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1.
Front Neurosci ; 18: 1305939, 2024.
Article in English | MEDLINE | ID: mdl-38784099

ABSTRACT

The development of innovative non-invasive neuroimaging methods and biomarkers is critical for studying brain disease. Imaging of cerebrospinal fluid (CSF) pulsatility may inform the brain fluid dynamics involved in clearance of cerebral metabolic waste. In this work, we developed a methodology to characterize the frequency and spatial localization of whole brain CSF pulsations in humans. Using 7 Tesla (T) human magnetic resonance imaging (MRI) and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture pulsations of the CSF signal. Physiological data were simultaneously collected and compared with the 7 T MR data. The primary components of signal pulsations were identified using spectral analysis, with the most evident frequency bands identified around 0.3, 1.2, and 2.4 Hz. These pulsations were mapped spatially and temporally onto the MR image domain and temporally onto the physiological measures of electrocardiogram and respiration. We identified peaks in CSF pulsations that were distinct from peaks in grey matter and white matter regions. This methodology may provide novel in vivo biomarkers of disrupted brain fluid dynamics.

2.
J Neurosci Methods ; 407: 110133, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38588922

ABSTRACT

BACKGROUND: High-precision neurosurgical targeting in nonhuman primates (NHPs) often requires presurgical anatomical mapping with noninvasive neuroimaging techniques (MRI, CT, PET), allowing for translation of individual anatomical coordinates to surgical stereotaxic apparatus. Given the varied tissue contrasts that these imaging techniques produce, precise alignment of imaging-based coordinates to surgical apparatus can be cumbersome. MRI-compatible stereotaxis with radiopaque fiducial markers offer a straight-forward and reliable solution, but existing commercial options do not fit in conformal head coils that maximize imaging quality. NEW METHOD: We developed a compact MRI-compatible stereotaxis suitable for a variety of NHP species (Macaca mulatta, Macaca fascicularis, and Cebus apella) that allows multimodal alignment through technique-specific fiducial markers. COMPARISON WITH EXISTING METHODS: With the express purpose of compatibility with clinically available MRI, CT, and PET systems, the frame is no larger than a human head, while allowing for imaging NHPs in the supinated position. This design requires no marker implantation, special software, or additional knowledge other than the operation of a common large animal stereotaxis. RESULTS: We demonstrated the applicability of this 3D-printable apparatus across a diverse set of experiments requiring presurgical planning: 1) We demonstrate the accuracy of the fiducial system through a within-MRI cannula insertion and subcortical injection of a viral vector. 2) We also demonstrated accuracy of multimodal (MRI and CT) alignment and coordinate transfer to guide a surgical robot electrode implantation for deep-brain electrophysiology. CONCLUSIONS: The computer-aided design files and engineering drawings are publicly available, with the modular design allowing for low cost and manageable manufacturing.


Subject(s)
Brain Mapping , Cebus , Magnetic Resonance Imaging , Animals , Magnetic Resonance Imaging/methods , Magnetic Resonance Imaging/instrumentation , Brain Mapping/methods , Brain Mapping/instrumentation , Stereotaxic Techniques/instrumentation , Brain/diagnostic imaging , Brain/surgery , Brain/anatomy & histology , Fiducial Markers , Multimodal Imaging/methods , Multimodal Imaging/instrumentation , Macaca mulatta , Male
3.
Mult Scler Relat Disord ; 86: 105520, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38582026

ABSTRACT

BACKGROUND: Previous studies have shown that thalamic and hippocampal neurodegeneration is associated with clinical decline in Multiple Sclerosis (MS). However, contributions of the specific thalamic nuclei and hippocampal subfields require further examination. OBJECTIVE: Using 7 Tesla (7T) magnetic resonance imaging (MRI), we investigated the cross-sectional associations between functionally grouped thalamic nuclei and hippocampal subfields volumes and T1 relaxation times (T1-RT) and subsequent clinical outcomes in MS. METHODS: High-resolution T1-weighted and T2-weighted images were acquired at 7T (n=31), preprocessed, and segmented using the Thalamus Optimized Multi Atlas Segmentation (THOMAS, for thalamic nuclei) and the Automatic Segmentation of Hippocampal Subfields (ASHS, for hippocampal subfields) packages. We calculated Pearson correlations between hippocampal subfields and thalamic nuclei volumes and T1-RT and subsequent multi-modal rater-determined and patient-reported clinical outcomes (∼2.5 years after imaging acquisition), correcting for confounders and multiple tests. RESULTS: Smaller volume bilaterally in the anterior thalamus region correlated with worse performance in gait function, as measured by the Patient Determined Disease Steps (PDDS). Additionally, larger volume in most functional groups of thalamic nuclei correlated with better visual information processing and cognitive function, as measured by the Symbol Digit Modalities Test (SDMT). In bilateral medial and left posterior thalamic regions, there was an inverse association between volumes and T1-RT, potentially indicating higher tissue degeneration in these regions. We also observed marginal associations between the right hippocampal subfields (both volumes and T1-RT) and subsequent clinical outcomes, though they did not survive correction for multiple testing. CONCLUSION: Ultrahigh field MRI identified markers of structural damage in the thalamic nuclei associated with subsequently worse clinical outcomes in individuals with MS. Longitudinal studies will enable better understanding of the role of microstructural integrity in these brain regions in influencing MS outcomes.


Subject(s)
Hippocampus , Magnetic Resonance Imaging , Multiple Sclerosis , Thalamic Nuclei , Humans , Hippocampus/diagnostic imaging , Hippocampus/pathology , Male , Female , Adult , Thalamic Nuclei/diagnostic imaging , Thalamic Nuclei/pathology , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Middle Aged , Cross-Sectional Studies
4.
Curr Protoc ; 4(3): e998, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38439594

ABSTRACT

Protein kinases catalyze the phosphorylation of proteins most commonly on Ser, Thr, and Tyr residues and regulate many cellular events in eukaryotic cells, such as cell cycle progression, transcription, metabolism, and apoptosis. Protein kinases each have a conserved ATP-binding site and one or more substrate-binding site(s) that exhibit recognition features for different protein substrates. By bringing ATP and a substrate into proximity, each protein kinase can transfer the γ phosphate of the ATP molecule to a hydroxyl group of the target residue on the substrate. In such a way, signaling pathways downstream from the substrate can be regulated based on the phosphorylated versus dephosphorylated status of the substrate. Although there are a number of ways to assay the activity of protein kinases, most of them are technically cumbersome and/or are indirect or based on quenched reactions. This protocol describes an assay employing a fluorescent peptide substrate to detect phosphorylation by protein kinases in real time. The assay is based on the principle that the phosphorylation of the peptide substrate leads to an increase in the fluorescence emission intensity of an appended fluorophore. We extend the application of this assay to an example of how to assess time-dependent covalent inhibition of kinases as well. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Measuring protein kinase activity using fluorescent peptides Alternate Protocol: Measuring protein kinase activity using a fluorescence plate reader Support Protocol: Labeling peptides with sox fluorophore Basic Protocol 2: Measuring time-dependent ATP-competitive inhibition of protein kinases using fluorescent peptides.


Subject(s)
Peptides , Protein Kinases , Phosphorylation , Fluorescent Dyes , Adenosine Triphosphate
5.
Brain Struct Funct ; 229(2): 273-283, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37812278

ABSTRACT

The paraventricular nucleus of the hypothalamus (PVN) is uniquely capable of proximal control over autonomic and neuroendocrine stress responses, and the bed nucleus of the stria terminalis (BNST) directly modulates PVN function, as well as playing an important role in stress control itself. The dorsal BNST (dBNST) is predominantly preautonomic, while the ventral BNST (vBNST) is predominantly viscerosensory, receiving dense noradrenergic signaling. Distinguishing the dBNST and vBNST, along with the PVN, may facilitate our understanding of dynamic interactions among these regions. T1-weighted MPRAGE and high resolution gradient echo (GRE) modalities were acquired at 7T. GRE was coregistered to MPRAGE and segmentations were performed in MRIcroGL based on their Atlas of the Human Brain depictions. The dBNST, vBNST and PVN were manually segmented in 25 participants; 10 images were rated by 2 raters. These segmentations were normalized and probabilistic atlases for each region were generated in MNI space, now available as resources for future research. We found moderate-high inter-rater reliability [n = 10; Mean Dice (SD); PVN = 0.69 (0.04); dBNST = 0.77 (0.04); vBNST = 0.62 (0.04)]. Probabilistic atlases were reverse normalized into native space for six additional participants that were segmented but not included in the original 25. We also found moderate to moderate-high reliability between the probabilistic atlases and manual segmentations [n = 6; Mean Dice (SD); PVN = 0.55 (0.12); dBNST = 0.60 (0.10); vBNST = 0.47 (0.12 SD)]. By isolating these hypothalamic and BNST subregions using ultra-high field MRI modalities, more specific delineations of these regions can facilitate greater understanding of mechanisms underlying stress-related function and psychopathology.


Subject(s)
Paraventricular Hypothalamic Nucleus , Septal Nuclei , Humans , Septal Nuclei/diagnostic imaging , Septal Nuclei/physiology , Reproducibility of Results , Signal Transduction , Magnetic Resonance Imaging
6.
medRxiv ; 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38105931

ABSTRACT

Development of innovative non-invasive neuroimaging methods and biomarkers are critical for studying brain disease. In this work, we have developed a methodology to characterize the frequency responses and spatial localization of oscillations and movements of cerebrospinal fluid (CSF) flow in the human brain. Using 7 Tesla human MRI and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture CSF oscillations and movements. Physiological data was simultaneously collected and correlated with the 7T MR data. The primary components of CSF oscillations were identified using spectral analysis (with frequency bands identified around 0.3Hz, 1.2Hz and 2.4Hz) and were mapped spatially and temporally onto the MR image domain and temporally onto the physiological domain. The developed methodology shows a good consistency and repeatability (standard deviation of 0.052 and 0.078 for 0.3Hz and 1.2Hz bands respectively) in-vivo for potential brain dynamics and CSF flow and clearance studies.

7.
Europace ; 25(12)2023 12 06.
Article in English | MEDLINE | ID: mdl-38006390

ABSTRACT

AIMS: The mechanisms of transition from regular rhythms to ventricular fibrillation (VF) are poorly understood. The concordant to discordant repolarization alternans pathway is extensively studied; however, despite its theoretical centrality, cannot guide ablation. We hypothesize that complex repolarization dynamics, i.e. oscillations in the repolarization phase of action potentials with periods over two of classic alternans, is a marker of electrically unstable substrate, and ablation of these areas has a stabilizing effect and may reduce the risk of VF. To prove the existence of higher-order periodicities in human hearts. METHODS AND RESULTS: We performed optical mapping of explanted human hearts obtained from recipients of heart transplantation at the time of surgery. Signals recorded from the right ventricle endocardial surface were processed to detect global and local repolarization dynamics during rapid pacing. A statistically significant global 1:4 peak was seen in three of six hearts. Local (pixel-wise) analysis revealed the spatially heterogeneous distribution of Periods 4, 6, and 8, with the regional presence of periods greater than two in all the hearts. There was no significant correlation between the underlying restitution properties and the period of each pixel. CONCLUSION: We present evidence of complex higher-order periodicities and the co-existence of such regions with stable non-chaotic areas in ex vivo human hearts. We infer that the oscillation of the calcium cycling machinery is the primary mechanism of higher-order dynamics. These higher-order regions may act as niduses of instability and may provide targets for substrate-based ablation of VF.


Subject(s)
Heart Ventricles , Heart , Humans , Arrhythmias, Cardiac , Ventricular Fibrillation/surgery , Action Potentials/physiology
8.
Curr Protoc ; 3(9): e839, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37668419

ABSTRACT

Only 1 out of 4 mammalian arrestin subtypes, arrestin-3, facilitates the activation of c-Jun N-terminal kinase (JNK) family kinases. Here, we describe two different sets of protocols used for elucidating the mechanisms involved. One is based on reconstitution of signaling modules from the following purified proteins: arrestin-3, MKK4, MKK7, JNK1, JNK2, and JNK3. The main advantage of this method is that it unambiguously establishes which effects are direct because only intended purified proteins are present in these assays. The key drawback is that the upstream-most kinases of these cascades, ASK1 or other MAP3Ks, are not available in purified form, limiting reconstitution to incomplete two-kinase modules. The other approach is used for analyzing the effects of arrestin-3 on JNK activation in intact cells. In this case, signaling modules include ASK1 and/or other MAP3Ks. However, as every cell expresses thousands of different proteins, their possible effects on the readout cannot be excluded. Nonetheless, the combination of in vitro reconstitution from purified proteins and cell-based assays makes it possible to elucidate the mechanisms of arrestin-3-dependent activation of JNK family kinases. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Construction of arrestin-3-scaffolded MKK4/7-JNK1/2/3 signaling modules in vitro using purified proteins Alternate Protocol 1: Characterization of arrestin-3-mediated JNK1/2 activation by MKK4/7 by measurement of JNK1/2 phosphorylation using immunoblotting with anti-phospho-JNK antibody Support Protocol 1: Expression, purification, and activation of GST-MKK4 Support Protocol 2: Expression, purification, and activation of GST-MKK7-His6 Support Protocol 3: Expression, purification, and activation of tagless JNK1Α1 Support Protocol 4: Expression, purification, and activation of tagless JNK2Α2 Basic Protocol 2: Analysis of the role of arrestin-3 in ASK1/MKK4/MKK7-induced JNK activation in intact cells Alternate Protocol 2: Analysis of the role of arrestin-3 in MKK4-induced JNK activation in intact cells Basic Protocol 3: Characterization of the biphasic effect of arrestin-3 on ASK1/MKK7-stimulated JNK phosphorylation in cells.


Subject(s)
JNK Mitogen-Activated Protein Kinases , Protein Processing, Post-Translational , Animals , Phosphorylation , beta-Arrestin 2 , Arrestins , MAP Kinase Kinase 4 , beta-Arrestin 1/genetics , Mammals
9.
iScience ; 26(10): 107817, 2023 Oct 20.
Article in English | MEDLINE | ID: mdl-37744034

ABSTRACT

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are dysregulated in many pervasive diseases. Recently, we discovered that ERK1/2 is oxidized by signal-generated hydrogen peroxide in various cell types. Since the putative sites of oxidation lie within or near ERK1/2's ligand-binding surfaces, we investigated how oxidation of ERK2 regulates interactions with the model substrates Sub-D and Sub-F. These studies revealed that ERK2 undergoes sulfenylation at C159 on its D-recruitment site surface and that this modification modulates ERK2 activity differentially between substrates. Integrated biochemical, computational, and mutational analyses suggest a plausible mechanism for peroxide-dependent changes in ERK2-substrate interactions. Interestingly, oxidation decreased ERK2's affinity for some D-site ligands while increasing its affinity for others. Finally, oxidation by signal-generated peroxide enhanced ERK1/2's ability to phosphorylate ribosomal S6 kinase A1 (RSK1) in HeLa cells. Together, these studies lay the foundation for examining crosstalk between redox- and phosphorylation-dependent signaling at the level of kinase-substrate selection.

10.
medRxiv ; 2023 Aug 21.
Article in English | MEDLINE | ID: mdl-37662394

ABSTRACT

Background: Repolarization alternans, defined as period-2 oscillation in the repolarization phase of the action potentials, provides a mechanistic link between cellular dynamics and ventricular fibrillation (VF). Theoretically, higher-order periodicities (e.g., periods 4, 6, 8,...) are expected but have minimal experimental evidence. Methods: We studied explanted human hearts obtained from recipients of heart transplantation at the time of surgery. Optical mapping of the transmembrane potential was performed after staining the hearts with voltage-sensitive fluorescent dyes. Hearts were stimulated at an increasing rate until VF was induced. Signals recorded from the right ventricle endocardial surface prior to induction of VF and in the presence of 1:1 conduction were processed using the Principal Component Analysis and a combinatorial algorithm to detect and quantify higher-order dynamics. Results were correlated to the underlying electrophysiological characteristics as quantified by restitution curves and conduction velocity. Results: A prominent and statistically significant global 1:4 peak (corresponding to period-4 dynamics) was seen in three of the six studied hearts. Local (pixel-wise) analysis revealed the spatially heterogeneous distribution of periods 4, 6, and 8, with the regional presence of periods greater than two in all the hearts. There was no significant correlation between the underlying restitution properties and the period of each pixel. Discussion: We present evidence of higher-order periodicities and the co-existence of such regions with stable non-chaotic areas in ex-vivo human hearts. We infer from the independence of the period to the underlying restitution properties that the oscillation of the excitation-contraction coupling and calcium cycling mechanisms is the primary mechanism of higher-order dynamics. These higher-order regions may act as niduses of instability that can degenerate into chaotic fibrillation and may provide targets for substrate-based ablation of VF.

11.
Materials (Basel) ; 16(15)2023 Aug 04.
Article in English | MEDLINE | ID: mdl-37570181

ABSTRACT

This paper studies the effect of the laser melting process (LMP) on the microstructure and hardness of a new modified AlCuMgMn alloy with zirconium (Zr) and Yttrium (Y) elements. Homogenized (480 °C/8 h) alloys were laser-surface-treated at room temperature and a heating platform with in situ heating conditions was used in order to control the formed microstructure by decreasing the solidification rate in the laser-melted zone (LMZ). Modifying the AlCuMgMn alloy with 0.4 wt% Zr and 0.6 wt% Y led to a decrease in grain size by 25% with a uniform grain size distribution in the as-cast state due to the formation of Al3(Y, Zr). The homogenization dissolved the nonequilibrium intermetallic phases into the (Al) matrix and spheroidized and fragmentized the equilibrium phase's particles, which led to the solidification of the crack-free LM zone with a nonuniform grain structure. The microstructure in the LMZ was improved by using the in situ heating approach, which decreased the temperature gradient between the BM and the melt pool. Two different microstructures were observed: ultrafine grains at the boundaries of the melted pool due to the extremely high concentration of optimally sized Al3(Y, Zr) and fine equiaxed grains at the center of the LMZ. The combination of the presence of ZrY and applying a heating platform during the LMP increased the hardness of the LMZ by 1.14 times more than the hardness of the LMZ of the cast AlCuMgMn alloy.

12.
Molecules ; 28(13)2023 Jun 25.
Article in English | MEDLINE | ID: mdl-37446653

ABSTRACT

For the creation of adaptable carbonyl compounds in organic synthesis, the oxidation of alcohols is a crucial step. As a sustainable alternative to the harmful traditional oxidation processes, transition-metal catalysts have recently attracted a lot of interest in acceptorless dehydrogenation reactions of alcohols. Here, using well-defined, air-stable palladium(II)-NHC catalysts (A-F), we demonstrate an effective method for the catalytic acceptorless dehydrogenation (CAD) reaction of secondary benzylic alcohols to produce the corresponding ketones and molecular hydrogen (H2). Catalytic acceptorless dehydrogenation (CAD) has been successfully used to convert a variety of alcohols, including electron-rich/electron-poor aromatic secondary alcohols, heteroaromatic secondary alcohols, and aliphatic cyclic alcohols, into their corresponding value-added ketones while only releasing molecular hydrogen as a byproduct.


Subject(s)
Alcohols , Ketones , Hydrogen , Catalysis , Palladium
13.
N Engl J Med ; 388(23): 2121-2131, 2023 Jun 08.
Article in English | MEDLINE | ID: mdl-37285526

ABSTRACT

BACKGROUND: Data showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited. METHODS: We conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation. RESULTS: A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation. CONCLUSIONS: In this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.).


Subject(s)
Brain Death , Heart Transplantation , Tissue and Organ Procurement , Adult , Humans , Graft Survival , Organ Preservation , Tissue Donors , Death , Patient Safety
14.
Polymers (Basel) ; 15(12)2023 Jun 13.
Article in English | MEDLINE | ID: mdl-37376308

ABSTRACT

This research sought to synthesize a new set of heteroaromatic thiazole-based polyurea derivatives with sulfur links in the polymers' main chains, which were denoted by the acronyms PU1-5. Using pyridine as a solvent, a diphenylsulfide-based aminothiazole monomer (M2) was polymerized via solution polycondensation with varied aromatic, aliphatic, and cyclic diisocyanates. Typical characterization methods were used to confirm the structures of the premonomer, monomer, and fully generated polymers. The XRD results revealed that aromatic-based polymers had higher crystallinity than aliphatic and cyclic derivatives. SEM was used to visualize the surfaces of PU1, PU4, and PU5, revealing spongy and porous shapes, shapes resembling wooden planks and sticks, and shapes resembling coral reefs with floral shapes at various magnifications. The polymers demonstrated thermal stability. The numerical results for PDTmax are listed in the following order, ranked from lowest to highest: PU1 < PU2 < PU3 < PU5 < PU4. The FDT values for the aliphatic-based derivatives (PU4 and PU5) were lower than those for the aromatic-based ones (616, 655, and 665 °C). PU3 showed the greatest inhibitory impact against the bacteria and fungi under investigation. In addition, PU4 and PU5 demonstrated antifungal activities that, in contrast with the other products, were on the lower end of the spectrum. Furthermore, the intended polymers were also tested for the presence of the proteins 1KNZ, 1JIJ, and 1IYL, which are frequently utilized as model organisms for E. coli (Gram-negative bacteria), S. aureus (Gram-positive bacteria), and C. albicans (fungal pathogens). This study's findings are consistent with the outcomes of the subjective screening.

15.
bioRxiv ; 2023 May 02.
Article in English | MEDLINE | ID: mdl-37205562

ABSTRACT

Background: Repolarization alternans, defined as period-2 oscillation in the repolarization phase of the action potentials, is one of the cornerstones of cardiac electrophysiology as it provides a mechanistic link between cellular dynamics and ventricular fibrillation (VF). Theoretically, higher-order periodicities (e.g., period-4, period-8,...) are expected but have very limited experimental evidence. Methods: We studied explanted human hearts, obtained from the recipients of heart transplantation at the time of surgery, using optical mapping technique with transmembrane voltage-sensitive fluorescent dyes. The hearts were stimulated at an increasing rate until VF was induced. The signals recorded from the right ventricle endocardial surface just before the induction of VF and in the presence of 1:1 conduction were processed using the Principal Component Analysis and a combinatorial algorithm to detect and quantify higher-order dynamics. Results: A prominent and statistically significant 1:4 peak (corresponding to period-4 dynamics) was seen in three of the six studied hearts. Local analysis revealed the spatiotemporal distribution of higher-order periods. Period-4 was localized to temporally stable islands. Higher-order oscillations (period-5, 6, and 8) were transient and primarily occurred in arcs parallel to the activation isochrones. Discussion: We present evidence of higher-order periodicities and the co-existence of such regions with stable non-chaotic areas in ex-vivo human hearts before VF induction. This result is consistent with the period-doubling route to chaos as a possible mechanism of VF initiation, which complements the concordant to discordant alternans mechanism. The presence of higher-order regions may act as niduses of instability that can degenerate into chaotic fibrillation.

16.
Elife ; 122023 03 21.
Article in English | MEDLINE | ID: mdl-36942851

ABSTRACT

To address the ongoing SARS-CoV-2 pandemic and prepare for future coronavirus outbreaks, understanding the protective potential of epitopes conserved across SARS-CoV-2 variants and coronavirus lineages is essential. We describe a highly conserved, conformational S2 domain epitope present only in the prefusion core of ß-coronaviruses: SARS-CoV-2 S2 apex residues 980-1006 in the flexible hinge. Antibody RAY53 binds the native hinge in MERS-CoV and SARS-CoV-2 spikes on the surface of mammalian cells and mediates antibody-dependent cellular phagocytosis and cytotoxicity against SARS-CoV-2 spike in vitro. Hinge epitope mutations that ablate antibody binding compromise pseudovirus infectivity, but changes elsewhere that affect spike opening dynamics, including those found in Omicron BA.1, occlude the epitope and may evade pre-existing serum antibodies targeting the S2 core. This work defines a third class of S2 antibody while providing insights into the potency and limitations of S2 core epitope targeting.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Animals , Spike Glycoprotein, Coronavirus/genetics , SARS-CoV-2 , Antibodies , Epitopes , Antibodies, Viral , Antibodies, Neutralizing , Mammals
17.
Molecules ; 28(5)2023 Mar 03.
Article in English | MEDLINE | ID: mdl-36903598

ABSTRACT

We reported herein efficient economic high-pressure synthesis procedures for the synthesis of bis(azoles) and bis(azines) by utilizing the bis(enaminone) intermediate. Bis(enaminone) reacted with hydrazine hydrate, hydroxylamine hydrochloride, guanidine hydrochloride, urea, thiourea, and malononitrile to form the desired bis azines and bis azoles. A combination of elemental analyses and spectral data was used to confirm the structures of the products. Compared with conventional heating, the high-pressure Q-Tube method promotes reactions in a short period of time and provides high yields.

18.
Materials (Basel) ; 16(6)2023 Mar 08.
Article in English | MEDLINE | ID: mdl-36984050

ABSTRACT

Recently, efficient decontamination of water and wastewater have attracted global attention due to the deficiency in the world's water sources. Herein, activated carbon (AC) derived from willow catkins (WCs) was successfully synthesized using chemical modification techniques and then loaded with different weight percentages of nickel ferrite nanocomposites (10, 25, 45, and 65 wt.%) via a one-step hydrothermal method. The morphology, chemical structure, and surface composition of the nickel ferrite supported on AC (NFAC) were analyzed by XRD, TEM, SEM, EDX, and FTIR spectroscopy. Textural properties (surface area) of the nanocomposites (NC) were investigated by using Brunauer-Emmett-Teller (BET) analysis. The prepared nanocomposites were tested on different dyes to form a system for water remediation and make this photocatalyst convenient to recycle. The photodegradation of rhodamine B dye was investigated by adjusting a variety of factors such as the amount of nickel in nanocomposites, the weight of photocatalyst, reaction time, and photocatalyst reusability. The 45NFAC photocatalyst exhibits excellent degradation efficiency toward rhodamine B dye, reaching 99.7% in 90 min under a simulated source of sunlight. To summarize, NFAC nanocomposites are potential photocatalysts for water environmental remediation because they are effective, reliable, and reusable.

19.
Materials (Basel) ; 16(4)2023 Feb 15.
Article in English | MEDLINE | ID: mdl-36837254

ABSTRACT

In this work, 2 mm thick medium-Mn austenitic stainless steel (MMn-SS) plates were joined with austenitic NiCr stainless steel (NiCr-SS) and low-carbon steel (LCS) using the gas tungsten arc welding technique. A precise adjustment of the welding process parameters was conducted to achieve high-quality dissimilar joints of MMn-SS with NiCr-SS and LCS. The microstructural evolution was studied using laser scanning confocal and electron microscopes. Secondary electron imaging and electron backscatter diffraction (EBSD) techniques were intensively employed to analyze the fine features of the weld structures. The mechanical properties of the joints were evaluated by uniaxial tensile tests and micro-indentation hardness (HIT). The microstructure of the fusion zone (FZ) in the MMn-SS joints exhibited an austenitic matrix with a small fraction of δ-ferrite, ~6%. The tensile strength (TS) of the MMn-SS/NiCr-SS joint is significantly higher than that of the MMn-SS/LCS joint. For instance, the TSs of MMn-SS joints with NiCr-SS and LCS are 610 and 340 MPa, respectively. The tensile properties of MMn-SS/LCS joints are similar to those of BM LCS, since the deformation behavior and shape of the tensile flow curve for that joint are comparable with the flow curve of LCS. The HIT measurements show that the MMn-SS/NiCr-SS joint is significantly stronger than the MMn-SS/LCS joint since the HIT values are 2.18 and 1.85 GPa, respectively.

20.
Heliyon ; 8(11): e11729, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36468107

ABSTRACT

Climate change is a challenge that endangers societal TBL elements' stability. The countries' economies focus on planning for reducing carbon emissions 'CE' and replacing them with low CE energy. This objective needs accurate prediction for CE till 2030 via recording the most significant variables related to CE causes. The variables ( L i q ) are divided into two types tacking in phase I through two steps. The first step classifying the government policies that tackling by the backcasting approach to ranking them. The second step classifies the nature of the energy source which produces CE in Mega ton by SVM. The second phase is fed by phase I outputs to generate a series of prediction values by the LSTM, which is supported by the grey recruitment technique GRPT ( 1 , 1 ) to reduce the forecasting errors. The proposed conceptual framework named (Green Eco-Safety Monitoring; GESM), which considered a methodology gathering the backcasting, SVM, and LSTM provided by GRPT ( 1 , 1 ) in phase II. The paper tracks 21 governorates' CE. Proactive monitoring helps take corrective actions, enhancing the reduction in errors gap to less than 2.4%. The paper reveals that the industrial sector extracting CE at (38.67%) to 2020 with hopeful reduction of 1.72% annually if the government's interested in supporting carbon sinks, which drastically decreased to 1% by 2020 and to 0.72% annually by 2030.

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