BACKGROUND AND PURPOSE—In malignant infarction, brain edema leads to secondary neurological deterioration and poor outcome. We sought to determine whether swelling is associated with outcome in ...smaller volume strokes.
METHODS—Two research cohorts of acute stroke subjects with serial brain MRI were analyzed. The categorical presence of swelling and infarct growth was assessed on diffusion-weighted imaging (DWI) by comparing baseline and follow-up scans. The increase in stroke volume (ΔDWI) was then subdivided into swelling and infarct growth volumes using region-of-interest analysis. The relationship of these imaging markers with outcome was evaluated in univariable and multivariable regression.
RESULTS—The presence of swelling independently predicted worse outcome after adjustment for age, National Institutes of Health Stroke Scale, admission glucose, and baseline DWI volume (odds ratio, 4.55; 95% confidence interval, 1.21–18.9; P<0.02). Volumetric analysis confirmed that ΔDWI was associated with outcome (odds ratio, 4.29; 95% confidence interval, 2.00–11.5; P<0.001). After partitioning ΔDWI into swelling and infarct growth volumetrically, swelling remained an independent predictor of poor outcome (odds ratio, 1.09; 95% confidence interval, 1.03–1.17; P<0.005). Larger infarct growth was also associated with poor outcome (odds ratio, 7.05; 95% confidence interval, 1.04–143; P<0.045), although small infarct growth was not. The severity of cytotoxic injury measured on apparent diffusion coefficient maps was associated with swelling, whereas the perfusion deficit volume was associated with infarct growth.
CONCLUSIONS—Swelling and infarct growth each contribute to total stroke lesion growth in the days after stroke. Swelling is an independent predictor of poor outcome, with a brain swelling volume of ≥11 mL identified as the threshold with greatest sensitivity and specificity for predicting poor outcome.
Billions of hectares of natural ecosystems have been degraded through human actions. The global community has agreed on targets to halt and reverse these declines, and the restoration sector faces ...the important but arduous task of implementing programmes to meet these objectives. Existing and emerging genomics tools offer the potential to improve the odds of achieving these targets. These tools include population genomics that can improve seed sourcing, meta-omics that can improve assessment and monitoring of restoration outcomes, and genome editing that can generate novel genotypes for restoring challenging environments. We identify barriers to adopting these tools in a restoration context and emphasize that regulatory and ethical frameworks are required to guide their use.
Chemically crosslinked cellulose hydrogels have wide applications in agriculture and biomedicine, but most crosslinking methods involve potentially toxic crosslinking chemistries or lack significant ...control over the final modulus of the material. To overcome these challenges, carboxymethyl cellulose (CMC) hydrogels were synthesized utilizing thiol-ene click chemistry. CMC was functionalized with norbornene groups through a base catalyzed, water-borne functionalization reaction with carbic anhydride, yielding a reactive norbornene group. Both reaction pH and anhydride concentration could be used to control the degree of norbornene functionalization of CMC up to 45% norbornene functionalization per CMC repeat unit. This new norbornene functionalized CMC (cCMC) was crosslinked though a UV-light initiated thiol-ene reaction with a 2,2′-(ethylenedioxy)diethanethiol (DEG) crosslinker. Both the ratio of thiols to norbornenes and the irradiation time could be varied at a constant polymer concentration to control the modulus over an order of magnitude. Interestingly, thiol to norbornene ratios of 1:2 and 1:1 yielded the same modulus values, which was attributed to the crosslinking limiting chain mobility early in the reaction and preventing increased crosslink density as the reaction progressed. Hydrolytic degradation of the hydrogels yielded two degradation regimes of initial burst release and continuous daily release. Burst release behavior was tied to the thiol to norbornene ratio used to fabricate the hydrogel, while the daily degradation rate could be correlated to the crosslinking density. Due to its straightforward synthesis and significant control over modulus and degradation rates, cCMC offers high utility for future applications where cellulose derived hydrogels are needed.
Graphical abstract
Dysregulation of the WNT and insulin-like growth factor 2 (IGF2) signaling pathways has been implicated in sporadic and syndromic forms of adrenocortical carcinoma (ACC). Abnormal β-catenin staining ...and CTNNB1 mutations are reported to be common in both adrenocortical adenoma and ACC, whereas elevated IGF2 expression is associated primarily with ACC. To better understand the contribution of these pathways in the tumorigenesis of ACC, we examined clinicopathological and molecular data and used mouse models. Evaluation of adrenal tumors from 118 adult patients demonstrated an increase in CTNNB1 mutations and abnormal β-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival. Mice with stabilized β-catenin exhibited a temporal progression of increased adrenocortical hyperplasia, with subsequent microscopic and macroscopic adenoma formation. Elevated Igf2 expression alone did not cause hyperplasia. With the combination of stabilized β-catenin and elevated Igf2 expression, adrenal glands were larger, displayed earlier onset of hyperplasia, and developed more frequent macroscopic adenomas (as well as one carcinoma). Our results are consistent with a model in which dysregulation of one pathway may result in adrenal hyperplasia, but accumulation of a second or multiple alterations is necessary for tumorigenesis.
In the present research, humidity sensing properties of polyaniline–carboxymethyl cellulose (PANI–CMC), a biopolymer composite, have been investigated. PANI and the composite were synthesized ...separately at room temperature without/with CMC, by simple chemical polymerization method. Improved crystallinity and π-electron delocalization of the composite as compared to PANI were confirmed by X-ray diffraction studies. CMC forming a kind of network on which PANI particles adhered in the composite was confirmed by scanning electron microscopic image. The appearance of band at 3444 cm
−1
in the fourier transform infrared spectrum of the composite attributed to hydrogen bonding between dopant ions of PANI and polar molecules of CMC confirmed interaction between PANI and CMC. Humidity sensing response of PANI and the composite at room temperature were tested at a selected frequency of 100 Hz using films of the respective materials deposited on glass substrate by spin coating technique. The study on sensing response of the composite film revealed change in its impedance by about three orders of magnitude, for a change in relative humidity (RH) from 25 to 75 %. The response and recovery time of the composite at 75 % RH were about 10 and 90 s respectively. The maximum humidity hysteresis of the composite was around 5 % at 65 % RH. Humidity sensing stability of the composite for a period of 1 month was also tested.
Autophagy is an important stress response pathway responsible for the removal and recycling of damaged or redundant cytosolic constituents. Mitochondrial damage triggers selective mitochondrial ...autophagy (mitophagy), mediated by a variety of response factors including the Pink1/Parkin system. Using human retinal pigment epithelial cells stably expressing autophagy and mitophagy reporters, we have conducted parallel screens of regulators of endoplasmic reticulum (ER) and mitochondrial morphology and function contributing to starvation-induced autophagy and damage-induced mitophagy. These screens identified the ER chaperone and Ca2+ flux modulator, sigma non-opioid intracellular receptor 1 (SIGMAR1), as a regulator of autophagosome expansion during starvation. Screens also identified phosphatidyl ethanolamine methyl transferase (PEMT) and the IP3-receptors (IP3Rs) as mediators of Parkin-induced mitophagy. Further experiments suggested that IP3R-mediated transfer of Ca2+ from the ER lumen to the mitochondrial matrix via the mitochondrial Ca2+ uniporter (MCU) primes mitochondria for mitophagy. Importantly, recruitment of Parkin to damaged mitochondria did not require IP3R-mediated ER-to-mitochondrial Ca2+ transfer, but mitochondrial clustering downstream of Parkin recruitment was impaired, suggesting involvement of regulators of mitochondrial dynamics and/or transport. Our data suggest that Ca2+ flux between ER and mitochondria at presumed ER/mitochondrial contact sites is needed both for starvation-induced autophagy and for Parkin-mediated mitophagy, further highlighting the importance of inter-organellar communication for effective cellular homeostasis.
Recently it was shown that circulating Ly6C(+) monocytes traffic from tissue to the draining lymph nodes (LNs) with minimal alteration in their overall phenotype. Furthermore, in the steady state, ...Ly6C(+) monocytes are as abundant as classical dendritic cells (DCs) within the draining LNs, and even more abundant during inflammation. However, little is known about the functional roles of constitutively trafficking Ly6C(+) monocytes. In this study we investigated whether Ly6C(+) monocytes can efferocytose (acquire dying cells) and cross-present cell-associated antigen, a functional property particularly attributed to Batf3(+) DCs. We demonstrated that Ly6C(+) monocytes intrinsically efferocytose and cross-present cell-associated antigen to CD8(+) T cells. In addition, efferocytosis was enhanced upon direct activation of the Ly6C(+) monocytes through its corresponding TLRs, TLR4 and TLR7. However, only ligation of TLR7, and not TLR4, enhanced cross-presentation by Ly6C(+) monocytes. Overall, this study outlines two functional roles, among others, that Ly6C(+) monocytes have during an adaptive immune response.
IMPORTANCE: Brain-computer interface (BCI) implants have previously required craniotomy to deliver penetrating or surface electrodes to the brain. Whether a minimally invasive endovascular technique ...to deliver recording electrodes through the jugular vein to superior sagittal sinus is safe and feasible is unknown. OBJECTIVE: To assess the safety of an endovascular BCI and feasibility of using the system to control a computer by thought. DESIGN, SETTING, AND PARTICIPANTS: The Stentrode With Thought-Controlled Digital Switch (SWITCH) study, a single-center, prospective, first in-human study, evaluated 5 patients with severe bilateral upper-limb paralysis, with a follow-up of 12 months. From a referred sample, 4 patients with amyotrophic lateral sclerosis and 1 with primary lateral sclerosis met inclusion criteria and were enrolled in the study. Surgical procedures and follow-up visits were performed at the Royal Melbourne Hospital, Parkville, Australia. Training sessions were performed at patients’ homes and at a university clinic. The study start date was May 27, 2019, and final follow-up was completed January 9, 2022. INTERVENTIONS: Recording devices were delivered via catheter and connected to subcutaneous electronic units. Devices communicated wirelessly to an external device for personal computer control. MAIN OUTCOMES AND MEASURES: The primary safety end point was device-related serious adverse events resulting in death or permanent increased disability. Secondary end points were blood vessel occlusion and device migration. Exploratory end points were signal fidelity and stability over 12 months, number of distinct commands created by neuronal activity, and use of system for digital device control. RESULTS: Of 4 patients included in analyses, all were male, and the mean (SD) age was 61 (17) years. Patients with preserved motor cortex activity and suitable venous anatomy were implanted. Each completed 12-month follow-up with no serious adverse events and no vessel occlusion or device migration. Mean (SD) signal bandwidth was 233 (16) Hz and was stable throughout study in all 4 patients (SD range across all sessions, 7-32 Hz). At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI. CONCLUSIONS AND RELEVANCE: Endovascular access to the sensorimotor cortex is an alternative to placing BCI electrodes in or on the dura by open-brain surgery. These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03834857
Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in ≥80% of recipients. Pf sporozoites (PfSPZ) administered by mosquito bites are the only immunogens ...shown to induce such protection in humans. Such protection is thought to be mediated by CD8⁺ T cells in the liver that secrete interferon-γ (IFN-γ). We report that purified irradiated PfSPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective. Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8⁺, IFN-γ-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice). Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria.
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