Metaplastic breast carcinoma (MpBC) typically consists of carcinoma of no special type (NST) with various metaplastic components. Although previous transcriptomic and proteomic studies have reported ...subtype-related heterogeneity, the intracase transcriptomic alterations between metaplastic components and paired NST components, which are critical for understanding the pathogenesis underlying the metaplastic processes, remain unclear.
Fifty-nine NST components and paired metaplastic components (spindle carcinomatous SPS, matrix-producing, rhabdoid RHA, and squamous carcinomatous SQC components) were microdissected from specimens obtained from 27 patients with MpBC for gene expression profiling using the NanoString Breast Cancer 360 Panel on a NanoString nCounter FLEX platform. BC360-defined signatures were scored using nSolver software.
Hierarchical clustering and principal component analysis revealed a heterogeneous gene expression profile (GEP) corresponding to the NST components, but the GEP of metaplastic components exhibited subtype dependence. Compared with the paired NST components, the SPS components demonstrated the upregulation of genes related to stem cells and epithelial-mesenchymal transition and displayed enrichment in claudin-low and macrophage signatures. Despite certain overlaps in the enriched functions and signatures between the RHA and SPS components, the specific differentially expressed genes differed. We observed the RHA-specific upregulation of genes associated with vascular endothelial growth factor signaling. The chondroid matrix-producing components demonstrated the upregulation of hypoxia-related genes and the downregulation of the immune-related MHC2 signature and the TIGIT gene. In the SQC components, TGF-β and genes associated with cell adhesion were upregulated. The differentially expressed genes among metaplastic components in the 22 MpBC cases with one or predominantly one metaplastic component clustered paired NST samples into clusters with correlation with their associated metaplastic types. These genes could be used to separate the 31 metaplastic components according to respective metaplastic types with an accuracy of 74.2%, suggesting that intrinsic signatures of NST may determine paired metaplastic type. Finally, the EMT activity and stem cell traits in the NST components were correlated with specimens displaying lymph node metastasis.
We presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs, which contributes to the understanding of the pathogenesis underlying morphologically distinct metaplasia in MpBCs.
A cyber-flipped course was conducted with the flipped classroom pedagogy by using a wholly online approach for all learning activities in asynchronous and synchronous class sessions. Literature ...suggests that traditional flipped courses can effectively enhance students' learning outcomes in comparison to non-flipped courses. However, conducting all asynchronous and synchronous learning activities using a wholly online approach has not been reported. This paper aimed to investigate how student engagement in four different types of learning activities affects their learning outcomes in a cyber-flipped course. Results show that the learning activities with the flipped classroom pedagogy can be successfully implemented and conducted in a wholly online course along with time and space flexibility for learners. This study also found that students who watched more pre-recorded video lectures tended to participate in the synchronous learning activities more actively and obtained a higher semester grade; higher completion of asynchronous learning activities had benefited students' understanding of the learning concepts. Furthermore, students who had a high level of readiness by attending synchronous class sessions on time and keeping their webcams activated had more frequent and proactive interactions with their peers and instructor.
There are limited therapeutic options for patients with Dravet syndrome (DS). The equilibrative nucleoside transporters 1 (ENT1) mediate both the influx and efflux of adenosine across the cell ...membrane exerted beneficial effects in the treatment of epilepsy. This study aimed to evaluate the anticonvulsant effect of the ENT1 inhibitor in an animal model of DS (Scn1a
mice). J7 (5 mg/kg) treatment was efficacious in elevating seizure threshold in Scn1a
mice after hyperthermia exposure. Moreover, the J7 treatment significantly reduced the frequency of spontaneous excitatory post-synaptic currents (sEPSCs, ~35% reduction) without affecting the amplitude in dentate gyrus (DG) granule cells. Pretreatment with the adenosine A1 receptor (A1R) antagonist, DPCPX, abolished the J7 effects on sEPSCs. These observations suggest that the J7 shows an anticonvulsant effect in hyperthermia-induced seizures in Scn1a
mice. This effect possibly acts on presynaptic A1R-mediated signaling modulation in granule cells.
Maternal high-fat (HF) diet is believed to induce oxidative stress and activate nutrient-sensing signals, which increase the risk of adult offspring to develop hypertension. We investigated whether ...resveratrol prevents the combined maternal plus postweaning HF-diets-induced hypertension in adult male offspring, with a focus on the kidney. Female Sprague–Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) for 5 weeks before mating and during gestation and lactation. The male offspring were placed on either the ND or HF diet from weaning to 4 months of age, resulting in four experimental groups (maternal diet/postweaning diet; n=8–10/group): ND/ND, ND/HF, HF/ND and HF/HF. Another group of HF/HF rats (n=10) was treated with 0.5% resveratrol in drinking water between 2 and 4 months of age (HF/HF+R). Rats were killed at 4 months of age. We found that HF/HF-induced hypertension in adult offspring was prevented by resveratrol. Resveratrol mediated its protective effect on HF/HF-induced hypertension in the kidneys of male offspring by diminishing oxidative stress; reducing renal asymmetric dimethylarginine levels; mediating the renin–angiotensin system (RAS) in favor of vasodilatation; restoring nutrient-sensing pathways via increased levels of silent information regulator transcript 1 (SIRT1), AMP-activated protein kinase 2α and peroxisome proliferator-activated receptor gamma coactivator 1-α; and inducing autophagy. Our data implicated an association between oxidative stress, RAS, nitric oxide, and nutrient-sensing signals in HF/HF-induced hypertension. Resveratrol, acting as an antioxidant as well as a SIRT1 activator, might be a therapeutic approach for hypertension.
Lung adenocarcinoma (ADC) is the predominant histological type of lung cancer, and radiotherapy is one of the current therapeutic strategies for lung cancer treatment. Unfortunately, biological ...complexity and cancer heterogeneity contribute to radioresistance development. Karyopherin α2 (KPNA2) is a member of the importin α family that mediates the nucleocytoplasmic transport of cargo proteins. KPNA2 overexpression is observed across cancer tissues of diverse origins. However, the role of KPNA2 in lung cancer radioresistance is unclear. Herein, we demonstrated that high expression of KPNA2 is positively correlated with radioresistance and cancer stem cell (CSC) properties in lung ADC cells. Radioresistant cells exhibited nuclear accumulation of KPNA2 and its cargos (OCT4 and c‐MYC). Additionally, KPNA2 knockdown regulated CSC‐related gene expression in radioresistant cells. Next‐generation sequencing and bioinformatic analysis revealed that STAT1 activation and nuclear phospholipid scramblase 1 (PLSCR1) are involved in KPNA2‐mediated radioresistance. Endogenous PLSCR1 interacting with KPNA2 and PLSCR1 knockdown suppressed the radioresistance induced by KPNA2 expression. Both STAT1 and PLSCR1 were found to be positively correlated with dysregulated KPNA2 in radioresistant cells and ADC tissues. We further demonstrated a potential positive feedback loop between PLSCR1 and STAT1 in radioresistant cells, and this PLSCR1‐STAT1 loop modulates CSC characteristics. In addition, AKT1 knockdown attenuated the nuclear accumulation of KPNA2 in radioresistant lung cancer cells. Our results collectively support a mechanistic understanding of a novel role for KPNA2 in promoting radioresistance in lung ADC cells.
Nuclear KPNA2 promotes radioresistance and regulates cancer stem cell properties in lung adenocarcinoma cells. A loop between PLSCR1 and STAT1 is involved in KPNA2‐mediated radioresistance.
We investigate the accuracy provided by different treatments of the exchange and correlation effects, in particular the London dispersion forces, on the properties of liquid water using ab initio ...molecular dynamics simulations with density functional theory. The lack of London dispersion forces in generalized gradient approximations (GGAs) is remedied by means of dispersion-corrected atom-centered potentials (DCACPs) or damped atom-pairwise dispersion corrections of the C 6 R –6 form. We compare results from simulations using GGA density functionals (BLYP, PBE, and revPBE) with data from their van der Waals (vdW) corrected counterparts. As pointed out previously, all vdW-corrected BLYP simulations give rise to highly mobile water whose softened structure is closer to experimental data than the one predicted by the bare BLYP functional. Including vdW interactions in the PBE functional, on the other hand, has little influence on both structural and dynamical properties of water. Augmenting the revPBE functional with either damped atom-pairwise dispersion corrections or DCACP evokes opposite behaviors. The former further softens the already under-structured revPBE water, whereas the latter makes it more glassy. These results demonstrate the delicacy needed in describing weak interactions in molecular liquids.
Altered expressions of pro-/anti-oxidant genes are known to regulate the pathophysiology of obstructive sleep apnea (OSA).We aim to explore the role of a novel long non-coding (lnc) RNA FKSG29 in the ...development of intermittent hypoxia with re-oxygenation (IHR)-induced endothelial dysfunction in OSA. Gene expression levels of key pro-/anti-oxidant genes, vasoactive genes, and the FKSG29 were measured in peripheral blood mononuclear cells from 12 subjects with primary snoring (PS) and 36 OSA patients. Human monocytic THP-1 cells and human umbilical vein endothelial cells (HUVEC) were used for gene knockout and double luciferase under IHR exposure. Gene expression levels of the FKSG29 lncRNA, NOX2, NOX5, and VEGFA genes were increased in OSA patients versus PS subjects, while SOD2 and VEGFB gene expressions were decreased. Subgroup analysis showed that gene expression of the miR-23a-3p, an endogenous competitive microRNA of the FKSG29, was decreased in sleep-disordered breathing patients with hypertension versus those without hypertension. In vitro IHR experiments showed that knock-down of the FKSG29 reversed IHR-induced ROS overt production, early apoptosis, up-regulations of the HIF1A/HIF2A/NOX2/NOX4/NOX5/VEGFA/VEGFB genes, and down-regulations of the VEGFB/SOD2 genes, while the protective effects of FKSG29 knock-down were abolished by miR-23a-3p knock-down. Dual-luciferase reporter assays confirmed that FKSG29 was a sponge of miR-23a-3p, which regulated IL6R directly. Immunofluorescence stain further demonstrated that FKSGH29 knock-down decreased IHR-induced uptake of oxidized low density lipoprotein and reversed IHR-induced IL6R/STAT3/GATA6/ICAM1/VCAM1 up-regulations. The findings indicate that the combined RNA interference may be a novel therapy for OSA-related endothelial dysfunction via regulating pro-/anti-oxidant imbalance or targeting miR-23a-IL6R-ICAM1/VCAM1 signaling.
Neuronal responses of sensory cortex are highly variable, and this variability is correlated across neurons. To assess how variability reflects factors shared across a neuronal population, we ...analyzed the activity of many simultaneously recorded neurons in visual cortex. We developed a simple model that comprises two sources of shared variability: a multiplicative gain, which uniformly scales each neuron’s sensory drive, and an additive offset, which affects different neurons to different degrees. This model captured the variability of spike counts and reproduced the dependence of pairwise correlations on neuronal tuning and stimulus orientation. The relative contributions of the additive and multiplicative fluctuations could vary over time and had marked impact on population coding. These observations indicate that shared variability of neuronal populations in sensory cortex can be largely explained by two factors that modulate the whole population.
•Response variability in V1 neuronal populations is largely shared across neurons•Shared variability involves two factors: a multiplicative gain and an additive offset•These two factors predict sensory responses of large populations on single trials•They determine pairwise correlations and constrain information coding
Cortical responses are highly variable. Using large-scale recordings in V1, Lin et al. show that this variability is shared across neurons and involves two simple factors: multiplicative and additive. These factors shape the joint variability of large populations of neurons.
Hypertension can originate from early-life exposure to oxidative stress. As reported, dimethyl fumarate (DMF) activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects against ...oxidative stress damage. We examined whether maternal DMF therapy protects adult offspring against hypertension programmed by prenatal dexamethasone (DEX) and postnatal high-fat (HF) diet exposure. We examined male Sprague Dawley rat offspring at 4 months of age from five groups (
= 11-13/group): control, DEX (0.1mg/kg i.p. from gestational day 16 to 22), HF (D12331 diet from weaning to 16 weeks of age), DEX+HF, and DEX+HF+DMF (50mg/kg/day via gastric gavage for 3 weeks during pregnancy). Maternal DMF therapy prevented male offspring against hypertension programmed by combined DEX and HF exposures. The protective effects of maternal DMF include reduced oxidative stress, decreased plasma asymmetric dimethylarginine (ADMA) levels, downregulated the renin-angiotensin system (i.e.
,
,
, and
), increased renal protein levels of certain nutrient-sensing signals, and promoted autophagy. In conclusion, maternal Nrf2 activation by DMF protects male adult offspring against hypertension programmed by combined DEX and HF exposures. Our results cast a new light on the therapeutic potential of targeting Nrf2 signaling pathway as reprogramming strategies to prevent programmed hypertension in children exposed to antenatal corticosteroids and postnatally excessive consumption of fat.
This study aimed to study the impact of a combination of maternal and post-weaning high-fat diets and whether resveratrol was beneficial. Sprague-Dawley dams were fed either chow or a high-fat diet, ...before mating, during pregnancy, and into lactation. At weaning, their offspring were randomly fed chow or a high-fat diet. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal high-fat/postnatal chow diet), CH (maternal chow/postnatal high-fat diet), and HH (maternal/postnatal high-fat diet). A fifth group consisted of HH plus resveratrol. The 4 month-old offspring of HH group had higher body weight, higher levels of plasma triglycerides, leptin, angiotensin I and angiotensin II and abnormal intraperitoneal glucose tolerance test results, which fulfilled the features of metabolic syndrome. The dysregulation of the renin-angiotensin system was seen in multiple organs. Sirtuin 1 expression/abundance was reduced by a maternal/postnatal high-fat diet, in all the organs examined. Resveratrol ameliorated most of the features of metabolic syndrome and molecular alterations. The administration of a high-fat diet in both periods showed interactive metabolic effects in the plasma and many organs. Our results suggest that a maternal high-fat diet sensitizes offspring to the adverse effects of subsequent high-fat intake on multiple organs.
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