential correlations between bacterial populations and metabolites, such that Bacillus was correlated significantly with 44 metabolites (P < 0.05) and Enterococcus was significantly associated with 15 metabolites (P < 0.05). Some of the main active components were significantly correlated with the bacteria, such as Enterococcus, Lactococcus and Carnobacterium. CONCLUSION: Not only Eurotium, but also the bacteria were involved in the changes of metabolomics profile in fermented FBT. The present study assists in providing new insights into metabolomics profile generation in fermented tea. The present research lays a foundation for controlling the FBT fermentation by artificial inoculation to improve quality. © 2021 Society of Chemical Industry.

A novel nomogram for predicting 3-year mortality in critically ill patients after coronary artery bypass grafting.

BACKGROUND: The long-term outcomes for patients after coronary artery bypass grafting (CABG) have been received more and more concern. The existing prediction models are mostly focused on in-hospital operative mortality after CABG, but there is still little research on long-term mortality prediction model for patients after CABG. OBJECTIVE: To develop and validate a novel nomogram for predicting 3-year mortality in critically ill patients after CABG. METHODS: Data for developing novel predictive model were extracted from Medical Information Mart for Intensive cart III (MIMIC-III), of which 2929 critically ill patients who underwent CABG at the first admission were enrolled. RESULTS: A novel prognostic nomogram for 3-year mortality was constructed with the seven independent prognostic factors, including age, congestive heart failure, white blood cell, creatinine, SpO2, anion gap, and continuous renal replacement treatment derived from the multivariable logistic regression. The nomogram indicated accurate discrimination in primary (AUC: 0.81) and validation cohort (AUC: 0.802), which were better than traditional severity scores. And good consistency between the predictive and observed outcome was showed by the calibration curve for 3-year mortality. The decision curve analysis also showed higher clinical net benefit than traditional severity scores. CONCLUSION: The novel nomogram had well performance to predict 3-year mortality in critically ill patients after CABG. The prediction model provided valuable information for treatment strategy and postdischarge management, which may be helpful in improving the long-term prognosis in critically ill patients after CABG.

Selective Strengthening of Intracortical Excitatory Input Leads to Receptive Field Refinement during Auditory Cortical Development.

In the primary auditory cortex (A1) of rats, refinement of excitatory input to layer (L)4 neurons contributes to the sharpening of their frequency selectivity during postnatal development. L4 neurons receive both feedforward thalamocortical and recurrent intracortical inputs, but how potential developmental changes of each component can account for the sharpening of excitatory input tuning remains unclear. By combining in vivo whole-cell recording and pharmacological silencing of cortical spiking in young rats of both sexes, we examined developmental changes at three hierarchical stages: output of auditory thalamic neurons, thalamocortical input and recurrent excitatory input to an A1 L4 neuron. In the thalamus, the tonotopic map matured with an expanded range of frequency representations, while the frequency tuning of output responses was unchanged. On the other hand, the tuning shape of both thalamocortical and intracortical excitatory inputs to a L4 neuron became sharpened. In particular, the intracortical input became better tuned than thalamocortical excitation. Moreover, the weight of intracortical excitation around the optimal frequency was selectively strengthened, resulting in a dominant role of intracortical excitation in defining the total excitatory input tuning. Our modeling work further demonstrates that the frequency-selective strengthening of local recurrent excitatory connections plays a major role in the refinement of excitatory input tuning of L4 neurons.SIGNIFICANCE STATEMENT During postnatal development, sensory cortex undergoes functional refinement, through which the size of sensory receptive field is reduced. In the rat primary auditory cortex, such refinement in layer (L)4 is mainly attributed to improved selectivity of excitatory input a L4 neuron receives. In this study, we further examined three stages along the hierarchical neural pathway where excitatory input refinement might occur. We found that developmental refinement takes place at both thalamocortical and intracortical circuit levels, but not at the thalamic output level. Together with modeling results, we revealed that the optimal-frequency-selective strengthening of intracortical excitation plays a dominant role in the refinement of excitatory input tuning.

Assembly of Black Phosphorus Nanosheets and MOF to Form Functional Hybrid Thin-Film for Precise Protein Capture, Dual-Signal and Intrinsic Self-Calibration Sensing of Specific Cancer-Derived Exosomes.

As the emerging and noninvasive biomarkers, exosomes play an important role in cancer screening, cancer-related immune response, and the physiological process. The sensitive, specific, and efficient detection of cancer cell-derived exosomes is of significance for early cancer diagnosis of patients. This work developed a novel dual-signal and intrinsic self-calibration aptasensor of exosomes based on a functional hybrid thin-film platform. This platform was constructed via facile assembly of black phosphorus nanosheets (BPNSs) and ferrocene (Fc)-doped metal-organic frameworks (ZIF-67) on indium tin oxide (ITO) slice, followed by combining methylene blue (MB)-labeled single- strand DNA aptamer on ITO slice. The resultant aptamer-BPNSs/Fc/ZIF-67/ITO platform had dual redox-signal responses of MB (labeled on aptamer) and Fc (doped into ZIF-67). In the presence of specific cancer cell-derived exosomes, the redox current of MB regularly reduced and that of Fc (as reference) hardly changed. An intrinsic self-calibration aptasensor was achieved and enabled sensitive detection of exosomes, showing a limit of detection down to 100 particles mL-1. The aptasensor with a capability of precise protein capture can efficiently determine specific cancer cell-derived exosomes in practical human serum and plasma samples from healthy individuals and breast cancer patients. In light of excellent performances, this aptasensor can be expanded to multiple biomarkers from cell line exosomes and is beneficial for exploring advanced techniques for high-performance detection of exosomes derived from different types of cancer cells. This work promotes the development of current techniques for early cancer screening and clinical diagnosis.

Preformulation Studies of a Stable PTEN-PDZ Lipopeptide Able to Cross an In Vitro Blood-Brain-Barrier Model as a Potential Therapy for Alzheimer's Disease.

PURPOSE: Amyloid ß (Aß) drives the accumulation of excess Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) at synapses, inducing synaptic depression and perturbing memory. This recruitment of PTEN to synapses in response to Aß drives its interaction with PSD95/Disc large/Zonula occludens-1 (PDZ) proteins and, indeed, we previously showed that an oligo lipopeptide (PTEN-PDZ) capable of blocking such PTEN:PDZ interactions rescues the synaptic and cognitive deficits in a mouse model of Alzheimer's disease. Hence, the PTEN:PDZ interaction appears to be crucial for Aß-induced synaptic and cognitive impairment. Here we have evaluated the feasibility of using PTEN-PDZ lipopeptides based on the human/mouse PTEN C-terminal sequence, testing their stability in biological fluids, their cytotoxicity, their ability to self-assemble and their in vitro blood-brain barrier (BBB) permeability. Myristoyl or Lauryl tails were added to the peptides to enhance their cell permeability. METHODS: Lipopeptides self assembly was assessed using electron microscopy and the thioflavin T assay. Stability studies in mouse plasma (50%), intestinal washing, brain and liver homogenates as well as permeability studies across an all human 2D blood-brain barrier model prepared with human cerebral endothelial cells (hCMEC/D3) and human astrocytes (SC-1800) were undertaken. RESULTS: The mouse lauryl peptide displayed enhanced overall stability in plasma, ensuring a longer half-life in circulation that meant there were larger amounts available for transport across the BBB (Papp0-4h: 6.28 ± 1.85 × 10-6 cm s-1). CONCLUSION: This increased availability, coupled to adequate BBB permeability, makes this peptide a good candidate for therapeutic parenteral (intravenous, intramuscular) administration and nose-to-brain delivery. Graphical Abstract.

Subunit-specific role for the amino-terminal domain of AMPA receptors in synaptic targeting.

The amino-terminal domain (ATD) of AMPA receptors (AMPARs) accounts for approximately 50% of the protein, yet its functional role, if any, remains a mystery. We have discovered that the translocation of surface GluA1, but not GluA2, AMPAR subunits to the synapse requires the ATD. GluA1A2 heteromers in which the ATD of GluA1 is absent fail to translocate, establishing a critical role of the ATD of GluA1. Inserting GFP into the ATD interferes with the constitutive synaptic trafficking of GluA1, but not GluA2, mimicking the deletion of the ATD. Remarkably, long-term potentiation (LTP) can override the masking effect of the GFP tag. GluA1, but not GluA2, lacking the ATD fails to show LTP. These findings uncover a role for the ATD in subunit-specific synaptic trafficking of AMPARs, both constitutively and during plasticity. How LTP, induced postsynaptically, engages these extracellular trafficking motifs and what specific cleft proteins participate in the process remain to be elucidated.