Schizophrenia involves abnormalities in the medial frontal cortex that lead to cognitive deficits. Here we investigate a novel strategy to normalize medial frontal brain activity by stimulating ...cerebellar projections. We used an interval timing task to study elementary cognitive processing that requires both frontal and cerebellar networks that are disrupted in patients with schizophrenia. We report three novel findings. First, patients with schizophrenia had dysfunctional delta rhythms between 1-4 Hz in the medial frontal cortex. We explored cerebellar-frontal interactions in animal models and found that both frontal and cerebellar neurons were modulated during interval timing and had delta-frequency interactions. Finally, delta-frequency optogenetic stimulation of thalamic synaptic terminals of lateral cerebellar projection neurons rescued timing performance as well as medial frontal activity in a rodent model of schizophrenia-related frontal dysfunction. These data provide insight into how the cerebellum influences medial frontal networks and the role of the cerebellum in cognitive processing.
Background
Exposure to environmental endocrine‐disrupting chemicals (EDCs) is associated with allergy, chronic inflammation, and immunodeficiency. Phthalates, the common EDCs used in plastic ...industry, may act as adjuvants to disrupt immune system and enhance allergy. Plasmacytoid DCs (pDCs) are predominant cells secreting type I interferon (IFN) against infection and are professional antigen‐presenting cells in regulating adaptive immunity. However, the effects of phthalates on the function of pDCs are unknown.
Methods
Circulating pDCs were isolated from healthy subjects, were pretreated with diethylhexyl phthalate (DEHP) and butyl benzyl phthalate (BBP), and were stimulated with Toll‐like receptor (TLR)‐9 agonist CpG. IFN‐α/IFN‐β levels, surface markers, and T‐cell stimulatory function were investigated using ELISA, flow cytometry, and pDC/T‐cell coculture assay. Mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting, and chromatin immunoprecipitation.
Results
Diethylhexyl phthalate and butyl benzyl phthalate suppressed CpG‐induced IFN‐α/IFN‐β expression in pDCs, and the effect was reversed by aryl hydrocarbon receptor (AHR) antagonist. Diethylhexyl phthalate suppressed CpG‐activated mitogen‐activated protein kinase (MAPK)‐MEK1/2‐ERK‐ELK1 and NFκB signaling pathways. Diethylhexyl phthalate suppressed CpG‐induced interferon regulatory factor (IRF)‐7 expression by suppressing histone H3K4 trimethylation at IRF7 gene promoter region through inhibiting translocation of H3K4‐specific trimethyltransferase WDR5 from cytoplasm into nucleus. Butyl benzyl phthalate or diethylhexyl phthalate‐treated pDCs suppressed IFN‐γ but enhanced IL‐13 production by CD4+ T cells.
Conclusion
Phthalates may interfere with immunity against infection and promote the deviation of Th2 response to increase allergy by acting on human pDCs via suppressing IFN‐α/IFN‐β expression and modulating the ability to stimulate T‐cell responses.
Context.
The properties of the population of Galactic supernova remnants (SNRs) are essential to our understanding of the dynamics of the interstellar medium (ISM) in the Milky Way. However, the ...completeness of the catalog of Galactic SNRs is expected to be only ~30%, with on order 700 SNRs yet to be detected. Deep interferometric radio continuum surveys of the Galactic plane help in rectifying this apparent deficiency by identifying low surface brightness SNRs and compact SNRs that have not been detected in previous surveys. However, SNRs are routinely confused with H
II
regions, which can have similar radio morphologies. Radio spectral index, polarization, and emission at mid-infrared (MIR) wavelengths can help distinguish between SNRs and H
II
regions.
Aims.
We aim to identify SNR candidates using continuum images from the
Karl G. Jansky
Very Large Array GLObal view of the STAR formation in the Milky Way (GLOSTAR) survey.
Methods.
GLOSTAR is a C-band (4–8 GHz) radio wavelength survey of the Galactic plane covering 358° ≤
l
≤ 60°, |
b
|≤ 1°. The continuum images from this survey, which resulted from observations with the most compact configuration of the array, have an angular resolution of 18″. We searched for SNRs in these images to identify known SNRs, previously identified SNR candidates, and new SNR candidates. We study these objects in MIR surveys and the GLOSTAR polarization data to classify their emission as thermal or nonthermal.
Results.
We identify 157 SNR candidates, of which 80 are new. Polarization measurements provide evidence of nonthermal emission from nine of these candidates. We find that two previously identified candidates are filaments. We also detect emission from 91 of the 94 known SNRs in the survey region. Four of these are reclassified as H
II
regions following detection in MIR surveys.
Conclusions.
The better sensitivity and resolution of the GLOSTAR data have led to the identification of 157 SNR candidates, along with the reclassification of several misidentified objects. We show that the polarization measurements can identify nonthermal emission, despite the diffuse Galactic synchrotron emission. These results underscore the importance of higher resolution and higher sensitivity radio continuum data in identifying and confirming SNRs.
The directed migration of cell collectives is essential in various physiological processes, such as epiboly, intestinal epithelial turnover, and convergent extension during morphogenesis, as well as ...during pathological events such as wound healing and cancer metastasis. Collective cell migration leads to the emergence of coordinated movements over multiple cells. Our current understanding emphasizes that these movements are mainly driven by large-scale transmission of signals through adherens junctions. In this study, we show that collective movements of epithelial cells can be triggered by polarity signals at the single-cell level through the establishment of coordinated lamellipodial protrusions. We designed a minimalistic model system to generate one-dimensional epithelial trains confined in ring-shaped patterns that recapitulate rotational movements observed in vitro in cellular monolayers and in vivo in genital or follicular cell rotation. Using our system, we demonstrated that cells follow coordinated rotational movements after establishing directed Rac1-dependent polarity over the entire monolayer. Our experimental and numerical approaches show that the maintenance of coordinated migration requires the acquisition of a front–rear polarity within each single cell but does not require the maintenance of cell–cell junctions. Taken together, these unexpected findings demonstrate that collective cell dynamics in closed environments as observed in multiple in vitro and in vivo situations can arise from single-cell behaviour through a sustained memory of cell polarity.Collective cell migration is usually attributed to large-scale transmission of signals through cell junctions. Here, the authors confine cells into a ring-shaped pattern and show that collective cell migration can arise at the single-cell level.
•A novel objective evaluation framework for nodule detection algorithms using the largest publicly available LIDC-IDRI data set.•The impact of combining individual systems on the detection ...performance was investigated.•The combination of classical candidate detectors and a combination of deep learning architectures generates excellent results, better than any individual system.•Our observer study has shown that CAD detects nodules that were missed by expert readers.•We released this set of additional nodules for further development of CAD systems.
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Automatic detection of pulmonary nodules in thoracic computed tomography (CT) scans has been an active area of research for the last two decades. However, there have only been few studies that provide a comparative performance evaluation of different systems on a common database. We have therefore set up the LUNA16 challenge, an objective evaluation framework for automatic nodule detection algorithms using the largest publicly available reference database of chest CT scans, the LIDC-IDRI data set. In LUNA16, participants develop their algorithm and upload their predictions on 888 CT scans in one of the two tracks: 1) the complete nodule detection track where a complete CAD system should be developed, or 2) the false positive reduction track where a provided set of nodule candidates should be classified. This paper describes the setup of LUNA16 and presents the results of the challenge so far. Moreover, the impact of combining individual systems on the detection performance was also investigated. It was observed that the leading solutions employed convolutional networks and used the provided set of nodule candidates. The combination of these solutions achieved an excellent sensitivity of over 95% at fewer than 1.0 false positives per scan. This highlights the potential of combining algorithms to improve the detection performance. Our observer study with four expert readers has shown that the best system detects nodules that were missed by expert readers who originally annotated the LIDC-IDRI data. We released this set of additional nodules for further development of CAD systems.
Summary
Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by dysregulated T cells. We hypothesized that the aberrant expression of microRNAs (miRNAs) in AS T cells involved ...in the pathogenesis of AS. The expression profile of 270 miRNAs in T cells from five AS patients and five healthy controls were analysed by real‐time polymerase chain reaction (PCR). Thirteen miRNAs were found potentially differential expression. After validation, we confirmed that miR‐16, miR‐221 and let‐7i were over‐expressed in AS T cells and the expression of miR‐221 and let‐7i were correlated positively with the Bath Ankylosing Spondylitis Radiology Index (BASRI) of lumbar spine in AS patients. The protein molecules regulated by miR‐16, miR‐221 and let‐7i were measured by Western blotting. We found that the protein levels of Toll‐like receptor‐4 (TLR‐4), a target of let‐7i, in T cells from AS patients were decreased. In addition, the mRNA expression of interferon (IFN)‐γ was elevated in AS T cells. Lipopolysaccharide (LPS), a TLR‐4 agonist, inhibited IFN‐γ secretion by anti‐CD3+anti‐CD28 antibodies‐stimulated normal T cells but not AS T cells. In the transfection studies, we found the increased expression of let‐7i enhanced IFN‐γ production by anti‐CD3+anti‐CD28+ lipopolysaccharide (LPS)‐stimulated normal T cells. In contrast, the decreased expression of let‐7i suppressed IFN‐γ production by anti‐CD3+anti‐CD28+ LPS‐stimulated AS T cells. In conclusion, we found that miR‐16, miR‐221 and let‐7i were over‐expressed in AS T cells, but only miR‐221 and let‐7i were associated with BASRI of lumbar spine. In the functional studies, the increased let‐7i expression facilitated the T helper type 1 (IFN‐γ) immune response in T cells.
Large fine mode–dominated aerosols (submicron radius) in size distributions retrieved from the Aerosol Robotic Network (AERONET) have been observed after fog or low‐altitude cloud dissipation events. ...These column‐integrated size distributions have been obtained at several sites in many regions of the world, typically after evaporation of low‐altitude cloud such as stratocumulus or fog. Retrievals with cloud‐processed aerosol are sometimes bimodal in the accumulation mode with the larger‐size mode often ∼0.4–0.5μm radius (volume distribution); the smaller mode, typically ∼0.12 to ∼0.20 μm, may be interstitial aerosol that were not modified by incorporation in droplets and/or aerosol that are less hygroscopic in nature. Bimodal accumulation mode size distributions have often been observed from in situ measurements of aerosols that have interacted with clouds, and AERONET size distribution retrievals made after dissipation of cloud or fog are in good agreement with particle sizes measured by in situ techniques for cloud‐processed aerosols. Aerosols of this type and large size range (in lower concentrations) may also be formed by cloud processing in partly cloudy conditions and may contribute to the “shoulder” of larger‐size particles in the accumulation mode retrievals, especially in regions where sulfate and other soluble aerosol are a significant component of the total aerosol composition. Observed trends of increasing aerosol optical depth (AOD) as fine mode radius increased suggests higher AOD in the near‐cloud environment and higher overall AOD than typically obtained from remote sensing owing to bias toward sampling at low cloud fraction.
Key Points
Fine mode bimodal size distributions observed after cloud/fog dissipation
Cloud‐processed mode radius in good agreement with in situ measurements
Fine mode large radius shoulder may indicate effects of cloud interaction
The wear and friction in the pitch region of the centre of polymer gear teeth are not well understood. The transition around this point of the tooth between rolling and sliding has an important ...effect on the durability of polymer gear drives and can be simulated using a twin-disc configuration. This paper investigates the rolling–sliding wear behaviour of two poly-ether-ether-ketone (PEEK) discs running against each other with a simplified method of analysing and understanding the dynamic response of high performance polymeric gear teeth.
Tests were conducted without external lubrication over a range of loads and slip ratios, using a twin-disc test rig. The wear and friction mechanisms were closely related to surface morphology, with changes in crystallinity correlating with the severity of operating conditions. Observed failure mechanisms were also related to the structure of the contact surfaces, and included surface melting and contact fatigue.
Overall the PEEK discs were capable of running at low slip ratios for both low and high loads. Their performance reduced with an increase of the slip ratio. The results presented can be used in conjunction with the design process to allow the PEEK to be engineered for a specific high performance gear contact conditions.
The wear of poly-ether-ether-ketone in unlubricated rolling–sliding contact – simulation of high performance polymer gear applications Display omitted
•Tribology of PEEK in dry, roll–slide conditions studied against load and slip-ratio.•Twin discs simulate extremes of polymer gear contact which are not well understood.•Wear, friction and temperature of PEEK discs increased with slip ratio and load.•Wear rates for PEEK were significantly lower than for other similarly tested polymers.•Results can be used to design more effective, highly loaded, and polymeric gear systems.
Summary
We investigated the incidence and predictors of post‐treatment hepatitis B virus (HBV) relapse and hepatitis B surface antigen (HBsAg) loss. After cessation of nucleoside analogue (NA) ...treatment in hepatitis B e antigen (HBeAg)‐negative patients with cirrhosis. The rates of HBsAg loss and hepatocellular carcinoma (HCC) development in HBeAg‐negative patients with cirrhosis who continued NA treatment were compared with those who discontinued treatment. Patients with compensated cirrhosis who had discontinued NA treatment for at least 12 months (discontinuing group; n=73) and patients who continued entecavir treatment for at least 4 years (continuing group; n=158) were recruited. Serum HBsAg levels were analysed at the end of treatment (discontinuing group) or at 2.5‐3 years of treatment (continuing group). In the discontinuing group, the 6‐year cumulative incidence of post‐treatment virological relapse and HBsAg loss were 56.3% and 46.7%, respectively. The end‐of‐treatment HBsAg level of 300 IU/mL was a cut‐off value for subsequent post‐treatment HBsAg loss and sustained response. In the continuing group, HBsAg loss occurred in five of 158 patients. Cox regression analysis showed that HBsAg levels in the discontinuing group were independent predictors for HBsAg loss in all patients and 104 propensity score (PS)‐matched patients. There was no significant difference in HCC development between the groups in all patients and 104 PS‐matched patients. Two patients experienced post‐treatment alanine aminotransferase flare with hepatic decompensation, and neither of them died after retreatment. In conclusion, HBeAg‐negative patients with cirrhosis who discontinued NA treatment might have a higher rate of HBsAg loss and their risk of developing HCC did not increase compared with those who continued entecavir treatment.
Complex tissues contain multiple cell types that are hierarchically organized within morphologically and functionally distinct compartments. Construction of engineered tissues with optimized tissue ...architecture has been limited by tissue fabrication techniques, which do not enable versatile microscale organization of multiple cell types in tissues of size adequate for physiological studies and tissue therapies. Here we present an 'Intaglio-Void/Embed-Relief Topographic molding' method for microscale organization of many cell types, including induced pluripotent stem cell-derived progeny, within a variety of synthetic and natural extracellular matrices and across tissues of sizes appropriate for in vitro, pre-clinical, and clinical studies. We demonstrate that compartmental placement of non-parenchymal cells relative to primary or induced pluripotent stem cell-derived hepatocytes, compartment microstructure, and cellular composition modulate hepatic functions. Configurations found to sustain physiological function in vitro also result in survival and function in mice for at least 4 weeks, demonstrating the importance of architectural optimization before implantation.
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