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Understanding the epidemic of chronic kidney disease of uncertain etiology may be critical for health policies and public health responses. Recent studies have shown that microplastics (MPs) contaminate our food chain and accumulate in the gut, liver, kidney, muscle, and so on. Humans manufacture many plastics-related products. Previous studies have indicated that particles of these products have several effects on the gut and liver. Polystyrene (PS)-MPs (PS-MPs) induce several responses, such as oxidative stress, and affect living organisms. The aim of this study was to investigate the effects of PS-MPs in kidney cells and . PS-MPs were evaluated in human kidney proximal tubular epithelial cells (HK-2 cells) and male C57BL/6 mice. Mitochondrial reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, inflammation, and autophagy were analyzed in kidney cells. , we evaluated biomarkers of kidney function, kidney ultrastructure, muscle mass, and grip strength, and urine protein levels, as well as the accumulation of PS-MPs in the kidney tissue. Uptake of PS-MPs at different concentrations by HK-2 cells resulted in higher levels of mitochondrial ROS and the mitochondrial protein Bad. Cells exposed to PS-MPs had higher ER stress and markers of inflammation. MitoTEMPO, which is a mitochondrial ROS antioxidant, mitigated the higher levels of mitochondrial ROS, Bad, ER stress, and specific autophagy-related proteins seen with PS-MP exposure. Furthermore, cells exposed to PS-MPs had higher protein levels of LC3 and Beclin 1. PS-MPs also had changes in phosphorylation of mitogen-activated protein kinase (MAPK) and protein kinase B (AKT)/mitogen-activated protein kinase (mTOR) signaling pathways. In an study, PS-MPs accumulated and the treated mice had more histopathological lesions in the kidneys and higher levels of ER stress, inflammatory markers, and autophagy-related proteins in the kidneys after PS-MPs treatment by oral gavage. The results suggest that PS-MPs caused mitochondrial dysfunction, ER stress, inflammation, and autophagy in kidney cells and accumulated in HK-2 cells and in the kidneys of mice. These results suggest that long-term PS-MPs exposure may be a risk factor for kidney health. https://doi.org/10.1289/EHP7612.

This protocol describes how to set up and use an in vitro model of the human microcirculation with the capability to recapitulate discrete steps of early metastatic seeding, including tumor cell arrest and transendothelial migration. Distant metastasis, which results in >90% of cancer-related deaths, is enabled by hematogenous dissemination of tumor cells via the circulation. This requires the completion of a sequence of complex steps including transit, initial arrest, extravasation, survival and proliferation. Increased understanding of the cellular and molecular players enabling each of these steps is key to uncovering new opportunities for therapeutic intervention during early metastatic dissemination. As a protocol extension, this article describes an adaptation to our existing protocol describing a microfluidic platform that offers additional applications. This protocol describes an in vitro model of the human microcirculation with the potential to recapitulate discrete steps of early metastatic seeding, including arrest, transendothelial migration and early micrometastases formation. The microdevice features self-organized human microvascular networks formed over 4–5 d, after which the tumor can be perfused and extravasation events are easily tracked over 72 h via standard confocal microscopy. Contrary to most in vivo and in vitro extravasation assays, robust and rapid scoring of extravascular cells, combined with high-resolution imaging, can be easily achieved because of the confinement of the vascular network to one plane close to the surface of the device. This renders extravascular cells clearly distinct and allows tumor cells of interest to be identified quickly as compared with those in thick tissues. The ability to generate large numbers of devices (∼36) per experiment further allows for highly parametric studies, which are required when testing multiple genetic or pharmacological perturbations. This is coupled with the capability for live tracking of single-cell extravasation events, allowing both tumor and endothelial morphological dynamics to be observed in high detail with a moderate number of data points.

Systemic inflammation occurring around the course of tumor progression and treatment are often correlatedwith adverse oncological outcomes. As such, it is suspected that neutrophils, the first line of defense against infection, may play important roles in linking inflammation and metastatic seeding. To decipher the dynamic roles of inflamed neutrophils during hematogenous dissemination, we employ a multiplexed microfluidic model of the human microvasculature enabling physiologically relevant transport of circulating cells combined with real-time, high spatial resolution observation of heterotypic cell–cell interactions. LPS-stimulated neutrophils (PMNs) and tumor cells (TCs) form heterotypic aggregates under flow, and arrest due to both mechanical trapping and neutrophil–endothelial adhesions. Surprisingly, PMNs are not static following aggregation, but exhibit a confined migration pattern near TC–PMN clusters. We discover that PMNs are chemotactically confined by self-secreted IL-8 and tumor-derived CXCL-1, which are immobilized by the endothelial glycocalyx. This results in significant neutrophil sequestration with arrested tumor cells, leading to the spatial localization of neutrophil-derived IL-8, which also contributes to increasing the extravasation potential of adjacent tumor cells through modulation of the endothelial barrier. Strikingly similar migration patterns and extravasation behaviors were also observed in an in vivo zebrafish model upon PMN–tumor cell coinjection into the embryo vasculature. These insights into the temporal dynamics of intravascular tumor–PMN interactions elucidate the mechanisms through which inflamed neutrophils can exert proextravasation effects at the distant metastatic site.

Osteosarcoma, a primary bone tumor, responds poorly to chemotherapy and radiation therapy in children and young adults; hence, as the basis for an alternative treatment, this study investigated the cytotoxic and antiproliferative effects of naringenin on osteosarcoma cell lines, HOS and U2OS, by using cell counting kit-8 and colony formation assays. DNA fragmentation and the increase in the G2/M phase in HOS and U2OS cells upon treatment with various naringenin concentrations were determined by using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and Annexin V/propidium iodide double staining, respectively. Flow cytometry was performed, and 2′,7′-dichlorodihydrofluorescein diacetate, JC-1, and Fluo-4 AM ester probes were examined for reactive oxygen species (ROS) generation, mitochondrial membrane potential, and intracellular calcium levels, respectively. Caspase activation, cell cycle, cytosolic and mitochondrial, and autophagy-related proteins were determined using western blotting. The results indicated that naringenin significantly inhibited viability and proliferation of osteosarcoma cells in a dose-dependent manner. In addition, naringenin induced cell cycle arrest in osteosarcoma cells by inhibiting cyclin B1 and cyclin-dependent kinase 1 expression and upregulating p21 expression. Furthermore, naringenin significantly inhibited the growth of osteosarcoma cells by increasing the intracellular ROS level. Naringenin induced endoplasmic reticulum (ER) stress-mediated apoptosis through the upregulation of ER stress markers, GRP78 and GRP94. Naringenin caused acidic vesicular organelle formation and increased autophagolysosomes, microtubule-associated protein-light chain 3-II protein levels, and autophagy. The findings suggest that the induction of cell apoptosis, cell cycle arrest, and autophagy by naringenin through mitochondrial dysfunction, ROS production, and ER stress signaling pathways contribute to the antiproliferative effect of naringenin on osteosarcoma cells.

BackgroundEndovascular thrombectomy is not available at all hospitals that offer intravenous thrombolysis, prompting debate regarding the preferred transport destination for acute ischemic stroke. This study aimed to quantify real-world travel time and distance of bypass and non-bypass transport models for large-vessel occlusion (LVO) and non-LVO stroke.MethodsThis cross-sectional study included population data of census tracts in the contiguous USA from the 2014–2018 United States Census Bureau’s American Community Survey, stroke (thrombolysis-capable) and thrombectomy-capable centers certified by a state or national body, and road network data from a mapping service. Census tracts were categorized by urbanization level. Data were retrieved from March to November 2020. Travel times and distances were calculated for each census tract to each of the following: nearest stroke center (nearest), nearest thrombectomy-capable center (bypass), and nearest stroke center then to the nearest thrombectomy-capable center (transfer). Population-weighted median and IQR were calculated nationally and by urbanization.Results72 538 census tracts, 2388 stroke hospitals, and 371 thrombectomy-capable centers were included. Nationally, population-weighted median travel time for nearest and bypass routing was 11.7 min (IQR 7.7–19.3) and 26.4 min (14.8–55.1), respectively. For transfer routing, the population-weighted median travel times with 60 min, 90 min, and 120 min door-in-door-out times were 94.1 min (78.5–127.7), 124.1 min (108.5–157.7), and 154.1 min (138.4–187.6), respectively.ConclusionsBypass routing offers modest travel time benefits for LVO patients and incurs modest penalties for non-LVO patients. Differences are greatest in rural areas. A majority of Americans live in areas for which current guidelines recommend bypass.

Background: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation for treatment-resistant obsessive compulsive disorder (OCD). We aim to compare the treatment outcomes of a newly developed dual-site cathodal tDCS method over the orbitofrontal cortex (OFC) and pre-supplementary motor area (pre-SMA) and two previously reported montages (cerebellum-OFC and pre-SMA) in patients with treatment-resistant OCD. Methods: Eighteen OCD patients were randomly assigned to receive twice-daily 2 mA/20 min sessions for 10 consecutive weekdays, with the active cathode placed on the cerebellum-OFC, bilateral pre-SMA, or OFC-pre-SMA tDCS. The primary outcome was the change in the Yale–Brown Obsessive Compulsive Scale (Y-BOCS). The resting electroencephalogram (EEG) was recorded to obtain the default mode network (DMN) via low-resolution electromagnetic tomography. Each patient received one-week and one-month follow-ups after two weeks of stimulation. Results: At the end of the stimulation, the Y-BOCS scores in the cerebellum-OFC, pre-SMA, and OFC-pre-SMA tDCS groups (n = 6 in each group) were decreased by 14.15 ± 13.31, 7.4 ± 9.59, and 20.75 ± 8.70%, respectively, but no significant differences were found among the groups. In the OFC-pre-SMA tDCS group, OC symptoms significantly decreased by a mean of −20.75% immediately after the 20th tDCS session, and the improvement remained at 1 week and 1 month after tDCS. EEG source functional connectivity analyses revealed increased functional connectivity within the frontal network after OFC-pre-SMA tDCS, whereas decreased functional connectivity within the DMN was observed after cerebellum-OFC tDCS. Conclusions: Dual-site cathodal tDCS over the OFC and pre-SMA might be considered a potential montage to treat patients with treatment-resistant OCD. Future studies using randomized sham-controlled designs are needed.

Background and Objectives: Attentional dysfunction has long been viewed as one of the fundamental underlying cognitive deficits in schizophrenia. There is an urgent need to understand its neural underpinning and develop effective treatments. In the process of attention, neural oscillation has a central role in filtering information and allocating resources to either stimulus-driven or goal-relevant objects. Here, we asked if resting-state EEG connectivity correlated with attentional performance in schizophrenia patients. Materials and Methods: Resting-state EEG recordings were obtained from 72 stabilized patients with schizophrenia. Lagged phase synchronization (LPS) was used to measure whole-brain source-based functional connectivity between 84 intra-cortical current sources determined by eLORETA (exact low-resolution brain electromagnetic tomography) for five frequencies. The Conners’ Continuous Performance Test-II (CPT-II) was administered for evaluating attentional performance. Linear regression with a non-parametric permutation randomization procedure was used to examine the correlations between the whole-brain functional connectivity and the CPT-II measures. Results: Greater beta-band right hemispheric fusiform gyrus (FG)-lingual gyrus (LG) functional connectivity predicted higher CPT-II variability scores (r = 0.44, p < 0.05, corrected), accounting for 19.5% of variance in the CPT-II VAR score. Greater gamma-band right hemispheric functional connectivity between the cuneus (Cu) and transverse temporal gyrus (TTG) and between Cu and the superior temporal gyrus (STG) predicted higher CPT-II hit reaction time (HRT) scores (both r = 0.50, p < 0.05, corrected), accounting for 24.6% and 25.1% of variance in the CPT-II HRT score, respectively. Greater gamma-band right hemispheric Cu-TTG functional connectivity predicted higher CPT-II HRT standard error (HRTSE) scores (r = 0.54, p < 0.05, corrected), accounting for 28.7% of variance in the CPT-II HRTSE score. Conclusions: Our study indicated that increased right hemispheric resting-state EEG functional connectivity at high frequencies was correlated with poorer focused attention in schizophrenia patients. If replicated, novel approaches to modulate these networks may yield selective, potent interventions for improving attention deficits in schizophrenia.

Negative symptoms represent an unmet need for schizophrenia treatment. The effect of theta frequency transcranial alternating current stimulation (theta-tACS) applied during working memory (WM) tasks on negative symptoms has not been demonstrated as of yet. We conducted a randomized, double-blind, sham-controlled trial of 36 stabilized schizophrenia patients, randomized to receive either twice daily, 6 Hz 2 mA, 20 min sessions of in-phase frontoparietal tACS or sham for five consecutive weekdays. Participants were concurrently engaged in WM tasks during stimulation. The primary outcome measure was the change over time in the Positive and Negative Syndrome Scale (PANSS) negative subscale score measured from baseline through to the 1-month follow-up. Secondary outcome measures were other symptom clusters, neurocognitive performance, and relevant outcomes. The intention-to-treat analysis demonstrated greater reductions in PANSS negative subscale scores at the end of stimulation in the active (−13.84%) than the sham (−3.78%) condition, with a large effect size (Cohen’s d = 0.96, p = 0.006). The positive effect endured for at least one month. Theta-tACS also showed efficacies for cognitive symptoms, WM capacity, and psychosocial functions. Online theta-tACS offers a novel approach to modulate frontoparietal networks to treat negative symptoms of schizophrenia. The promising results require large-scale replication studies in patients with predominantly negative symptoms.

In the retina, the L-type voltage-gated calcium channels (L-VGCCs) are responsible for neurotransmitter release from photoreceptors and are under circadian regulation. Both the current densities and protein expression of L-VGCCs are significantly higher at night than during the day. However, the underlying mechanisms of circadian regulation of L-VGCCs in the retina are not completely understood. In this study, we demonstrated that the mechanistic/mammalian target of rapamycin complex (mTORC) signaling pathway participated in the circadian phase-dependent modulation of L-VGCCs. The activities of the mTOR cascade, from mTORC1 to its downstream targets, displayed circadian oscillations throughout the course of a day. Disruption of mTORC1 signaling dampened the L-VGCC current densities, as well as the protein expression of L-VGCCs at night. The decrease of L-VGCCs at night by mTORC1 inhibition was in part due to a reduction of L-VGCCα1 subunit translocation from the cytosol to the plasma membrane. Finally, we showed that mTORC1 was downstream of the phosphatidylionositol 3 kinase-protein kinase B (PI3K-AKT) signaling pathway. Taken together, mTORC1 signaling played a role in the circadian regulation of L-VGCCs, in part through regulation of ion channel trafficking and translocation, which brings to light a new functional role for mTORC1: the modulation of ion channel activities.

Schizophrenia is associated with increased resting-state large-scale functional network connectivity in the gamma frequency. High-frequency transcranial random noise stimulation (hf-tRNS) modulates gamma-band endogenous neural oscillations in healthy individuals through the application of low-amplitude electrical noises. Yet, it is unclear if hf-tRNS can modulate gamma-band functional connectivity in patients with schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast hf-tRNS (N = 17) and sham stimulation (N = 18) for treating negative symptoms in 35 schizophrenia patients. Short continuous currents without neuromodulatory effects were applied in the sham group to mimic real-stimulation sensations. We used electroencephalography to investigate if a five-day, twice-daily hf-tRNS protocol modulates gamma-band (33–45 Hz) functional network connectivity in schizophrenia. Exact low resolution electromagnetic tomography (eLORETA) was used to compute intra-cortical activity from regions within the default mode network (DMN) and fronto-parietal network (FPN), and functional connectivity was computed using lagged phase synchronization. We found that hf-tRNS reduced gamma-band within-DMN and within-FPN connectivity at the end of stimulation relative to sham stimulation. A trend was obtained between the change in within-FPN functional connectivity from baseline to the end of stimulation and the improvement of negative symptoms at the one-month follow-up (r = −0.49, p = 0.055). Together, our findings suggest that hf-tRNS has potential as a network-level approach to modulate large-scale functional network connectivity pertaining to negative symptoms of schizophrenia.