A Disconnection for Rapid Access to Heterocyclic Benzylic Amines with Fully Substituted α-Carbons.

2- or 4-Pyridyl benzylic amines represent a privileged motif in drug discovery. However, the formation of heterocyclic benzylic amines with fully substituted α-carbons can require the execution of lengthy synthetic routes, which limit their application. Addition of various nucleophilic agents to Ellman's imines has been well established; however, there is no precedented literature reported for pyridyl-type nucleophiles, which are very important for medicinal chemistry. In this letter, we disclose the development of a one-step synthesis of heterocyclic benzylic amines with fully substituted α-carbons from heteroaryl halides and sulfinyl imines. Starting from 2,4-dibromopyridine, regioselective synthesis of 2- or 4-pyridyl benzylic amines could be achieved by choosing toluene or MTBE as a solvent.

Intra-abdominal pressure and residual renal function decline in peritoneal dialysis: a threshold-based investigation.

BACKGROUND: The potential impact of elevated intra-abdominal pressure (IAP) on residual renal function (RRF) has not been determined. The objective of this study was to investigate the relationship between IAP and the rate of RRF decline in newly initiated peritoneal dialysis (PD) patients, and to identify the optimal IAP threshold value for delaying the deterioration of RRF. METHODS: A cohort of 62 newly initiated PD patients who completed both 6- and 12-month follow-up evaluations was obtained using the Durand method. A logistic regression model was used to identify variables associated with a rapid decline in RRF. Receiver operating characteristic (ROC) curves were generated to determine the optimal threshold value. Another retrospective cohort analysis was performed to validate the identified critical value. RESULTS: For each 1 cmH2O increase in IAP, the risk of a rapid decline in the RRF increased by a factor of 1.679. Subsequent analysis revealed that patients in the high IAP group had more significant decreases in residual renal estimated glomerular filtration rate (eGFR) (Z = -3.694, p < 0.001) and urine volume (Z = -3.121, p < 0.001) than did those in the non-high IAP group. Furthermore, an IAP ≥15.65 cmH2O was a robust discriminator for the prediction of the rate of RRF decline. CONCLUSION: Patients in the high IAP group experienced a more rapid decline in RRF. Additionally, an optimal critical pressure of 15.65 cmH2O was identified for predicting the rate of RRF decline. IAP, as one of the factors contributing to the rapid decline in RRF in the first year of PD, should be given due attention.

Shift-Based Penalty for Evolutionary Constrained Multiobjective Optimization and its Application.

This article presents a new constraint-handling technique (CHT), called shift-based penalty (ShiP), for solving constrained multiobjective optimization problems. In ShiP, infeasible solutions are first shifted according to the distributions of their neighboring feasible solutions. The degree of shift is adaptively controlled by the proportion of feasible solutions in the current parent and offspring populations. Then, the shifted infeasible solutions are penalized based on their constraint violations. This two-step process can encourage infeasible solutions to approach/enter the feasible region from diverse directions in the early stage of evolution, and guide diverse feasible solutions toward the Pareto optimal solutions in the later stage of evolution. Moreover, ShiP can achieve an adaptive transition from both diversity and feasibility in the early stage of evolution to both diversity and convergence in the later stage of evolution. ShiP is flexible and can be embedded into three well-known multiobjective optimization frameworks. Experiments on benchmark test problems demonstrate that ShiP is highly competitive with other representative CHTs. Further, based on ShiP, we propose an archive-assisted constrained multiobjective evolutionary algorithm (CMOEA), called ShiP+, which outperforms two other state-of-the-art CMOEAs. Finally, ShiP is applied to the vehicle scheduling of the urban bus line successfully.

Dependence of wetting on cavitation during the spreading of a filler droplet on the ultrasonically agitated Al substrate.

The cavitation characteristics during the spreading of a pure Sn liquid droplet subjected to ultrasonication were studied for the first time through high-speed photography to reveal the wetting mechanism. Ultrasonic vibration realized the spreading of Sn droplet on the nonwetting pure Al substrate. However, the oxide layer of the substrate at the spreading front is difficult to remove. The high-speed photography result shows that a noncavitation region consistently appears at the spreading front, because the acoustic pressure is below the cavitation threshold of 1.26 MPa. In particular, the width of the noncavitation region gradually increases as the size of the spreading area increases. Such a result accounts for the condition wherein the oxide layer at the spreading front is difficult to remove. Furthermore, the bubble density during spreading gradually decreases due to the decreased acoustic pressure of the thinned liquid. Finally, the bubble dynamics were calculated to verify the wetting mechanism.

Effects of Long Non-Coding RNA LINC00963 on Renal Interstitial Fibrosis and Oxidative Stress of Rats with Chronic Renal Failure via the Foxo Signaling Pathway.

BACKGROUND/AIMS: Chronic renal failure (CRF) is usually associated with chronic diseases such as congestive heart failure and diabetes mellitus, the prevalence of which is increased with age. This study is designed to investigate the role of long intergenic non-coding RNA (lincRNA) LINC00963 in renal interstitial fibrosis (RIF) and oxidative stress (OS) of CRF via the forkhead box O (FoxO) signaling pathway. METHODS: Microarray data and annotated probe files related to CRF were downloaded by retrieving Gene Expression Omnibus (GEO) database to screen differentially expressed lncRNA. Multi Experiment Matrix (MEM) website and dual-luciferase reporter gene assay were used to predict and verify the target gene of LINC00963, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify the major signaling pathways involved. A total of 60 Wistar male rats were randomly selected and divided into the sham (n = 10) and model (n = 50) groups. Five rats in the sham group and thirty rats in the model group were sub-categorized into the control, blank, negative control (NC), LINC00963 vector, si-LINC00963, si-FoxO3, and si-LINC00963 + si-FoxO3 groups (n = 5). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were performed to evaluate the expressions of LINC00963, FoxO3a, TGF-ß1, FN, GSH-PX, Bax, and Bcl-2. Measurement of changes in OS indexes including BUN, MDA, GSH-Px, SOD, and Na+-K+-ATP were conducted. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of inflammatory factors including TNF-α, IL-6, ICAM-1 and FN. TUNEL staining was performed to evaluate cell apoptosis. RESULTS: LINC00963 was highly expressed in CRF rats and FoxO3 was predicted and then verified as a target gene of LINC00963. FoxO3 gene participated in the FOXO signaling pathway. Compared with the blank and NC groups, there were significantly decreased expressions of LINC00963, TGF-ß1, FN, and Bax in the si-LINC00963 group, while increased expressions of GSH-PX, FoxO3a, and Bcl-2. The vitality values of BUN and MDA in the si-LINC00963 group declined, while enzymatic activities of GSH-Px, SOD and Na+-K+-ATP elevated in comparison to the blank and NC groups. The levels of TNF-α, IL-6, ICAM-1 and FN, and cell apoptosis rate in the si-LINC00963 group decreased in comparison to the blank and NC groups. All the results in the si-LINC00963 group were opposite in the LINC00963 vector and si-FoxO3 groups. CONCLUSION: Taken together, we conclude that down-regulation of LINC00963 suppresses RIF and OS of CRF by activating the FoxO signaling pathway.

Role of ESAT-6 in renal injury by regulating microRNA-155 expression via TLR4/MyD88 signaling pathway in mice with Mycobacterium tuberculosis infection.

The study aims to investigate the underlying mechanism involved in the early secretory antigenic target-6 (ESAT-6) in renal injury through regulation of the expression of miR-155 through the oll-like receptor (TLR)-4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway in Mycobacterium tuberculosis (MTB)-infected mice. Sixty C57BL/6 mice with MTB-induced renal injury were randomly assigned into control, MTB, mimic, inhibitor, inhibitor + ESAT6, and inhibitor + ESAT6 + TAK242 groups. Body weight, the ratio of kidney weight to body weight (Kw/Bw), blood urea nitrogen (BUN), and serum creatinine (Scr) of mice were measured. Flow cytometry was used to detect renal activation in mice. Expressions of miR-155 and ESAT6 were detected by quantitative real-time PCR (qRT-PCR), and Western blotting was used to examine the expressions of ESAT6, TLR4, and MyD88. Expressions of tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), and interferon-γ (IFN-γ) were measured by qRT-PCR and ELISA. Compared with the control group, the BUN and Scr levels as well as the expression levels of miR-155, TLR4, MyD88, TNF-α, IL-17, and IFN-γ increased, while Kw/Bw decreased in the MTB and mimic groups. In comparison with the MTB group, the above indexes except Kw/Bw were elevated in the mimic group, but were reduced in the inhibitor group, while the Kw/Bw dropped in the mimic group but increased in the inhibitor group. Compared with the inhibitor group, the Kw/Bw decreased while the rest of the indexes increased in the inhibitor + ESAT6 group. ESAT6 may induce renal injury by promoting miR-155 expression through the TLR-4/MyD88 signaling pathway in MTB-infected mice.

A new RNA-seq method to detect the transcription and non-coding RNA in prostate cancer.

Prostate cancer is a big killer in many regions especially American men, and this year, the diagnosed rate rises rapidly. We aimed to find the biomarker or any changing in prostate cancer patients. With the development of next generation sequencing, much genomic alteration has been found. Here, basing on the RNA-seq result of human prostate cancer tissue, we tried to find the transcription or non-coding RNA expressed differentially between normal tissue and prostate cancer tissue. 10 T sample data is the RNA-seq data for prostate cancer tissue in this study, we found the differential gene is TFF3-Trefoil factor 3, which was more than seven fold change from prostate cancer tissue to normal tissue, and the most outstanding transcript is C15orf21. Additionally, 9 lncRNAs were found according our method. Finally, we found the many important non-coding RNA related to prostate cancer, some of them were long non-coding RNA (lncRNA).

Automatic removal of the eye blink artifact from EEG using an ICA-based template matching approach.

Independent component analysis (ICA) proves to be effective in the removing the ocular artifact from electroencephalogram recordings (EEG). While using ICA in ocular artifact correction, a crucial step is to correctly identify the artifact components among the decomposed independent components. In most previous works, this step of selecting the artifact components was manually implemented, which is time consuming and inconvenient when dealing with a large amount of EEG data. We present a new method which automatically selects the eye blink artifact components based on the pattern of their scalp topographies, which can be exemplified as a template matching approach. The feasibility of using a fixed template for singling out the eye blink component after ICA decomposition was validated by an experiment in which 18 subjects among the 21 subjects involved exhibited a highly consistent pattern of eye blink scalp topographies. Since only the spatial feature is employed for singling out the eye blink component, the proposed method is very efficient and easy to implement. Objective evaluation of the real results shows that the proposed algorithm can remove the eye blink artifact from the EEG while causing little distortion to the underlying brain activities.