Nao Tan Qing ameliorates Alzheimer's disease-like pathology by regulating glycolipid metabolism and neuroinflammation: A network pharmacology analysis and biological validation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and currently there are no available treatments. Alongside the conventional Aß and tau hypotheses, neuroinflammation and metabolism disruption have also been regarded as crucial hallmarks of AD. In this study, a novel Chinese formula Nao Tan Qing (NTQ) was developed and shown to improve AD. In vivo experiments showed that NTQ significantly mitigated cognitive impairment, Aß burden and neuroinflammation in a transgenic AD mouse model (5×FAD). Network pharmacology results revealed that the active components of NTQ could target inflammatory and metabolic pathways. In addition, hippocampal transcriptomics suggested that NTQ regulated signaling pathways related to inflammation and lipid metabolism. Consistently, serum metabolomics further indicated that NTQ could modulate glycolipid metabolism. In summary, a combination of systems pharmacology analysis and biological validation study demonstrates that NTQ could alleviate behavioral abnormality and pathological alterations of AD by targeting glycolipid metabolism and neuroinflammation, and is accordingly a potential therapeutic agent for AD.

Registration errors among patients receiving blood transfusions: a national analysis from 2008 to 2017.

BACKGROUND AND OBJECTIVES: The key first step for a safe blood transfusion is patient registration for identification and linking to past medical and transfusion history. In Canada, any deviation from standard operating procedures in transfusion is an error voluntarily reportable to a national database (Transfusion Error Surveillance System [TESS]). We used this database to characterize the subset of registration-related errors impacting transfusion care, including where, when and why the errors occurred, and to identify frequent high-risk errors. MATERIALS AND METHODS: A retrospective analysis was conducted on transfusion errors reported to TESS by sentinel reporting sites relating to patient registration and patient armbands, between 2008 and 2017. Free-text comments describing the error were coded to further categorize into common error types. The number of specimens received in the transfusion laboratory was used as the denominator for rates to allow for comparison between hospital sites. RESULTS: Five hundred and fifty-four registration errors were reported from 10 hospitals, for a global error rate of 5·4/10 000 samples (median 5·0 [interquartile range 3·7-7·0]). The potential severity was high in 85·7% of errors (n = 475). The patient experienced a consequence in 10·8% of errors (n = 60), but none resulted in patient harm. Rates varied widely and differed by nature across sites. Errors most commonly occurred in outpatient clinics or procedure units (n = 160, 28·8%) and in emergency departments (n = 130, 23·5%). CONCLUSION: Registration errors affect transfusion at every step and location in the hospital and are commonly high risk. Further research into common root causes is warranted to identify preventative strategies.

Broadband terahertz absorption enabled by coating an ultrathin antireflection film on doped semiconductor.

We show that perfect absorption of terahertz wave can be achieved in a compact system where an ultrathin film of lossless dielectric is coated on a doped semiconductor substrate. Due to the nontrivial reflection phase shift at the interface between the two media, strong resonant behavior and the concomitant antireflection occur at wavelengths that are much larger than the thickness of the dielectric film, resulting in strong absorption of the incident wave in a wide frequency range. Using this mechanism, we design a broadband terahertz absorber by coating a Ge film on a highly doped GaAs substrate. We show that such a system not only has a perfect absorption peak, but also exhibits high absorptance (over 0.9) within a fractional bandwidth of over 20%. By varying the free carrier density in the GaAs substrate, the central frequency of the absorption band can be tuned from 1.79 to 2.69 THz. In addition, the absorption performance of the proposed system is shown to be insensitive to both incident angle and polarization. Our results offer a low-cost way for the design of absorption-based THz devices.

Zinc finger protein 451 is a novel Smad corepressor in transforming growth factor-ß signaling.

ZNF451 is a transcriptional cofactor localized to promyelocytic leukemia bodies. Here, we present evidence demonstrating that ZNF451 physically interacts with Smad3/4 and functionally inhibits TGF-ß signaling. Increased expression of ZNF451 attenuates TGF-ß-induced growth inhibitory and gene transcriptional responses, whereas depletion of ZNF451 enhances TGF-ß responses. Mechanistically, ZNF451 blocks the ability of Smad3/4 to recruit p300 in response to TGF-ß, which causes reduction of histone H3K9 acetylation on the promoters of TGF-ß target genes. Taken together, ZNF451 acts as a transcriptional corepressor for Smad3/4 and negatively regulates TGF-ß signaling.

Tunable all-optical plasmonic diode based on Fano resonance in nonlinear waveguide coupled with cavities.

Tunable all-optical plasmonic diode is proposed based on the Fano resonance in an asymmetric and nonlinear system, comprising metal-insulator-metal waveguides coupled with nanocavities. The spatial asymmetry of the system gives rise to the nonreciprocity of the field localizations at the nonlinear gap between the coupled cavities and to the nonreciprocal nonlinear response. Nonlinear Fano resonance, originating from the interference between the discrete cavity mode and the continuum traveling mode, is observed and effectively tuned by changing the input power. By combining the unidirectional nonlinear response with the steep dispersion of the Fano asymmetric line shape, a transmission contrast ratio up to 41.46 dB can be achieved between forward and backward transmission. Our all-optical plasmonic diode with compact structure can find important applications in integrated optical nanocircuits.

Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.

Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.

Machine learning and experimental screening of chromatin regulator signatures and potential drugs in hepatitis B related hepatocellular carcinoma.

Many evidences have confirmed that chromatin regulator factors (CRs) are involved in the progression of cancer, but its potential mechanism of affecting hepatitis B related hepatocellular carcinoma still needs to be studied. Our study detected the CRs that affect hepatitis B related hepatocellular carcinoma (HBV-HCC) through machine learning analysis, conducted the analysis of immune cells, constructed the relevant risk model and immune function infiltration, and predicted the potential therapeutic drugs. We found that these CRs were significantly related to the immune cells of Macrophages, B cells, CD8+T cells, etc., and PBK, AURKA, TOP2A and AURKB were the potential risk CRs of HBV-HCC. The expression levels of these four CRs increased in HepG2.2.15 cells and the liver of HBV-HCC patients, consistent with the predicted risk model. Subsequently, ten potential drugs closely related to the risk CRs were finally obtained, experimental research on resveratrol has shown that it can inhibit the proliferation of HepG2.2.15 cells and potentially inhibit the occurrence and development of HBV-HCC. Our study provides novel insights into the function of CRs in HBV-HCC and certain ideas for more accurate targeted therapy.Communicated by Ramaswamy H. Sarma.

Global profiling of AMG510 modified proteins identified tumor suppressor KEAP1 as an off-target.

KRAS inhibitor AMG510 covalently modifies the G12C residue and inactivates the KRAS/G12C function. Because there are many reactive cysteines in the proteome, it is important to characterize AMG510 on-target modification and off-targets. Here, we presented a streamlined workflow to measure abundant AMG510 modified peptides including that of KRAS/G12C by direct profiling, and a pan-AMG510 antibody peptide IP workflow to profile less abundant AMG510 off-targets. We identified over 300 off-target sites with three distinct kinetic patterns, expanding the AMG510 modified proteome involved in the nucleocytoplasmic transport, response to oxidative stress, adaptive immune system, and glycolysis. We found that AMG510 covalently modified cys339 of ALDOA and inhibited its enzyme activity. Moreover, AMG510 modified KEAP1 cys288 and induced NRF2 accumulation in the nuclear of NSCLC cells independent of KRAS/G12C mutation. Our study provides a comprehensive resource of protein off-targets of AMG510 and elucidates potential toxicological sideeffects for this covalent KRASG12C inhibitor.

Efficacy and safety of sacubitril/valsartan in the treatment of middle-aged and elderly patients with hypertension: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: With the increase of hypertensive patients worldwide, the need for better antihypertensive drugs to achieve blood pressure standards and reduce complications is of great clinical significance. As an angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan has been widely used in the treatment of heart failure, but its efficacy and safety in the treatment of middle-aged and elderly hypertensive patients are still controversial. Therefore, we performed a meta-analysis to compare the efficacy and safety of sacubitril/valsartan and other antihypertensive drugs in the treatment of middle-aged and elderly patients with hypertension. METHODS: The databases of PubMed, Embase, and Web of Science were systematically searched from their establishment to February 2022 to collect the randomized controlled trials (RCTs) of sacubitril/valsartan and other antihypertensive drugs in the treatment of middle-aged and elderly hypertensive patients. The Cochrane Collaboration's tool was used to assess risk of bias for included studies, and the meta-analysis was performed by using RevMan 5.3. RESULTS: In all, 7 studies which met the criteria were included, with a total sample size of 3,323 patients, including 1,899 patients treated with sacubitril/valsartan, and 1,424 patients treated with angiotensin II receptor blockers (ARBs). The meta-analysis showed that compared with other antihypertensive drugs, sacubitril/valsartan can significantly reduce mean reductions in sitting systolic blood pressure [mean difference (MD) =-4.70, 95% confidence interval (CI): -5.79 to -3.61, P<0.001], mean reductions in sitting diastolic blood pressure (MD =-2.29, 95% CI: -2.53 to -2.04, P<0.001), 24-hour mean reductions in ambulatory systolic blood pressure (MD =-3.36, 95% CI: -4.08 to -2.64, P<0.001), and 24-hour mean reductions in ambulatory diastolic blood pressure (MD =-1.49, 95% CI: -1.99 to -0.99, P<0.001), while there was no significant difference in the incidence of adverse events [odds ratio (OR) =1.14, 95% CI: 1.00 to 1.31, P=0.06], serious adverse events (OR =1.06, 95% CI: 0.64 to 1.76, P=0.81), and discontinuations due to adverse events (OR =0.86, 95% CI: 0.51 to 1.46, P=0.58). DISCUSSION: Compared with other antihypertensive drugs, sacubitril/valsartan may be more effective in lowering blood pressure, and its safety may be comparable to that of ARBs. However, these results have to be confirmed by future RCTs with larger sample sizes and higher quality, and the long-term benefits of sacubitril/valsartan require further observation.

A urinary proteomic landscape of COVID-19 progression identifies signaling pathways and therapeutic options.

Signaling pathway alterations in COVID-19 of living humans as well as therapeutic targets of the host proteins are not clear. We analyzed 317 urine proteomes, including 86 COVID-19, 55 pneumonia and 176 healthy controls, and identified specific RNA virus detector protein DDX58/RIG-I only in COVID-19 samples. Comparison of the COVID-19 urinary proteomes with controls revealed major pathway alterations in immunity, metabolism and protein localization. Biomarkers that may stratify severe symptoms from moderate ones suggested that macrophage induced inflammation and thrombolysis may play a critical role in worsening the disease. Hyper activation of the TCA cycle is evident and a macrophage enriched enzyme CLYBL is up regulated in COVID-19 patients. As CLYBL converts the immune modulatory TCA cycle metabolite itaconate through the citramalyl-CoA intermediate to acetyl-CoA, an increase in CLYBL may lead to the depletion of itaconate, limiting its anti-inflammatory function. These observations suggest that supplementation of itaconate and inhibition of CLYBL are possible therapeutic options for treating COVID-19, opening an avenue of modulating host defense as a means of combating SARS-CoV-2 viruses.

[Application of endovascular embolization for brain arteriovenous malformation].

Endovascular embolization has increasingly been applied for brain arteriovenous malformation (BAVM). With our better understanding of BAVM and the continuous improvement of micro-catheter technology and embolic materials, the therapeutic effectiveness has constantly increased. This paper reviews recent advances in research on BAVM and the application of endovascular embolization.

Simultaneous Separation and Quantification of Vitamins by Microemulsion Liquid Chromatography.

Microemulsion eluents have been found to have excellent potential uses in high-performance liquid chromatography (HPLC). Here, a novel, environmentally benign and simple method using concentration/flow-rate double-gradient elution using a microemulsion eluent was used to separate water- and fat-soluble vitamins simultaneously and rapidly. Preliminary screening experiments were performed to determine the optimum column type, surfactant concentration, co-surfactant to surfactant ratio, oil, mobile phase pH and microemulsion concentration. The resolution and analysis time were simultaneously optimized using concentration/flow-rate double-gradient elution. The optimized method simultaneously separated water- and fat-soluble vitamins using a Venusil ASB C8 column and a combination of isocratic and linear gradient elution modes using a microemulsion mobile phase (solvent A) consisting of 3.5% (w/w) sodium dodecyl sulfate, 10.5% (w/w) n-butanol, 0.8% (w/w) n-octanol and 85.2% (w/w) water and water (solvent B) at pH 2.50. The optimum detection wavelength was 283 nm. The method was validated and used to analyze a solid pharmaceutical sample.

Efficacy and safety of endovascular coiling vs surgical clipping for patients with ruptured carotid-ophthalmic aneurysm: A protocol for systematic review and meta-analysis.

BACKGROUND: Carotid-ophthalmic aneurysms are relatively rare, and represent 1% of all intracranial aneurysms. Generally, endovascular coiling and surgical clipping are the 2 most commonly used methods to treat ruptured carotid-ophthalmic aneurysms, it provides the most favorable outcome for a patient. This study aims to assess the efficiency and safety of endovascular coiling vs surgical clipping for patients with a ruptured carotid-ophthalmic aneurysm. METHODS: A comprehensive systematic literature review was done in PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI), and WanFang databases. Only randomized trials that compared endovascular coiling with surgical clipping in patients with ruptured carotid-ophthalmic aneurysm was included. Data was extracted independently by 2 review authors. Moreover, the quality of study and bias risk was evaluated by utilizing an appropriate method. Triallists will be contacted to acquire missing information. The data is presented as risk ratio and mean difference, or standardized mean difference with 95% confidence intervals. RESULTS: The results from the present research shall be published in a peer-reviewed journal. CONCLUSION: The present study summarizes the direct and in-direct evidence to judge the efficiency and safety of these 2 methodologies to treat ruptured carotid-ophthalmic aneurysms and attempt to find the most efficiency and safety therapeutical method. ETHICS AND DISSEMINATION: The present study is a meta-analysis based on published evidence. As a result, ethics approval and patient consent are not needed.

Formation and Nature of Carbon-Containing Tribofilms.

Minimizing friction and wear at a rubbing interface continues to be a challenge and has resulted in the recent surge toward the use of coatings such as diamond-like carbon (DLC) on machine components. The problem with the coating approach is the limitation of coating wear life. Here, we report a lubrication approach in which lubricious, wear-protective carbon-containing tribofilms can be self-generated and replenishable, without any surface pretreatment. Such carbon-containing films were formed under modest sliding conditions in a lubricant consisting of cyclopropanecarboxylic acid as an additive dissolved in polyalphaolefin base oil. These tribofilms show the same Raman D and G signatures that have been interpreted to be due to the presence of graphite- or DLC films. Our experimental measurements and reactive molecular dynamics simulations demonstrate that these tribofilms are in fact high-molecular weight hydrocarbons acting as a solid lubricant.

ALK phosphorylates SMAD4 on tyrosine to disable TGF-ß tumour suppressor functions.

Loss of TGF-ß tumour suppressive response is a hallmark of human cancers. As a central player in TGF-ß signal transduction, SMAD4 (also known as DPC4) is frequently mutated or deleted in gastrointestinal and pancreatic cancer. However, such genetic alterations are rare in most cancer types and the underlying mechanism for TGF-ß resistance is not understood. Here we describe a mechanism of TGF-ß resistance in ALK-positive tumours, including lymphoma, lung cancer and neuroblastoma. We demonstrate that, in ALK-positive tumours, ALK directly phosphorylates SMAD4 at Tyr 95. Phosphorylated SMAD4 is unable to bind to DNA and fails to elicit TGF-ß gene responses and tumour suppressing responses. Chemical or genetic interference of the oncogenic ALK restores TGF-ß responses in ALK-positive tumour cells. These findings reveal that SMAD4 is tyrosine-phosphorylated by an oncogenic tyrosine kinase during tumorigenesis. This suggests a mechanism by which SMAD4 is inactivated in cancers and provides guidance for targeted therapies in ALK-positive cancers.

Fabricating hierarchical micro and nano structures on implantable Co-Cr-Mo alloy for tissue engineering by one-step laser ablation.

Surface texturing is one of the effective strategies to improve bioactivity of implantable materials. In this study, hierarchical micro and nano structure (HMN) were fabricated on Co-Cr-Mo alloy substrate by a movable picosecond laser irradiation. Respectively, microgrooves with nano ripples and islands were produced on Co-Cr-Mo alloy by low and high laser power density. X-ray diffraction apparatus (XRD) phase analysis illustrated that substrate was in the phase of γ- face-centered cubic structure (FCC) before laser treatment, while it was in ε-hexagonal closest packing structure (HCP) phase dominant after laser treatment. Cell adhesion and proliferation studies showed that the HMN surface exhibits enhanced adhesion of MC3TC-E1 osteoblast and promoted cell activity. Analyzing of the morphology of osteoblast cells indicated cells were in high ratio of elongation on the HMN surface, while they mainly kept in round shape on the polished surface. Results indicated the formation of hierarchical structure on Co-Cr-Mo alloy was able to improve biological performances, suggesting the potential application in cobalt based orthopedic implants.

Gender differences in physical aggression: A prospective population-based survey of children before and after 2 years of age.

There has been much controversy over the past decades on the origins of gender differences in children's aggressive behavior. A widely held view is that gender differences emerge sometime after 2 years of age and increase in magnitude thereafter because of gender-differentiated socialization practices. The objective of this study was to test for (a) gender differences in the prevalence of physical aggression in the general population of 17-month-old children and (b) change in the magnitude of these differences between 17 and 29 months of age. Contrary to the differential socialization hypothesis, the results showed substantial gender differences in the prevalence of physical aggression at 17 months of age, with 5% of boys but only 1% of girls manifesting physically aggressive behaviors on a frequent basis. The results suggest that there is no change in the magnitude of these differences between 17 and 29 months of age.

Age differences in the prevalence of physical aggression among 5-11-year-old Canadian boys and girls.

It has been proven extremely difficult in the past to estimate the prevalence of physical aggression in children for two main reasons: (a) a heterogeneous sampling of behaviors (i.e., mix between physically aggressive and non-physically aggressive antisocial behaviors), and (b) a lack of a "gold standard" to identify children who exhibit physically aggressive behaviors on a frequent basis. The goal of this study was to test for age differences in the prevalence of physical aggression in the Canadian population of school-aged boys and girls, using cross-sectional data from the National Longitudinal Survey of Children and Youth (NLSCY). The first wave of the NLSCY included a representative sample of 12,292 Canadian children aged 5-11 years. We used latent class analysis to identify children whose propensity to exhibit physically aggressive behaviors was much higher than that of other children of the same age and sex in the population. The prevalence of physical aggression was estimated at 3.7% in 5-11-year-old boys and ranged from .5% to 2.3% in 11 and 5-year-old girls, respectively. Hence, the results show a decreasing trend in the prevalence of physical aggression with age for girls, but not for boys. These findings suggest the importance of considering the developmental pathways of physical aggression for boys and girls separately.

The evolution of problem and social competence behaviors during toddlerhood: A prospective population-based cohort survey.

Research in developmental psychopathology has long been preoccupied with rather broad categories of behavior, but we know little about the specific behaviors that comprise these categories. The objective of this study was to: (a) estimate the prevalence of problem and social competence behaviors in the general population of children at 17 months of age, and (b) describe the continuity and discontinuity in the degree to which children exhibit these behaviors between 17 and 29 months of age. The results show that frequent problem behaviors are not typical of children under two years of age. Further, the results suggest that it is possible to distinguish between different types of problem behaviors before two years of age. In addition, the results show that gender differences in some problem behaviors are already present before two years of age, and increase in magnitude during toddlerhood. Finally, the results show that interindividual differences in problem behaviors observed before two years of age are stable. The predictive accuracy of frequent problem behaviors in children at 17 months of age was limited, however, with often a majority of toddlers not behaving this way a year later. Overall, our results suggest that toddlerhood represents a critical period when behavioral and emotional problems of potentially clinical significance emerge. Pediatricians should routinely ask parents to report the frequency of their young children's problem behaviors during child health supervision visits so that children whose frequent problem behaviors persist over time can be identified and possibly referred for treatment.