Porcine islet xenografts have the potential to provide an inexhaustible source of islets for β cell replacement. Proof‐of‐concept has been established in nonhuman primates. However, significant ...barriers to xenoislet transplantation remain, including the poorly understood instant blood‐mediated inflammatory reaction and a thorough understanding of early xeno‐specific immune responses. A paucity of data exist comparing xeno‐specific immune responses with alloislet (AI) responses in primates. We recently developed a dual islet transplant model, which enables direct histologic comparison of early engraftment immunobiology. In this study, we investigate early immune responses to neonatal porcine islet (NPI) xenografts compared with rhesus islet allografts at 1 hour, 24 hours, and 7 days. Within the first 24 hours after intraportal infusion, we identified greater apoptosis (caspase 3 activity and TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling)‐positive cells) of NPIs compared with AIs. Macrophage infiltration was significantly greater at 24 hours compared with 1 hour in both NPI (wild‐type) and AIs. At 7 days, IgM and macrophages were highly specific for NPIs (α1,3‐galactosyltransferase knockout) compared with AIs. These findings demonstrate an augmented macrophage and antibody response toward xenografts compared with allografts. These data may inform future immune or genetic manipulations required to improve xenoislet engraftment.
A nonhuman primate dual transplant model of islet transplantation compares allogeneic islets to porcine xenogeneic islets and demonstrates an augmented macrophage and antibody response toward xenografts and an early increase in xenograft cell death.
Abstract
The fast transitions between different types of quasi-periodic oscillations (QPOs) are generally observed in black hole transient sources (BHTs). We present a detailed study of the timing ...and spectral properties of the transitions of type-B QPOs in MAXI J1348–630, observed by Insight-HXMT. The fractional rms variability–energy relationship and energy spectra reveal that type-B QPOs probably originate from jet precession. Compared to a weak power-law dominated power spectrum, when type-B QPOs are present, the corresponding energy spectrum shows an increase in the Comptonization component and the need for the
xillverCp
component, and a slight increase in the height of the corona when using the
relxilllp
model. Therefore, we suggest that a coupled inner disk-jet region is responsible for the observed type-B QPO transitions. The timescale for the appearance/disappearance of type-B QPOs is either long or short (seconds), which may indicate instability of the disk-jet structure. For these phenomena, we hypothesize that the Bardeen–Petterson effect causes the disk-jet structure to align with the BH spin axis or that the disappearance of small-scale jets bound by the magnetic flux tubes leads to the disappearance of type-B QPOs. We observed three events regarding the B/C transitions, one of which occurred over a short time period from ∼9.2 Hz (C) to ∼4.8 Hz (B). The energy spectral analysis for the other two transitions shows that when type-C QPO is present, the Comptonization flux is higher, the spectrum is harder, and the inner radius of the disk changes insignificantly. We suggest that type-C QPOs probably originate from relatively stronger jets or the corona.
Abstract
The X9.3 flare SOL20170906T11:55 was observed by the CsI detector aboard the first Chinese X-ray observatory Hard X-ray Modulation telescope (Insight-HXMT). Using the wavelets method, we ...report 22 s quasiperiodic pulsations during the impulsive phase. The spectra from 100 keV to 800 keV show the evolution with the gamma-ray flux of a power-law photon index from ∼1.8 before the peak, ∼2.0 around the flare peak, to ∼1.8 again. The gyrosynchrotron microwave spectral analysis reveals a 36.″6 ± 0.″6 radius gyrosynchrotron source with mean transverse magnetic field around 608.2 Gauss. The penetrated ≥10 keV non-thermal electron density is about 10
6.7
cm
−3
at peak time. The magnetic field strength followed the evolution of high-frequency radio flux. Further gyrosynchrotron source modeling analysis implies that there exists a quite steady gyrosynchrotron source, and the non-thermal electron density and transverse magnetic field evolution are similar to higher-frequency light curves. The temporal spectral analysis reveals that those non-thermal electrons are accelerated by repeated magnetic reconnection, likely from a lower corona source.
β‐Amyloid peptide (Aβ), a 39 – 43 amino acid peptide, is believed to induce oxidative stress and inflammation in the brain, which are postulated to play important roles in the pathogenesis of ...Alzheimer's disease. Ferulic acid is an antioxidant and anti‐inflammatory agent derived from plants; therefore, the potential protective activity of ferulic acid against Aβ toxicity in vivo was examined.
Mice were allowed free access to drinking water (control) or water containing ferulic acid (0.006%). After 4 weeks, Aβ1‐42 (410 pmol) was administered via intracerebroventricular injection.
Injection of control mice with Aβ1‐42 impaired performance on the passive avoidance test (35% decrease in step‐through latency), the Y‐maze test (19% decrease in alternation behaviour), and the water maze test (32% decrease in percentage time in platform‐quadrant). In contrast, mice treated with ferulic acid prior to Aβ1‐42 administration were protected from these changes (9% decrease in step‐through latency; no decrease in alternation behaviour; 14% decrease in percentage time in platform‐quadrant). Aβ1‐42 induced 31% decrease in acetylcholine level in the cortex, which was tended to be ameliorated by ferulic acid.
In addition, Aβ1‐42 increased immunoreactivities of the astrocyte marker glial fibrillary acidic protein (GFAP) and interleukin‐1β (IL‐1β) in the hippocampus, effects also suppressed by pretreatment with ferulic acid.
Administration of ferulic acid per se unexpectedly induced a transient and slight increase in GFAP and IL‐1β immunoreactivity in the hippocampus on day 14, which returned to basal levels on day 28. A slight (8%) decrease in alternation behaviour was observed on day 14.
These results demonstrate that long‐term administration of ferulic acid induces resistance to Aβ1‐42 toxicity in the brain, and suggest that ferulic acid may be a useful chemopreventive agent against Alzheimer's disease.
British Journal of Pharmacology (2001) 133, 89–96; doi:10.1038/sj.bjp.0704047
Costimulation blockade (CoB) via belatacept is a lower‐morbidity alternative to calcineurin inhibitor (CNI)‐based immunosuppression. However, it has higher rates of early acute rejection. These early ...rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)‐1. LFA‐1 exists in two forms: a commonly expressed, low‐affinity form and a transient, high‐affinity form, expressed only during activation. We have shown that antibodies reactive with LFA‐1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL‐579, each of which targets the high‐affinity form of LFA‐1, to determine whether this more precise targeting prevents belatacept‐resistant rejection. Despite evidence of ex vivo and in vivo ligand‐specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL‐579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA‐1 blockade may not be a suitable adjuvant agent for CoB‐resistant rejection.
This study examines the use of belatacept with either depletion or inhibition of the high‐affinity form of LFA‐1 in a nonhuman primate model of kidney transplantation.
Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal ...dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear.
To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands.
TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations.
The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.
We report a unique hydrologic time series which indicates that water levels in lakes and aquifers across the upper Great Lakes region of North America have been dominated by a climatically driven, ...near‐decadal oscillation for at least 70 years. The historical oscillation (~13 years) is remarkably consistent among small seepage lakes, groundwater tables, and the two largest Laurentian Great Lakes despite substantial differences in hydrology. Hydrologic analyses indicate that the oscillation has been governed primarily by changes in the net atmospheric flux of water (P − E) and stage‐dependent outflow. The oscillation is hypothetically connected to large‐scale atmospheric circulation patterns originating in the midlatitude North Pacific that support the flux of moisture into the region from the Gulf of Mexico. Recent data indicate an apparent change in the historical oscillation characterized by an ~12 years downward trend beginning in 1998. Record low water levels region wide may mark the onset of a new hydroclimatic regime.
Key Points
A climatically driven decadal oscillation dominates the regional water cycle
The oscillation is governed by (P − E) and a stage‐dependent runoff flux
A recent change in oscillation may mark the onset of a new hydroclimatic regime
We aimed to analyze clinical characteristics, treatment patterns, and prognosis of patients with reversible cerebral vasoconstriction syndrome (RCVS).
Two investigators independently searched PubMed ...and EMBASE, and 191 cases were included in this study. Information regarding demographics, triggering factors, brain imaging findings, treatment modalities, recurrence, and clinical outcome was collected.
The mean age of the patients was 39.9 years, and 155 (81.2%) were female. The most common triggering factor for RCVS was an exposure to vasoactive substances (41.4%), followed by pregnancy/postpartum (20.9%), and sexual intercourse (10.5%). Multifocal stenosis (84.0%) and beading shape (82.4%) were the leading abnormal findings on angiography, while cerebral ischemic lesions (47.6%) and cerebral hemorrhage (mainly subarachnoid hemorrhage) (35.1%) were the main findings on brain computed tomography (CT)/magnetic resonance imaging (MRI). Calcium channel blockers (nimodipine/verapamil) were the most commonly used medications (44.5%) in the treatment of RCVS. Multivariate analysis identified that RCVS was precipitated by trauma/surgery/procedure (hazard ratio (HR): 3.29, 95% confidence interval (CI) (1.21-8.88), p=0.019), and presence of aphasia/neglect/apraxia during the acute phase of the disease (HR: 3.83, 95% CI (1.33-11.05), p=0.013) were found to be the two independent risk factors for residual neurological deficit after RCVS.
In our systematic review, vasoactive substances were the most frequent triggers for RCVS, which was most commonly accompanied by angiographic findings of multifocal stenotic lesions. Patients with RCVS precipitated by trauma or surgical procedures and those with focal cortical deficits had a higher risk of residual neurological deficits, and these patients should closely be monitored.
ABSTRACT
In this paper, we presented a detailed timing analysis of a prominent outburst of 4U 0115+63 detected by Insight-HXMT in 2017 August. The spin period of the neutron star was determined to be ...3.613 98 ± 0.000 02 s at MJD 57978. We measured the period variability and extract the orbital elements of the binary system. The angle of periastron evolved with a rate of $0.048^\circ \pm 0.003^\circ \rm \, yr^{-1}$. The light curves are folded to sketch the pulse profiles in different energy ranges. A multipeak structure in 1–10 keV is clearly illustrated. We introduced wavelet analysis into our data analysis procedures to study quasi-periodic oscillation (QPO) signals and perform a detailed wavelet analysis in many different energy ranges. Through the wavelet spectra, we report the discovery of a QPO at the frequency of ∼10 mHz. In addition, the X-ray light curves showed multiple QPOs in the period of ∼16–32 and ∼67–200 s. We found that the ∼100 s QPO was significant in most of the observations and energies. There exist positive relations between X-ray luminosity and their Q-factors and S-factors, while the QPO periods have no correlation with X-ray luminosity. In wavelet phase maps, we found that the pulse phase of ∼67–200 s QPO is drifting frequently while that of ∼16–32 s QPO is scarcely drifting. The dissipation of oscillations from high energy to low energy was also observed. These features of QPOs in 4U 0115+63 provide a new challenge to our understanding of their physical origins.
We have obtained Spitzer Space Telescope MIPS (Multiband Imaging Photometer for Spitzer) observations of 39 A- through M-type dwarfs, with estimated ages between 12 and 600 Myr; IRAC observations for ...a subset of 11 stars; and follow-up CSO SHARCII 350 km observations for a subset of two stars. None of the objects observed with IRAC possess infrared excesses at 3.6-8.0 km; however, seven objects observed with MIPS possess 24 and/or 70 km excesses. Four objects ( Phe, HD 92945, HD 119124, and AU Mic), with estimated ages 12-200 Myr, possess strong 70 km excesses, .100% larger than their predicted photospheres, and no 24 km excesses, suggesting that the dust grains in these systems are cold. One object (HD 112429) possesses moderate 24 and 70 km excesses with a color temperature, T sub(gr) = 100 K. Two objects (a super(1) Lib and HD 177724) possess such strong 24 km excesses that their 12,24, and 70 km fluxes cannot be self-consistently modeled using a modified blackbody despite a 70 km excess >2 times greater than the photosphere around a super(1) Lib. The strong 24 km excesses may be the result of emission in spectral features, as observed toward the Hale-Bopp star HD 69830.
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