For wireless charging of electric vehicle (EV) batteries, high-frequency magnetic fields are generated from magnetically coupled coils. The large air-gap between two coils may cause high leakage of ...magnetic fields and it may also lower the power transfer efficiency (PTE). For the first time, in this paper, we propose a new set of coil design formulas for high-efficiency and low harmonic currents and a new design procedure for low leakage of magnetic fields for high-power wireless power transfer (WPT) system. Based on the proposed design procedure, a pair of magnetically coupled coils with magnetic field shielding for a 1-kW-class golf-cart WPT system is optimized via finite-element simulation and the proposed design formulas. We built a 1-kW-class wireless EV charging system for practical measurements of the PTE, the magnetic field strength around the golf cart, and voltage/current spectrums. The fabricated system has achieved a PTE of 96% at the operating frequency of 20.15 kHz with a 156-mm air gap between the coils. At the same time, the highest magnetic field strength measured around the golf cart is 19.8 mG, which is far below the relevant electromagnetic field safety guidelines (ICNIRP 1998/2010). In addition, the third harmonic component of the measured magnetic field is 39 dB lower than the fundamental component. These practical measurement results prove the effectiveness of the proposed coil design formulas and procedure of a WPT system for high-efficiency and low magnetic field leakage.
Saturated fatty acids can activate Toll-like receptor 2 (TLR2) and TLR4 but polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA) inhibit the activation. Lipopolysaccharides (LPS) and ...lipopetides, ligands for TLR4 and TLR2, respectively, are acylated by saturated fatty acids. Removal of these fatty acids results in loss of their ligand activity suggesting that the saturated fatty acyl moieties are required for the receptor activation. X-ray crystallographic studies revealed that these saturated fatty acyl groups of the ligands directly occupy hydrophobic lipid binding domains of the receptors (or co-receptor) and induce the dimerization which is prerequisite for the receptor activation. Saturated fatty acids also induce the dimerization and translocation of TLR4 and TLR2 into lipid rafts in plasma membrane and this process is inhibited by DHA. Whether saturated fatty acids induce the dimerization of the receptors by interacting with these lipid binding domains is not known. Many experimental results suggest that saturated fatty acids promote the formation of lipid rafts and recruitment of TLRs into lipid rafts leading to ligand independent dimerization of the receptors. Such a mode of ligand independent receptor activation defies the conventional concept of ligand induced receptor activation; however, this may enable diverse non-microbial molecules with endogenous and dietary origins to modulate TLR-mediated immune responses. Emerging experimental evidence reveals that TLRs play a key role in bridging diet-induced endocrine and metabolic changes to immune responses.
•Exosomes have been identified to hold exceptional value in clinical diagnostics and tumor therapy.•A short overview of conventional methods of exosome isolation is summarized.•The recent ...advancements of microfluidic strategy for exosomes isolation and detection are overviewed.•A brief overview of exosome-based drug delivery for tumor therapy is provided.•The current challenges and outlook of these fields are assessed.
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Exosomes are a class of cell-secreted, nano-sized extracellular vesicles with a bilayer membrane structure of 30–150 nm in diameter. Their discovery and application have brought breakthroughs in numerous areas, such as liquid biopsies, cancer biology, drug delivery, immunotherapy, tissue repair, and cardiovascular diseases. Isolation of exosomes is the first step in exosome-related research and its applications. Standard benchtop exosome separation and sensing techniques are tedious and challenging, as they require large sample volumes, multi-step operations that are complex and time-consuming, requiring cumbersome and expensive instruments. In contrast, microfluidic platforms have the potential to overcome some of these limitations, owing to their high-precision processing, ability to handle liquids at a microscale, and integrability with various functional units, such as mixers, actuators, reactors, separators, and sensors. These platforms can optimize the detection process on a single device, representing a robust and versatile technique for exosome separation and sensing to attain high purity and high recovery rates with a short processing time. Herein, we overview microfluidic strategies for exosome isolation based on their hydrodynamic properties, size filtration, acoustic fields, immunoaffinity, and dielectrophoretic properties. We focus especially on advances in label-free isolation of exosomes with active biological properties and intact morphological structures. Further, we introduce microfluidic techniques for the detection of exosomal proteins and RNAs with high sensitivity, high specificity, and low detection limits. We summarize the biomedical applications of exosome-mediated therapeutic delivery targeting cancer cells. To highlight the advantages of microfluidic platforms, conventional techniques are included for comparison. Future challenges and prospects of microfluidics towards exosome isolation applications are also discussed. Although the use of exosomes in clinical applications still faces biological, technical, regulatory, and market challenges, in the foreseeable future, recent developments in microfluidic technologies are expected to pave the way for tailoring exosome-related applications in precision medicine.
Some evidence suggests that bisphosphonates may reduce atherosclerosis, while concerns have been raised about atrial fibrillation. We conducted a meta-analysis to determine the effects of ...bisphosphonates on total adverse cardiovascular (CV) events, atrial fibrillation, myocardial infarction (MI), stroke, and CV death in adults with or at risk for low bone mass.
A systematic search of MEDLINE and EMBASE through July 2014 identified 58 randomized controlled trials with longer than 6 months in duration that reported CV events. Absolute risks and the Mantel-Haenszel fixed-effects odds ratios (ORs) and 95% confidence intervals (CIs) of total CV events, atrial fibrillation, MI, stroke, and CV death were estimated. Subgroup analyses by follow-up duration, population characteristics, bisphosphonate types, and route were performed.
Absolute risks over 25-36 months in bisphosphonate-treated versus control patients were 6.5% versus 6.2% for total CV events; 1.4% versus 1.5% for atrial fibrillation; 1.0% versus 1.2% for MI; 1.6% versus 1.9% for stroke; and 1.5% versus 1.4% for CV death. Bisphosphonate treatment up to 36 months did not have any significant effects on total CV events (14 trials; ORs 95% CI: 0.98 0.84-1.14; I2 = 0.0%), atrial fibrillation (41 trials; 1.08 0.92-1.25; I2 = 0.0%), MI (10 trials; 0.96 0.69-1.34; I2 = 0.0%), stroke (10 trials; 0.99 0.82-1.19; I2 = 5.8%), and CV death (14 trials; 0.88 0.72-1.07; I2 = 0.0%) with little between-study heterogeneity. The risk of atrial fibrillation appears to be modestly elevated for zoledronic acid (6 trials; 1.24 0.96-1.61; I2 = 0.0%), not for oral bisphosphonates (26 trials; 1.02 0.83-1.24; I2 = 0.0%). The CV effects did not vary by subgroups or study quality.
Bisphosphonates do not have beneficial or harmful effects on atherosclerotic CV events, but zoledronic acid may modestly increase the risk of atrial fibrillation. Given the large reduction in fractures with bisphosphonates, changes in osteoporosis treatment decision due to CV risk are not justified.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Over the past decade, an increasing number of observational studies have examined the effectiveness or safety of treatments for rheumatoid arthritis. Unlike randomized controlled trials (RCTs), ...however, observational studies of drug effects have methodological limitations such as confounding by indication. Active-comparator designs and new-user designs can help mitigate such biases in observational studies and improve the validity of their findings by making them more closely approximate RCTs. In an active-comparator study, the drug of interest is compared with another agent commonly used for the same indication, rather than with no treatment (a 'non-user' group). This principle helps to ensure that treatment groups have similar treatment indications, attenuating both measured and unmeasured differences in patient characteristics. The new-user study includes a cohort of patients from the time of treatment initiation, enabling assessment of patients' pretreatment characteristics and capture of all events occurring during follow-up. These two principles should be considered when designing or reviewing observational studies of drug effects.
ABSTRACT
Although there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral ...fractures (AFF). Recent published studies examining this potential association are conflicting regarding the existence and strength of this association. We conducted a systematic review and meta‐analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random‐effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta‐analysis: five case‐control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF, with adjusted RR of 1.70 (95% confidence interval CI, 1.22–2.37). Subgroup analysis of studies using the American Society for Bone and Mineral Research criteria to define AFF suggests a higher risk of AFF, with bisphosphonate use with RR of 11.78 (95% CI, 0.39–359.69) as compared to studies using mainly diagnosis codes (RR, 1.62; 95% CI, 1.18–2.22), although there is a wide confidence interval and severe heterogeneity (I2 = 96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI, 1.29–2.04). This meta‐analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long‐term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear.
Acute graft-versus-host disease (GvHD) is a major cause of mortality in allogeneic bone marrow transplantation (BMT), for which administration of FoxP3+ regulatory T (Treg) cells has been proposed as ...a therapy. However, the phenotypic stability of Treg cells is controversial, and STAT3-dependent cytokines can inhibit FoxP3 expression. We assessed whether the elimination of STAT3 in T cells could limit the severity of GvHD. We found STAT3 limited FoxP3+ Treg cell numbers following allogeneic BMT by two pathways: instability of natural Treg (nTreg) cells and inhibition of induced Treg (iTreg) cell polarization from naive CD4+ T cells. Deletion of STAT3 within only the nTreg cell population was not sufficient to protect against lethal GvHD. In contrast, transfer of STAT3-deficient naive CD4+ T cells increased FoxP3+ Treg cells post-BMT and prevented lethality, suggesting that the consequence of STAT3 signaling may be greater for iTreg rather than nTreg cells during GvHD.
► Acute graft versus host disease requires the presence of T cell STAT3 ► Transferred nTreg cells are unstable in the setting of acute GvHD ► Loss of nTreg cell FoxP3 expression in acute GvHD is largely dependent on STAT3 ► STAT3-deficient, but not wild-type, naive T cells become iTreg cells during acute GvHD
The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 ...EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The claustrum, a subcortical nucleus forming extensive connections with the neocortex, has been implicated in sensory selection. Sensory-evoked claustrum activity is thought to modulate the ...neocortex’s context-dependent response to sensory input. Recording from claustrum neurons while mice performed a tactile-visual sensory-selection task, we found that neurons in the anterior claustrum, including putative optotagged claustrocortical neurons projecting to the primary somatosensory cortex (S1), were rarely modulated by sensory input. Rather, they exhibited different types of direction-tuned motor responses. Furthermore, we found that claustrum neurons encoded upcoming movement during intertrial intervals and that pairs of claustrum neurons exhibiting synchronous firing were enriched for pairs preferring contralateral lick directions, suggesting that the activity of specific ensembles of similarly tuned claustrum neurons may modulate cortical activity. Chemogenetic inhibition of claustrocortical neurons decreased lick responses to inappropriate sensory stimuli. Altogether, our data indicate that the claustrum is integrated into higher-order premotor circuits recently implicated in decision-making.
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•Anterior claustrum neurons exhibit motor responses•Claustrum neurons, including S1-projecting neurons, encode lick direction•Neuron pairs with synchronous firing during intertrial intervals are similarly tuned•Chemogenetic inhibition of claustrocortical neurons decreases false alarms
Chevée, Finkel et al. show that the activity of neurons in the anterior claustrum recorded during a cross-modal sensory selection task reflects movement rather than sensory input. Premotor activity in individual claustrum neurons was biased for ipsilateral or contralateral movements and encoded upcoming lick direction during intertrial intervals.
Autism spectrum disorder (ASD) manifests as alterations in complex human behaviors including social communication and stereotypies. In addition to genetic risks, the gut microbiome differs between ...typically developing (TD) and ASD individuals, though it remains unclear whether the microbiome contributes to symptoms. We transplanted gut microbiota from human donors with ASD or TD controls into germ-free mice and reveal that colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors. The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes. Microbiome and metabolome profiles of mice harboring human microbiota predict that specific bacterial taxa and their metabolites modulate ASD behaviors. Indeed, treatment of an ASD mouse model with candidate microbial metabolites improves behavioral abnormalities and modulates neuronal excitability in the brain. We propose that the gut microbiota regulates behaviors in mice via production of neuroactive metabolites, suggesting that gut-brain connections contribute to the pathophysiology of ASD.
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•Mice harboring human ASD, but not TD, microbiomes exhibit ASD-like behaviors•ASD and TD microbiota produce differential metabolome profiles in mice•Extensive alternative splicing of risk genes in brains of mice with ASD microbiota•BTBR mice treated with 5AV or taurine improved repetitive and social behaviors
Repetitive and social behavioral abnormalities in mice with microbiomes from patients with autism spectrum disorder can be corrected by the administration of specific metabolites.
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