Concurrent Activation Research Articles

Association of Cardiovascular Mortality with Concurrent Coronary Artery Calcification and Physical Activity: A Cohort Study

Background: Increased coronary artery calcification (CAC) has been reported in individuals with high levels of physical activity (PA). However, the association between increased CAC in a physically active population and cardiovascular mortality has not yet been well-established. This study aimed to investigate the association between PA levels and the presence or absence of CAC and cardiovascular mortality. Methods: A cohort study was conducted from 1 January 2011 to 30 December 2019. Mortality data were updated until 30 December 2020. The study population comprised 56,469 individuals who had completed the International Physical Activity Short Form Questionnaire and had undergone CAC score evaluation using a CT scan. We divided the participants into four groups: physically inactive individuals without CAC, physically inactive individuals with CAC, moderately active and health-enhancing physically active (HEPA) individuals without CAC, and moderately active and HEPA individuals with CAC. The primary outcome was cardiovascular mortality. The Cox proportional hazard model with confounding factor adjustment was conducted. Inverse probability of treatment weighting-based marginal-structural modelling was conducted. Results: The median follow-up duration was 6.60 years. The mean (SD) age of the study participants was 41.67 (±10.91) years, with 76.78% (n = 43,359) men. Compared with individuals without CAC, individuals with CAC demonstrated higher cardiovascular disease mortality regardless of PA level (Inactive and CAC > 0, HR 2.81, 95% CI: 1.76-19.19; moderately active and HEPA HR 3.27, 95% CI: 1.14-9.38). Conclusions: The presence of CAC might be associated with cardiovascular mortality regardless of PA level.

Seen and Unseen: Narratives of In/Visibility of Black Youth Who Attend a Predominantly Latinx High School

Background/Context: Scholars have identified how antiblackness operates as a specific organizational culture across the educational enterprise by examining Black students in various schooling contexts. However, there remains limited empirical research exploring Black students’ unique experiences in predominantly Latinx educational settings. The presence of Black bodies in institutions like schools from which they have been historically or conceptually excluded, marginalized, or “othered” presents an intriguing context to investigate the intersection of race, place, and the politics of visibility. Research Design: Drawing from an extensive ethnographic project on antiblackness in borderland contexts, this article interrogates Black students’ narratives of in/visibility—stories detailing moments when they felt seen and unseen. I used purposive sampling and recruited 20 Black students to participate in focus groups and individual interviews. Focus groups and interviews were semi-structured, using open-ended questions but centered on circumstances related to in/visibility. I also conducted observations in classrooms, hallways, the cafeteria, and other locations across the school campus. Data Collection and Analysis: Data analysis for this study included coding and recoding transcripts and field notes, and writing analytic memos. The analytic memos served as a site of conversation about the data where I could think deeply about the experiences that my participants shared. Coding and writing analytic memos were concurrent data analytic activities. During analysis, I paid close attention to how students described moments of invisibility, visibility, and hypervisibility. I conducted thematic coding and analysis of the data, which generated key themes. Finally, I reorganized emerging themes several times in relation to the extant literature and theoretical framework. Findings: Building on prior research on antiblackness in education, I use the notions of seen and unseen to describe Black students’ experiences with antiblack structures, practices, and encounters with their non-Black peers and adults. Black youth narratives reveal that their Blackness is simultaneously rendered hypervisible and invisible through the everydayness of antiblackness. The data also reveal that their racialized experiences with in/visibility were concurrently spatial and had implications for how Black students navigated the physical geographies of schools. I found that unseeing is an active process of not acknowledging the bias accompanying explicit practices that enable different people to exist differently in the same space. To unsee is a rejection of the specificity of Black that encodes how Black students navigate spaces where they are not the somatic norm. Further, this posture impacts Black bodies by making them feel simultaneously like outsiders and insiders. As a result, some bodies are deemed as having the right to belong, while others are marked as trespassers. Conclusions and Recommendations Racial moments have material, emotional, and educational consequences for Black students. Being “different” from the somatic norm renders Black bodies simultaneously highly visible and invisible. Research tends to collapse Black and Latinx students into a broader category of “students of color” without disaggregating the distinctive ways in which racialized school systems impact these groups differently. Further, the data presented here demonstrate how antiblack racism shapes the experiences of Black students and draws attention to the urgency of dismantling the people of color colorblindness in research analysis.

Characterization and applications of evoked responses during epidural electrical stimulation

BackgroundEpidural electrical stimulation (EES) of the spinal cord has been FDA approved and used therapeutically for decades. However, there is still not a clear understanding of the local neural substrates and consequently the mechanism of action responsible for the therapeutic effects.MethodEpidural spinal recordings (ESR) are collected from the electrodes placed in the epidural space. ESR contains multi-modality signal components such as the evoked neural response (due to tonic or BurstDR™ waveforms), evoked muscle response, stimulation artifact, and cardiac response. The tonic stimulation evoked compound action potential (ECAP) is one of the components in ESR and has been proposed recently to measure the accumulative local potentials from large populations of neuronal fibers during EES.ResultHere, we first review and investigate the referencing strategies, as they apply to ECAP component in ESR in the domestic swine animal model. We then examine how ECAP component can be used to sense lead migration, an adverse outcome following lead placement that can reduce therapeutic efficacy. Lastly, we show and isolate concurrent activation of local back and leg muscles during EES, demonstrating that the ESR obtained from the recording contacts contain both ECAP and EMG components.ConclusionThese findings may further guide the implementation of recording and reference contacts in an implantable EES system and provide preliminary evidence for the utility of ECAP component in ESR to detect lead migration. We expect these results to facilitate future development of EES methodology and implementation of use of different components in ESR to improve EES therapy.

High levels of histone H3 K27 acetylation and tri-methylation are associated with shorter survival in oral squamous cell carcinoma patients.

Acetylation and trimethylation of histone H3 lysine 27 (H3K27ac and H3K27me3) generally activate and repress transcription, respectively. Concurrent activation of H3K27ac and H3K27me3 has been reported to correlate with poor prognosis in hepatocellular carcinoma. A high level of H3K27me3 has been shown to be associated with advanced oral squamous cell carcinoma (OSCC) tumour stage, but prognostic impact of H3K27ac level alone/or in combination with H3K27me3 in OSCC patients had not yet been reported. In this study, immunohistochemistry using specific antibodies against H3K27ac and H3K27me3 was performed on a series of 72 OSCC samples to investigate the association between H3K27ac and H3K27me3 levels and OSCC patient's survival. For each mark, the proportion of labelled cells (percentage) and the intensity of the labelling were measured, and a score of percentage x intensity was calculated. A high percentage of H3K27me3 positive cells was significantly associated with survival in univariate and multivariate analyses (logrank p-value < 0.05). Patients with high total scores of H3K27ac and H3K27me3 labelling also showed significantly shorter survival probabilities (logrank p-value < 0.05) compared to patients with low total scores of labelling for these histone posttranslational modifications (PTMs). Our findings suggest that the detection of both H3K27ac and H3k27me3 could help evaluating prognosis in OSCC patients.

Changes in cardiac function in Navy divers during four days of successive dives in very cold diving conditions.

There is limited knowledge of cumulative effect of repetitive cold-water diving on cardiac function. Single cold dives cause some known cardiological risks, such as malign arrhythmia, due to a concurrent activation of the sympathetic and parasympathetic autonomic nervous system. A previous study from warmer water dives has shown that successive dives cause a decrease in vagal tone and a less responsive cardiovascular system. The aim of this study was to evaluate changes in cardiac function with 2D echocardiography during 4 days of diving in near-freezing water. Left ventricle systolic function measures did not show any uniform changes. E/A ratio seemed to decrease successively with the number of dives. The diastolic tissue velocity of relaxing basal septum (e') showed a decreasing trend as well. Diastolic blood pressure seemed to increase from predive (mean: 83 RR mmHg) to postdive values (mean: 87 RR mmHg) (p=NS). Heart rate decreased significantly from predive (mean: 71 bpm, range: 56-103) to postdive values (mean: 60 bpm, range: 37-88) (p < 0.03). The study was conducted in very cold condition and with limited number of divers. Results of this preliminary study suggested a decreasing trend in left ventricular diastolic function in successive cold dives. Cumulative changes in cardiac function may cause health risks that need to be considered during cold water diving operations.

Electron-Rich Bi Nanosheets Promotes CO2•- Formation for High-Performance and pH-Universal Electrocatalytic CO2 Reduction.

Electrochemical CO2 reduction reaction (CO2RR) to chemical fuels such as formate offers a promising pathway to carbon-neutral future, but its practical application is largely inhibited by the lack of effective activation of CO2 molecules and pH-universal feasibility. Here, we report an electronic structure manipulation strategy to electron-rich Bi nanosheets, where electrons transfer from Cu donor to Bi acceptor in bimetallic Cu-Bi, enabling CO2RR towards formate with concurrent high activity, selectivity and stability in pH-universal (acidic, neutral and alkaline) electrolytes. Combined in situ Raman spectra and computational calculations unravel that electron-rich Bi promote CO2•- formation to activate CO2 molecules, and enhance the adsorption strength of *OCHO intermediate with an up-shifted p-band center, thus leading to its superior activity and selectivity of formate. Further integration of the robust electron-rich Bi nanosheets into III-V-based photovoltaic solar cell results in an unassisted artificial leaf with a high solar-to-formate (STF) efficiency of 13.7%.

Electron‐Rich Bi Nanosheets Promote CO2⋅− Formation for High‐Performance and pH‐Universal Electrocatalytic CO2 Reduction

AbstractElectrochemical CO2 reduction reaction (CO2RR) to chemical fuels such as formate offers a promising pathway to carbon‐neutral future, but its practical application is largely inhibited by the lack of effective activation of CO2 molecules and pH‐universal feasibility. Here, we report an electronic structure manipulation strategy to electron‐rich Bi nanosheets, where electrons transfer from Cu donor to Bi acceptor in bimetallic Cu−Bi, enabling CO2RR towards formate with concurrent high activity, selectivity and stability in pH‐universal (acidic, neutral and alkaline) electrolytes. Combined in situ Raman spectra and computational calculations unravel that electron‐rich Bi promotes CO2⋅− formation to activate CO2 molecules, and enhance the adsorption strength of *OCHO intermediate with an up‐shifted p‐band center, thus leading to its superior activity and selectivity of formate. Further integration of the robust electron‐rich Bi nanosheets into III–V‐based photovoltaic solar cell results in an unassisted artificial leaf with a high solar‐to‐formate (STF) efficiency of 13.7 %.

Lens Epithelial Explants Treated with Vitreous Humor Undergo Alterations in Chromatin Landscape with Concurrent Activation of Genes Associated with Fiber Cell Differentiation and Innate Immune Response.

Lens epithelial explants are comprised of lens epithelial cells cultured in vitro on their native basement membrane, the lens capsule. Biologists have used lens epithelial explants to study many different cellular processes including lens fiber cell differentiation. In these studies, fiber differentiation is typically measured by cellular elongation and the expression of a few proteins characteristically expressed by lens fiber cells in situ. Chromatin and RNA was collected from lens epithelial explants cultured in either un-supplemented media or media containing 50% bovine vitreous humor for one or five days. Chromatin for ATAC-sequencing and RNA for RNA-sequencing was prepared from explants to assess regions of accessible chromatin and to quantitatively measure gene expression, respectively. Vitreous humor increased chromatin accessibility in promoter regions of genes associated with fiber differentiation and, surprisingly, an immune response, and this was associated with increased transcript levels for these genes. In contrast, vitreous had little effect on the accessibility of the genes highly expressed in the lens epithelium despite dramatic reductions in their mRNA transcripts. An unbiased analysis of differentially accessible regions revealed an enrichment of cis-regulatory motifs for RUNX, SOX and TEAD transcription factors that may drive differential gene expression in response to vitreous.

Concurrence of Eosinophilic Esophagitis and Dyshidrotic Eczema: a Case Series

While eosinophilic esophagitis (EoE) is strongly associated with atopic conditions including asthma, allergic rhinitis, food allergy, and atopic dermatitis, its association with dyshidrotic eczema (DE) – a distinct form of eczema characterized by pruritic vesicles commonly localized to the hands and feet – has not been described. Here we present four patients with EoE and DE with concurrent disease activity.

Solvent-Dependent Selective Synthesis of CF3-Tethered Indazole Derivatives Based on Multiple Bond Activations

Presented herein is a solvent-dependent selective synthesis of CF3-tethered indazole derivatives via the cascade reactions of 1-arylpyrazolidinones with trifluoromethyl ynones. Mechanistically, the formation of the title products involves cascade N-H/C-H/C-N/C-C bond cleavage along with pyrazole ring formation and pyrazolidinone ring opening. For the formation of a pyrazole scaffold, 1-phenylpyrazolidinone acts as a C2N2 synthon, while trifluoromethyl ynone serves as a C1 synthon. Meanwhile, trifluoromethyl ynone also acts as an enol unit to facilitate the ring opening of the pyrazolidinone ring and provide a trifluoropropenoxy fragment via cleavage of the alkynyl triple bond and migration of the cleaved moiety. When the reaction was run in trifluoroethanol instead of DCE, it selectively afforded indazole derivatives tethered with a trifluoroethoxy moiety through in situ transesterification. To our knowledge, this is the first synthesis of CF3-tethered indazole derivatives via concurrent alkynyl activation, pyrazole formation, and CF3 migration.

Potential health risks of mRNA-based vaccine therapy: A hypothesis

Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 under control. To date, there are no published studies on the biodistribution, cellular uptake, endosomal escape, translation rates, functional half-life and inactivation kinetics of synthetic mRNA, rates and duration of vaccine-induced antigen expression in different cell types. Furthermore, despite the assumption that there is no possibility of genomic integration of therapeutic synthetic mRNA, only one recent study has examined interactions between vaccine mRNA and the genome of transfected cells, and reported that an endogenous retrotransposon, LINE-1 is unsilenced following mRNA entry to the cell, leading to reverse transcription of full length vaccine mRNA sequences, and nuclear entry. This finding should be a major safety concern, given the possibility of synthetic mRNA-driven epigenetic and genomic modifications arising. We propose that in susceptible individuals, cytosolic clearance of nucleotide modified synthetic (nms-mRNAs) is impeded. Sustained presence of nms-mRNA in the cytoplasm deregulates and activates endogenous transposable elements (TEs), causing some of the mRNA copies to be reverse transcribed. The cytosolic accumulation of the nms-mRNA and the reverse transcribed cDNA molecules activates RNA and DNA sensory pathways. Their concurrent activation initiates a synchronized innate response against non-self nucleic acids, prompting type-I interferon and pro-inflammatory cytokine production which, if unregulated, leads to autoinflammatory and autoimmune conditions, while activated TEs increase the risk of insertional mutagenesis of the reverse transcribed molecules, which can disrupt coding regions, enhance the risk of mutations in tumour suppressor genes, and lead to sustained DNA damage. Susceptible individuals would then expectedly have an increased risk of DNA damage, chronic autoinflammation, autoimmunity and cancer. In light of the current mass administration of nms-mRNA vaccines, it is essential and urgent to fully understand the intracellular cascades initiated by cellular uptake of synthetic mRNA and the consequences of these molecular events.

Writing fluency instructional practices for college-level multilinguals in a U.S. intensive writing course: From an activity theory perspective

This study examined how one teacher conceptualized writing fluency for college-level emergent multilingual students and how instructional practices of writing fluency supported the development of the teacher’s conceptualization and pedagogy of writing fluency in an intensive English writing course. From an activity theory perspective, I conducted an interpretive case study at a large state university in the Northeastern United States. Drawing on activity systems analysis, I analyzed multiple data sources: interview transcripts, field notes, and analytic memos. First, findings revealed that the teacher conceptualized writing fluency as the ability to make a quick association of cognitive, linguistic, and social elements for written communication by navigating the competing objects and interplay of the complex and concurrent activity systems of the teacher, institution, and students. Second, findings demonstrated that prompted writing, blackboard writing, and freewriting practices supported the teacher in developing her conceptualization of the practice of writing fluency: prompting emergent multilingual students to make a quick association of cognitive, linguistic, and social skills for written communication; advising the students to complete written work in a short time and learn from each other through the in-the-moment peer assessment; and facilitating the students’ free associations of diverse topics in a self-directed way. This study has implications for teachers, researchers, and policymakers who invest in curriculum development and classroom instruction of writing fluency for college-level emergent multilingual students.

Development of an integrated microperfusion-EEG electrode for unbiased multimodal sampling of brain interstitial fluid and concurrent neural activity

Objective. To modify off-the-shelf components to build a device for collecting electroencephalography (EEG) from macroelectrodes surrounded by large fluid access ports sampled by an integrated microperfusion system in order to establish a method for sampling brain interstitial fluid (ISF) at the site of stimulation or seizure activity with no bias for molecular size. Approach. Twenty-four 560 µm diameter holes were ablated through the sheath surrounding one platinum–iridium macroelectrode of a standard Spencer depth electrode using a femtosecond UV laser. A syringe pump was converted to push–pull configuration and connected to the fluidics catheter of a commercially available microdialysis system. The fluidics were inserted into the lumen of the modified Spencer electrode with the microdialysis membrane removed, converting the system to open flow microperfusion. Electrical performance and analyte recovery were measured and parameters were systematically altered to improve performance. An optimized device was tested in the pig brain and unbiased quantitative mass spectrometry was used to characterize the perfusate collected from the peri-electrode brain in response to stimulation. Main results. Optimized parameters resulted in >70% recovery of 70 kDa dextran from a tissue analog. The optimized device was implanted in the cortex of a pig and perfusate was collected during four 60 min epochs. Following a baseline epoch, the macroelectrode surrounded by microperfusion ports was stimulated at 2 Hz (0.7 mA, 200 µs pulse width). Following a post-stimulation epoch, the cortex near the electrode was stimulated with benzylpenicillin to induce epileptiform activity. Proteomic analysis of the perfusates revealed a unique inflammatory signature induced by electrical stimulation. This signature was not detected in bulk tissue ISF. Significance. A modified dual-sensing electrode that permits coincident detection of EEG and ISF at the site of epileptiform neural activity may reveal novel pathogenic mechanisms and therapeutic targets that are otherwise undetectable at the bulk tissue level.

Psi promotes Drosophila wing growth via direct transcriptional activation of cell cycle targets and repression of growth inhibitors.

The first characterised FUSE Binding Protein family member, FUBP1, binds single-stranded DNA to activate MYC transcription. Psi, the sole FUBP protein in Drosophila, binds RNA to regulate P-element and mRNA splicing. Our previous work revealed pro-growth functions for Psi, which depend, in part, on transcriptional activation of Myc. Genome-wide functions for FUBP family proteins in transcriptional control remain obscure. Here, through the first genome-wide binding and expression profiles obtained for a FUBP family protein, we demonstrate that, in addition to being required to activate Myc to promote cell growth, Psi also directly binds and activates stg to couple growth and cell division. Thus, Psi knockdown results in reduced cell division in the wing imaginal disc. In addition to activating these pro-proliferative targets, Psi directly represses transcription of the growth inhibitor tolkin (tok, a metallopeptidase implicated in TGFβ signalling). We further demonstrate tok overexpression inhibits proliferation, while tok loss of function increases mitosis alone and suppresses impaired cell division caused by Psi knockdown. Thus, Psi orchestrates growth through concurrent transcriptional activation of the pro-proliferative genes Myc and stg, in combination with repression of the growth inhibitor tok.

The influence of training status and parasympathetic blockade on the cardiac rate, rhythm and functional response to autonomic stress.

Apnea (breath-holding) elicits co-activation of sympathetic and parasympathetic nervous systems, affecting cardiac control. In situations of autonomic co-activation (e.g., cold water immersion), cardiac arrhythmias are observed during apnea. Chronic endurance training reduces resting heart rate in part via elevation in parasympathetic tone, and has been identified as a risk factor for development of arrhythmias. However, few studies have investigated autonomic control of the heart in trained athletes during stress. Therefore, we determined whether heightened vagal tone resulting from endurance training promotes a higher incidence of arrhythmia during apnea. We assessed the heart rate, rhythm (ECG lead II), and cardiac inotropic (speckle-tracking echocardiography) response to apnea in 10 endurance trained and 7 untrained participants. Participants performed an apnea at rest and following sympathetic activation using post-exercise circulatory occlusion (PECO). All apneas were performed prior to (CON) and following vagal block using glycopyrrolate (GLY). Trained participants had lower heart rates at rest (p=0.03) and during apneas (p=0.009) under CON. At rest, 3 trained participants exhibited instances of junctional rhythm and 4 trained participants developed ectopy during CON apneas, whereas 3 untrained participants developed ectopic beats only with concurrent sympathetic activation (PECO). Following GLY, no arrhythmias were noted in either group. Vagal block also revealed increased cardiac chronotropy (heart rate) and inotropy (strain rate) during apnea, demonstrating a greater sympathetic influence in the absence of parasympathetic drive. Our results highlight that endurance athletes may be more susceptible to ectopy via elevated vagal tone, whereas untrained participants may only develop ectopy through autonomic conflict. .

Cooperative Asymmetric Dual Catalysis Involving a Chiral N-Heterocyclic Carbene Organocatalyst and Palladium in an Annulation Reaction: Mechanism and Origin of Stereoselectivity

The increasing number of examples on cooperative dual catalysis involving organocatalysts and transition metal catalysts indicate their wider acceptance and utility in synthetic applications. In such reactions, the concurrent activation of substrates is likely to present mechanistic complexities. In one of the studies, designed for intermolecular annulation aimed at making a biologically important class of benzazepines, chiral N-heterocyclic carbenes engage an enal in the form of a Breslow intermediate (nucleophilic partner) and Pd(0) activates rac-vinyl benzoxazinanone as a Pd-π-allyl intermediate (electrophile). Given the current importance and the lack of molecular insights on the origin of high enantio-/diastereoselectivities and cooperativity in such dual catalytic reactions, we have undertaken a detailed computational investigation using density functional theory. The kinetically most accessible Pd-π-allyl intermediate from the (S)- and (R)-vinyl benzoxazinanone is found to be Cre and Csi (where re and si denote the open prochiral faces through which the nucleophile can add), respectively. An energetically favorable change in configuration from Csi to Cre, via a PPh3-induced π–σ–π isomerization, suggests that an enantioconvergent mechanism was responsible for the enrichment of the desired Cre Pd-π-allyl species. Ready availability of Cre and the higher energy transition state (TS) for the alternative nucleophilic addition to the Csi is responsible for the high ee (computed >99%, experimental 99%). Improved shape complementarity between the chiral electrophile and nucleophile in the most preferred C–C bond formation TS as well as the noncovalent interactions (C–H··· π, π···π, and H-bonding) therein dictates the diastereoselectivity. An intramolecular C–N bond formation to the final annulated product is the turnover-determining TS. Molecular insights and energetic features, as obtained through our computations, are found to be in concert with several experimental observations, even beyond the sense and extent of stereoselectivities.

Oleic acid-induced metastasis of KRAS/p53-mutant colorectal cancer relies on concurrent KRAS activation and IL-8 expression bypassing EGFR activation.

Background: Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy. Understanding the molecular mechanisms regulating anti-EGFR-resistant CRC metastasis can improve CRC therapy. This study aimed to investigate the effects of IL-8 and the activation of KRAS on reactive oxygen species (ROS) production and metastasis of hyperlipidemia-associated CRC harboring mutations of KRAS and p53. Methods: The cytokine array analysis determined the up-expression of secreted factors, including IL-8. The clinical relevance of the relationship between IL-8 and angiopoietin-like 4 (ANGPTL4) was examined in CRC patients from National Cheng Kung University Hospital and TCGA dataset. Expressions of IL-8, ANGPTL4, NADPH oxidase 4 (NOX4), and epithelial-mesenchymal transition (EMT) markers in free fatty acids (FFAs)-treated KRAS/p53 mutant CRC cells were determined. The hyperlipidemia-triggered metastatic ability of CRC cells under treatments of antioxidants, statin, and cetuximab or knockdown of IL-8, KRAS, and EGFR was evaluated in vitro and in vivo. In addition, the effects of antioxidants and depletion of IL-8 and KRAS on the correlation between ROS production and hyperlipidemia-promoted CRC metastasis were also clarified. Results: In this study, we found that free fatty acids promoted KRAS/p53-mutant but not single-mutant or non-mutant CRC cell metastasis. IL-8, the most abundant secreted factor in KRAS/p53-mutant cells, was correlated with the upregulation of NOX4 expression and ROS production under oleic acid (OA)-treated conditions. In addition, the metastasis of KRAS/p53-mutant CRC relies on the ANGPTL4/IL-8/NOX4 axis and the activation of KRAS. The antioxidants and inactivation of KRAS also inhibited OA-induced EMT and metastasis. Although KRAS mediated EGF- and OA-promoted CRC cell invasion, the inhibition of EGFR did not affect OA-induced ANGPTL4/IL-8/NOX4 axis and CRC metastasis. The high-fat diet mice fed with vitamin E and statin or in IL-8-depleted cells significantly inhibited tumor extravasation and metastatic lung growth of CRC. Conclusion: The antioxidants, statins, and targeting IL-8 may provide better outcomes for treating metastatic CRC that harbors multigene mutations and anti-EGFR resistance.

Kinetic study of NADPH activation using ubiquinone-rhodol fluorescent probe and an IrIII-complex promoter at the cell interior.

Nicotine adenine dinucleotide derivatives NADH and NADPH are intimately involved in energy and electron transport within cells. The fluorescent ubiquinone-rhodol (Q-Rh) probe is used for NADPH activation monitoring. Q-Rh reacts with NADPH yielding its quenched hydroquinone-rhodol (H2Q-Rh) form with concurrent NADPH activation (i.e. NADP+ formation). NADPH activation can be enhanced by the addition of an IrIII-complex (i.e. [(η5-C5Me5)Ir(phen)(H2O)]2+) as a promoter. The rate of the Q-Rh fluorescence quenching process is proportional to the NADPH activation rate, which can be used to monitor NADPH. Experiments were performed in phosphate-buffered saline (PBS) solution and on HeLa cell cultures to analyze the kinetics of Q-Rh reduction and the influence of the IrIII-complex promoter on the activation of NADPH (in PBS) and of other intracellular reducing agents (in HeLa cells). There is a substantial increase in Q-Rh reduction rate inside HeLa cells especially after the addition of IrIII-complex promoter. This increase is partly due to a leakage process (caused by IrIII-complex-induced downstream processes which result in cell membrane disintegration) but also involves the nonspecific activation of other intracellular reducing agents, including NADH, FADH2, FMNH2 or GSH. In the presence only of Q-Rh, the activation rate of intracellular reducing agents is 2 to 8 times faster in HeLa cells than in PBS solution. When both Q-Rh and IrIII-complex are present, the rate of the IrIII-complex catalyzed reduction reaction is 7 to 23 times more rapid in HeLa cells. Concentration- and time-dependent fluorescence attenuation of Q-Rh with third-order reaction kinetics (reasonably approximated as pseudo-first-order in Q-Rh) has been observed and modelled. This reaction and its kinetics present an example of "bioparallel chemistry", where the activation of a molecule can trigger a unique chemical process. This approach stands in contrast to the conventional concept of "bioorthogonal chemistry", which refers to chemical reactions that occur without disrupting native biological processes.

Evaluation of some biochemical markers in alopecia areata

Background: It has recently evidenced that autoimmune diseases are associated with concurrent activation of inflammation, immune system, and coagulation. Given that alopecia areata (AA) is an autoimmune disease, there is a possibility that inflammation and coagulation processes may participate in the disease pathogenesis and could be associated with patients’ poor outcome. The aim of this work was to investigate the serum levels of some biochemical and hematological markers reflecting the inflammatory and coagulative status, as well as the thyroid functions in patients with AA. Patients and Methods: This study included 25 patients with AA and an equal number of matched healthy individuals. The study patients underwent laboratory investigations including erythrocyte sedimentation rate (ESR), complete blood count (CBC), C-reactive protein (CRP), fibrinogen, D-dimer, and thyroid stimulating hormone (TSH). ‎Results: Statistically significant lower MCH and platelets count, and higher WBCs count, ESR, CRP, D-dimer, and TSH were seen in patients with AA. Receiver Operating Characteristic Curve (ROC) revealed that all these markers were of predictive value of the disease occurrence. The CRP and D-dimer levels showed the best diagnostic performance with sensitivities of 92% for both, and specificities of 80% and 76%, respectively. Conclusion: This study supports the association between the coagulation system dysfunction, acute inflammatory state, and auto immune reactions in AA.

Perfluoroalkoxylation reaction via dual concurrent catalysis.

A catalytic amount of CsI enables dual concurrent activation of poorly reactive perfluoroalkoxide and alkyl halides, especially alkyl chlorides, leading to the formation of diverse perfluoroalkoxylated organic compounds. Installation of perfluoroalkoxy groups by this methodology is cost-effective, circumventing the need for over-stoichiometric cesium or silver salts. This methodology also provides high functional group compatibility and tolerance of sterically hindered substrates.