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Lower gray matter integrity is associated with greater lap time variation in high-functioning older adults. - Experimental gerontology
Lower integrity of cerebral gray matter is associated with higher gait variability. It is not known whether gray matter integrity is associated with higher lap time variation (LTV), a clinically accessible measure of gait variability, high levels of which have been associated with mortality. This study examines the cross-sectional association between gray matter mean diffusivity (MD) and LTV in community-dwelling older adults.Study participants consisted of 449 high-functioning adults aged 50 and older (56.8% female) in the Baltimore Longitudinal Study of Aging, free of overt neurological disease. The magnitude of MD in the gray matter, a measure of impaired tissue integrity, was assessed by diffusion tensor imaging in 16 regions of interest (ROIs) involved with executive function, sensorimotor function, and memory. LTV was assessed as variability in lap time based on individual trajectories over ten 40-m laps. Age, sex, height, and weight were covariates. The model additionally adjusted for mean lap time and health conditions that may affect LTV.Higher levels of average MD across 16 ROIs were significantly associated with higher LTV after adjustment for covariates. Specifically, higher MD in the precuneus and the anterior and middle cingulate cortices was strongly associated with higher LTV, as compared to other ROIs. The association persisted after adjustment for mean lap time, hypertension, and diabetes.Lower gray matter integrity in selected areas may underlie greater LTV in high-functioning community-dwelling older adults. Longitudinal studies are warranted to examine whether changes in gray matter integrity precede more variable gait.Copyright Â© 2015. Published by Elsevier Inc.
Threonine 209 phosphorylation on RUNX3 by Pak1 is a molecular switch for its dualistic functions. - Oncogene
P21 Activated Kinase 1 (Pak1), an oncogenic serine/threonine kinase, is known to have a significant role in the regulation of cytoskeleton and cellular morphology. Runx3 was initially known for its role in tumor suppressor function, but recent studies have reported the oncogenic role of Runx3 in various cancers. However, the mechanism that controls the paradoxical functions of Runx3 still remains unclear. In this study, we show that Runx3 is a physiologically interacting substrate of Pak1. We identified the site of phosphorylation in Runx3 as Threonine 209 by mass spectrometry analysis and site-directed mutagenesis, and further confirmed the same with a site-specific antibody. Results from our functional studies showed that Threonine 209 phosphorylation in Runx3 alters its subcellular localization by protein mislocalization from the nucleus to the cytoplasm and subsequently converses its biological functions. This was further supported by in vivo tumor xenograft studies in nude mouse models which clearly demonstrated that PANC-28 cells transfected with the Runx3-T209E clone showed high tumorigenic potential as compared with other clones. Our results from clinical samples also suggest that Threonine 209 phosphorylation by Pak1 could be a potential therapeutic target and of great clinical relevance with implications for Runx3 inactivation in cancer cells where Runx3 is known to be oncogenic. The findings presented in this study provide evidence of Runx3-Threonine 209 phosphorylation as a molecular switch in dictating the tissue-specific dualistic functions of Runx3 for the first time.Oncogene advance online publication, 22 February 2016; doi:10.1038/onc.2016.18.
Death receptor-based enrichment of Cas9-expressing cells. - BMC biotechnology
The CRISPR/Cas9 genome editing system has greatly facilitated and expanded our capacity to engineer mammalian genomes, including targeted gene knock-outs. However, the phenotyping of the knock-out effect requires a high DNA editing efficiency.Here, we report a user-friendly strategy based on the extrinsic apoptosis pathway that allows enrichment of a polyclonal gene-edited cell population, by selecting Cas9-transfected cells that co-express dominant-negative mutants of death receptors. The extrinsic apoptosis pathway can be triggered in many mammalian cell types, and ligands are easy to produce, do not require purification and kill much faster than the state-of-the-art selection drug puromycin. Stringent assessment of our advanced selection strategy via Sanger sequencing, T7 endonuclease I (T7E1) assay and direct phenotyping confirmed a strong and rapid enrichment of Cas9-expressing cell populations, in some cases reaching up to 100Â % within one hour. Notably, the efficiency of target DNA cleavage in these enriched cells reached high levels that exceeded the reliable range of the T7E1 assay, a conclusion that can be generalized for editing efficiencies above 30Â %. Moreover, our data emphasize that the insertion and deletion pattern induced by a specific gRNA is reproducible across different cell lines.The workflow and the findings reported here should streamline a wide array of future low- or high-throughput gene knock-out screens, and should largely improve data interpretation from CRISPR experiments.
Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance. - Scientific reports
Tamoxifen is the accepted therapy for patients with estrogen receptor-Î± (ERÎ±)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERÎ±-positive and ERÎ±-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer.
Cardiogenic shock from atypical Takotsubo cardiomyopathy attributed to acute disseminated encephalomyelitis lesion involving the medulla. - Clinical autonomic research : official journal of the Clinical Autonomic Research Society
We present here a case of atypical Takotsubo cardiomyopathy arising as a result of a lesion in the medulla oblongata. The patient was diagnosed with acute disseminated encephalomyelitis, and had improvement with intravenous steroids.
Methods for SWATHâ„¢: Data Independent Acquisition on TripleTOF Mass Spectrometers. - Methods in molecular biology (Clifton, N.J.)
Data independent acquisition (DIA also termed SWATH) is an emerging technology in the field of mass spectrometry based proteomics. Although the concept of DIA has been around for over a decade, the recent advancements, in particular the speed of acquisition, of mass analyzers have pushed the technique into the spotlight and allowed for high-quality DIA data to be routinely acquired by proteomics labs. In this chapter we will discuss the protocols used for DIA acquisition using the Sciex TripleTOF mass spectrometers and data analysis using the Sciex processing software.
Efficacy of ultrasound-guided transversus abdominis plane block for postoperative analgesia in patients undergoing inguinal hernia repair. - Local and regional anesthesia
Transversus abdominis plane block (TAP block) is a novel procedure to provide postoperative analgesia following inguinal hernia surgery. The utilization of ultrasound has greatly augmented the success rate of this block and additionally avoiding complications. The aim of our study was to gauge the analgesic efficacy of ultrasound-guided TAP block in patients undergoing unilateral inguinal hernia repair.Sixty patients scheduled for elective inguinal hernia repair were selected for the study. At the end of the surgical procedure, they were randomly divided into two groups. Ultrasound-guided TAP block was performed with 20 mL of ropivacaine 0.2% (group A) or normal saline (group B). Visual analog scale (VAS) scores were used to assess pain. Paracetamol was given if VAS > 3 and tramadol was used when VAS > 6. Patients were monitored for VAS scores and total analgesic consumption for the 24-hour period.The TAP block with ropivacaine (group A) reduced VAS scores at 4, 6, and 12 hours. There was no distinction in VAS scores at 0, 2, and 24 hours between the two groups. The duration of analgesia for TAP block with ropivacaine lasted for 390 minutes. Total analgesics consumption was also significantly reduced in group A than group B. No complication was reported to TAP block in both the groups.The ultrasound-guided TAP block provides good postoperative analgesia, reduces analgesic requirements, and provides good VAS scores with fewer complications following inguinal hernia surgery.
Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor. - ACS medicinal chemistry letters
We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
Nanofibril scaffold assisted MEMS artificial hydrogel neuromasts for enhanced sensitivity flow sensing. - Scientific reports
We present the development and testing of superficial neuromast-inspired flow sensors that also attain high sensitivity and resolution through a biomimetic hyaulronic acid-based hydrogel cupula dressing. The inspiration comes from the spatially distributed neuromasts of the blind cavefish that live in completely dark undersea caves; the sensors enable the fish to form three-dimensional flow and object maps, enabling them to maneuver efficiently in cluttered environments. A canopy shaped electrospun nanofibril scaffold, inspired by the cupular fibrils, assists the drop-casting process allowing the formation of a prolate spheroid-shaped artificial cupula. Rheological and nanoindentation characterizations showed that the Young's modulus of the artificial cupula closely matches the biological cupula (10-100 Pa). A comparative experimental study conducted to evaluate the sensitivities of the naked hair cell sensor and the cupula-dressed sensor in sensing steady-state flows demonstrated a sensitivity enhancement by 3.5-5 times due to the presence of hydrogel cupula. The novel strategies of sensor development presented in this report are applicable to the design and fabrication of other biomimetic sensors as well. The developed sensors can be used in the navigation and maneuvering of underwater robots, but can also find applications in biomedical and microfluidic devices.
A novel copper(II) complex identified as a potent drug against colorectal and breast cancer cells and as a poison inhibitor for human topoisomerase IIÎ±. - Inorganic chemistry communications
A novel complex, [Cu(acetylethTSC)Cl]Clâ€¢0.25C2H5OH 1 (where acetylethTSC = (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide), was shown to have anti-proliferative activity against various colon and aggressive breast cancer cell lines. In vitro studies showed that complex 1 acted as a poison inhibitor of human topoisomerase IIÎ±, which may account for the observed anti-cancer effects.
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