In this work, the electrochemical performance of NiFe2O4 nanofibers synthesized by an electrospinning approach have been discussed in detail. Lithium storage properties of nanofibers are evaluated ...and compared with NiFe2O4 nanoparticles by galvanostatic cycling and cyclic voltammetry studies, both in half-cell configurations. Nanofibers exhibit a higher charge-storage capacity of 1000 mAh g–1 even after 100 cycles with high Coulmbic efficiency of 100 % between 10 and 100 cycles. Ex situ microscopy studies confirmed that cycled nanofiber electrodes maintained the morphology and remained intact even after 100 charge–discharge cycles. The NiFe2O4 nanofiber electrode does not experience any structural stress and eventual pulverisation during lithium cycling and hence provides an efficient electron conducting pathway. The excellent electrochemical performance of NiFe2O4 nanofibers is due to the unique porous morphology of continuous nanofibers.
The northern acorn barnacle (Semibalanus balanoides) is a robust system to study the genetic basis of adaptations to highly heterogeneous environments. Adult barnacles may be exposed to highly ...dissimilar levels of thermal stress depending on where they settle in the intertidal (i.e., closer to the upper or lower tidal boundary). For instance, barnacles near the upper tidal limit experience episodic summer temperatures above recorded heat coma levels. This differential stress at the microhabitat level is also dependent on the aspect of sun exposure. In the present study, we used pool‐seq approaches to conduct a genome wide screen for loci responding to intertidal zonation across the North Atlantic basin (Maine, Rhode Island, and Norway). Our analysis discovered 382 genomic regions containing SNPs which are consistently zonated (i.e., SNPs whose frequencies vary depending on their position in the rocky intertidal) across all surveyed habitats. Notably, most zonated SNPs are young and private to the North Atlantic. These regions show high levels of genetic differentiation across ecologically extreme microhabitats concomitant with elevated levels of genetic variation and Tajima's D, suggesting the action of non‐neutral processes. Overall, these findings support the hypothesis that spatially heterogeneous selection is a general and repeatable feature for this species, and that natural selection can maintain functional genetic variation in heterogeneous environments.
We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine ...microglia and TREM2‐expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N‐terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding. Peptidomimetic protease inhibitors highlighted a possible cleavage site, and mass spectrometry confirmed that shedding occurred predominantly at the H157‐S158 peptide bond for both wild‐type and H157Y human TREM2 and for the wild‐type murine orthologue. Crucially, we also show that the Alzheimer's disease‐associated H157Y TREM2 variant was shed more rapidly than wild type from HEK293 cells, possibly by a novel, batimastat‐ and ADAM10‐siRNA‐independent, sheddase activity. These insights offer new therapeutic targets for modulating the innate immune response in Alzheimer's and other neurological diseases.
Synopsis
Sequence variation in the microglial receptor protein TREM2 is linked to risk for Alzheimer's disease. The disease‐linked H157Y variant of TREM2 is found to affect the sheddase site and accelerates proteolytic loss of TREM2 from the cell surface.
TREM2 was shed rapidly from primary macrophages and microglia under basal conditions.
The sheddase site was identified using peptidomimetic inhibitors and mass spectrometry.
The Alzheimer's disease‐linked H157Y TREM2 sheddase‐cleavage‐site variant was shed more rapidly than wild type.
For both wild type and variant TREM2 the major sheddase was ADAM10, however an additional proteolytic activity might be recruited by the H157Y variant.
The protection of TREM2 from proteolysis might represent a novel therapeutic approach.
Sequence variation in the microglial receptor protein TREM2 is linked to risk for Alzheimer's disease. The disease‐linked H157Y variant of TREM2 is found to affect the sheddase site and accelerates proteolytic loss of TREM2 from the cell surface.
Pin-fin heat exchangers are widely used and there is an increasing interest in the design of compact units. This work investigated the prediction of the heat transfer rate in pin-fin channel flows ...using numerical simulation, considering pins of cylindrical geometry in aligned and staggered arrangements. The simulations were performed using the Reynolds-averaged Navier–Stokes equations together with the shear stress transport turbulence model. The main purpose of this work was to develop and validate a quick numerical procedure to evaluate the heat transfer rate in pin-fin channel flows using their quasi-steady behavior. The procedure was validated by comparing the mean Nusselt number results with time-averaged Nusselt numbers obtained from transient simulations. It was also shown that these values are in good agreement with available experimental data. This procedure could determine the overall mean Nusselt number up to 25 times faster. The importance of the quasi-steady flow behavior on the heat transfer was also quantified.
The appropriate duration of postoperative antibiotics for complex appendicitis is unclear. The increasing global threat of antimicrobial resistance warrants restrictive antibiotic use, which could ...also reduce side-effects, length of hospital stay, and costs.
In this pragmatic, open-label, non-inferiority trial in 15 hospitals in the Netherlands, patients with complex appendicitis (aged ≥8 years) were randomly assigned (1:1) to receive 2 days or 5 days of intravenous antibiotics after appendicectomy. Randomisation was stratified by centre, and treating physicians and patients were not masked to treatment allocation. The primary endpoint was a composite endpoint of infectious complications and mortality within 90 days. The main outcome was the absolute risk difference (95% CI) in the primary endpoint, adjusted for age and severity of appendicitis, with a non-inferiority margin of 7·5%. Outcome assessment was based on electronic patient records and a telephone consultation 90 days after appendicectomy. Efficacy was analysed in the intention-to-treat and per-protocol populations. Safety outcomes were analysed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register, NL5946.
Between April 12, 2017, and June 3, 2021, 13 267 patients were screened and 1066 were randomly assigned, 533 to each group. 31 were excluded from intention-to-treat analysis of the 2-day group and 30 from the 5-day group owing to errors in recruitment or consent. Appendicectomy was done laparoscopically in 955 (95%) of 1005 patients. The telephone follow-up was completed in 664 (66%) of 1005 patients. The primary endpoint occurred in 51 (10%) of 502 patients analysed in the 2-day group and 41 (8%) of 503 patients analysed in the 5-day group (adjusted absolute risk difference 2·0%, 95% CI −1·6 to 5·6). Rates of complications and re-interventions were similar between trial groups. Fewer patients had adverse effects of antibiotics in the 2-day group (45 9% of 502 patients) than in the 5-day group (112 22% of 503 patients; odds ratio OR 0·344, 95% CI 0·237 to 0·498). Re-admission to hospital was more frequent in the 2-day group (58 12% of 502 patients) than in the 5-day group (29 6% of 503 patients; OR 2·135, 1·342 to 3·396). There were no treatment-related deaths.
2 days of postoperative intravenous antibiotics for complex appendicitis is non-inferior to 5 days in terms of infectious complications and mortality within 90 days, based on a non-inferiority margin of 7·5%. These findings apply to laparoscopic appendicectomy conducted in a well resourced health-care setting. Adopting this strategy will reduce adverse effects of antibiotics and length of hospital stay.
The Netherlands Organization for Health Research and Development.
We have studied a spontaneous self-organization dynamics in a closed, dissipative (in terms of guansine 5'-triphosphate energy dissipation), reaction-diffusion system of acentrosomal microtubules ...(those nucleated and organized in the absence of a microtubule-organizing centre) multitude constituted of straight and curved acentrosomal microtubules, in highly crowded conditions, in vitro. Our data give experimental evidence that cross-diffusion in conjunction with excluded volume is the underlying mechanism on basis of which acentrosomal microtubule multitudes of different morphologies (straight and curved) undergo a spatial-temporal demix. Demix is constituted of a bifurcation process, manifested as a slow isothermal spinodal decomposition, and a dissipative process of transient periodic spatio-temporal pattern formation. While spinodal decomposition is an energy independent process, transient periodic spatio-temporal pattern formation is accompanied by energy dissipative process. Accordingly, we have determined that the critical threshold for slow, isothermal spinodal decomposition is 1.0 ± 0.05 mg/ml of microtubule protein concentration. We also found that periodic spacing of transient periodic spatio-temporal patterns was, in the overall, increasing versus time. For illustration, we found that a periodic spacing of the same pattern was 0.375 ± 0.036 mm, at 36 °C, at 155th min, while it was 0.540 ± 0.041 mm at 31 °C, and at 275th min after microtubule assembly started. The lifetime of transient periodic spatio-temporal patterns spans from half an hour to two hours approximately. The emergence of conditions of macroscopic symmetry breaking (that occur due to cross-diffusion in conjunction with excluded volume) may have more general but critical importance in morphological pattern development in complex, dissipative, but open cellular systems.
Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized (13)C magnetic resonance (MR), in which (13)C-labelled metabolites are followed using MR imaging ...(MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized (13)Cpyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease.
Dilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized 2-(13)Cpyruvate was administered intravenously, and (13)C MRS monitored (13)Cglutamate production; (31)P MRS assessed cardiac energetics phosphocreatine (PCr)/ATP; and hyperpolarized 1-(13)Cpyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via (13)Cbicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and (13)Cglutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and (13)Cbicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively.
Despite early changes associated with cardiac energetics and (13)C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart's capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized (13)C MR may be important to characterize metabolic changes that occur during heart failure progression.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease selectively targeting motor neurons in the brain and spinal cord. The reasons for differential motor neuron susceptibility remain ...elusive. We developed a stem cell-based motor neuron assay to study cell-autonomous mechanisms causing motor neuron degeneration, with implications for ALS. A small-molecule screen identified cyclopiazonic acid (CPA) as a stressor to which stem cell-derived motor neurons were more sensitive than interneurons. CPA induced endoplasmic reticulum stress and the unfolded protein response. Furthermore, CPA resulted in an accelerated degeneration of motor neurons expressing human superoxide dismutase 1 (hSOD1) carrying the ALS-causing G93A mutation, compared to motor neurons expressing wild-type hSOD1. A secondary screen identified compounds that alleviated CPA-mediated motor neuron degeneration: three kinase inhibitors and tauroursodeoxycholic acid (TUDCA), a bile acid derivative. The neuroprotective effects of these compounds were validated in human stem cell-derived motor neurons carrying a mutated SOD1 allele (hSOD1A4V). Moreover, we found that the administration of TUDCA in an hSOD1G93A mouse model of ALS reduced muscle denervation. Jointly, these results provide insights into the mechanisms contributing to the preferential susceptibility of ALS motor neurons, and they demonstrate the utility of stem cell-derived motor neurons for the discovery of new neuroprotective compounds.
In this study, Thams and colleagues present a new stem cell-based motor neuron screening platform, which was used to detect stressor compounds of relevance for studying neurodegeneration. The authors used one of the hit compounds, which induced ER stress, in a subsequent rescue screen to identify neuroprotective compounds.
Multiple cell types are being proposed for cardiac repair, but side-by-side comparisons are lacking. We tested the hypothesis that intracardiac transplantation of autologous bone marrow- or skeletal ...muscle-derived progenitor cells improve regional heart function to a similar degree.
Thirty-nine New Zealand White rabbits underwent cryoinjury of the left ventricle and simultaneous hind limb bone marrow aspiration or soleus muscle biopsy. Both muscle and bone marrow cells were expanded in vitro. After 2 weeks, 10(8) skeletal muscle (SM group) or bone marrow-derived progenitor cells (BM group) were injected into the cryoinjured region (SM: n=12; BM: n=8). Medium alone was injected into the remaining animals (Control: n=16). Regional systolic function was measured using micromanometry and sonomicrometry at baseline, before, and 4 weeks after cell injection. Cell treatment resulted in a similar degree of improvement in a derivative of stroke work in the SM and BM groups (P=0.0026 and P=0.0085 versus Control, respectively). No significant difference was seen between BM and SM groups (P=0.9). On histology, engrafted cells were found in all of the cell treated animals. Injected myoblasts formed myotubes or muscle cells throughout the scar that expressed slow and fast myosin heavy chain. A subset of bone marrow cells differentiated toward a myogenic phenotype, as indicated by expression of desmin and alpha-sarcomeric actin in the engrafted areas.
Transplantation and myogenic differentiation of bone marrow-derived progenitor cells increased regional systolic heart function after myocardial injury to a similar degree as skeletal myoblasts.
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