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Abstract Circular RNAs (circRNAs) as biomarkers for cancer detection have been extensively explored, however, the biogenesis mechanism is still elusive. In contrast to linear splicing (LS) involved in linear transcript formation, the so-called back splicing (BS) process has been proposed to explain circRNA formation. To investigate the potential mechanism of BS via the machine learning approach, we curated a high-quality BS and LS exon pairs dataset with evidence-based stringent filtering. Two convolutional neural networks (CNN) base models with different structures for processing splicing junction sequences including motif extraction were created and compared after extensive hyperparameter tuning. In contrast to the previous study, we are able to identify motifs corresponding to well-established BS-associated genes such as MBNL1, QKI, and ESPR2. Importantly, despite prevalent high false positive rates in existing circRNA detection pipelines and databases, our base models demonstrated a notable high specificity (greater than 90%). To further improve the model performance, a novo fast numerical method was proposed and implemented to calculate the reverse complementary matches (RCMs) crossing two flanking regions and within each flanking region of exon pairs. Our CircCNNs framework that incorporated RCM information into the optimal base models further reduced the false positive rates leading to 88% prediction accuracy.

Abstract White matter hyperintensities (WMH) are markers of subcortical ischemic vascular cognitive impairment (SIVCI) associated with impaired postural balance. Physical reserve (PR) is a recently established construct that reflects one’s capacity to maintain physical function despite brain pathology. This cross-sectional study aims to map functional networks associated with PR, and examining the relationship between PR, WMH, and postural balance. PR was defined in 22 community-dwelling older adults with SIVCI. Functional networks of PR were computed using general linear model. Subsequent analyses examined whether PR and relevant networks moderated the relationship between WMH and postural balance under two conditions—eyes open while standing on foam (EOF) or on floor (EONF). We found that PR and the relevant networks—frontoparietal network (FPN) and default mode network (DMN)—significantly moderated the association between WMH and postural balance. For individuals with high PR, postural balance remained stable regardless of the extent of WMH load; whereas for those with low PR, postural balance worsened as WMH load increased. These results suggest the attenuated effects of WMH on postural stability due to PR may be underpinned by functional neural network reorganization in the FPN and DMN as a part of compensatory processes.

PurposeBased on the efficacy data from the previous study of B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell injection, we further examined the delayed toxicity for 8 weeks after a single dose of BCMA CAR T-cell injection to observe possible toxic reactions.MethodsB-NDG mice transplanted with multiple myeloma (MM) cells were given a single dose of BCMA CAR T-cell injection at two dosages or human normal T cells and then subjected to examinations including clinical signs, weight and food intake measurements, haematology, blood biochemical analysis, cytokine assay, T-lymphocyte subpopulation quantification and histopathology on days 28 and 56 after dosing. In addition, quantitative polymerase chain reaction (qPCR) was used to quantify DNA fragments in different tissues to assess the tissue distribution of CAR and provide a basis for its preclinical safety evaluation and clinical dosing.ResultsIn the delayed toxicity study, no mortality or significant toxic effects such as reductions in food intake, body weight, relevant biochemical parameters and target organ weights were observed in the BCMA CAR T-cell-treated groups. Compared to the model group, restorative changes in clinical signs and clinicopathology indicating therapeutic effects were seen in the BCMA CAR T-cell-treated groups. Human-derived cytokines interleukin-2 (IL-2), IL-4, IL-6, IL-12, IL-10, tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ) could be detected in all cancer cell–bearing mice by cytokine level measurement. IFN-γ levels showed a geometric increase due to the graft versus host disease (GVHD) response induced in the mice, while the levels of the other cytokines did not show significant changes. Histopathological examination indicated that the BCMA CAR T-cell treatment groups showed mixed cellular infiltration of human-derived T cells, cancer cells, and inflammatory cells in several target organs including the liver, spleen, lung, and kidney, and some of them showed mild tissue damage, but the number of the animals and the severity of damage were significantly less than those of the T-cell control group as well as the model group. The results of the tissue distribution study showed that BCMA CAR T cells were mainly concentrated in the kidney, lung, bone marrow and the related immune organs/tissues, and the distribution of BCMA CAR T cells was highly consistent with that of MM cells, suggesting that BCMA CAR T cells could follow the cancer cells during metastatic targeting of the tissues.ConclusionsThe present study demonstrated a low toxicity of BCMA CAR T-cell injection, with manageable side effects and good anticancer activity and without observable adverse effects. This study provides data to support future clinical studies of BCMA CAR T-cell injection for MM.

Older adults residing in long-term care often experience declines in physical and cognitive functions despite the access to in-house physical activity (PA) programs. This study aimed to evaluate the associations of PA with physical function and global cognitive function in older adults living in long-term care, while examining potential sex differences. A cross-sectional analysis of baseline data from a two-arm cluster randomized controlled trial was conducted, involving 67 participants (34 men, 33 women). PA levels were assessed using tri-axial accelerometers. Physical function, including muscular strength, postural sway, and Short Physical Performance Battery (SPPB) and cognitive function were measured. Spearman correlation analysis revealed no significant associations between PA metrics and muscular strength, postural sway, or global cognitive function across the entire samples (p ≥ 0.091). Multiple linear regression models were developed for the entire sample, males, and females to examine the associations between PA and physical function measures and global cognitive function. After adjustments for confounders, light PA was significantly associated with higher SPPB sub-scores (gait: β = 0.600, p

Based on disappointing results of stem cell-based application in clinical trials for patients with critical limb ischemia, we hypothesized that the acidic environment might be the key factor limiting cell survival and function. In the present study, we used microdialysis to determine presence of acidosis and metabolic imbalance in critical ischemia. Moreover, we explored the effect of extracellular acidosis on adipose-derived stem cells (ADSCs) at molecular and transcriptional level. Our data demonstrate that low pH negatively regulates cell proliferation and survival, also, it results in cell cycle arrest, mitochondrial dynamics disorder, DNA damage as well as the impairment of proangiogenic function in a pH-dependent manner. Further transcriptome profiling identified the pivotal signaling pathways and hub genes in response to acidosis. Collectively, these findings provide strong evidences for a critical role of acidosis in ADSCs impairment with ischemic condition and suggest treatments focus on tissue pH balance and acidosis-mediated hub genes may have therapeutic potential in stem cell-based application.

The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.

Abstract A sedentary lifestyle offers immediate gratification, but at the expense of long-term health. It is thus critical to understand how the brain evaluates immediate rewards and long-term health effects in the context of deciding whether to engage in moderate-to-vigorous physical activity (MVPA) or sedentary behaviour (SB). In this secondary analysis of a 6-month randomized controlled trial to increase MVPA and reduce SB among community-dwelling adults, we explored how neural activity during an executive control task was associated with MVPA and SB levels. At baseline, a subset of participants (n = 26/61) underwent task-based functional magnetic resonance imaging (fMRI) to examine neural activity underlying executive control using the Now/Later task. MVPA and SB were measured objectively using the Sensewear Mini at baseline, and 2, 4, and 6 months follow-up. We then examined the associations of baseline neural activation underlying executive control with: (1) baseline MVPA or SB; and (2) changes in MVPA and SB over 6 months. Our results determined that there is a complex neurocognitive system associated with MVPA levels, while SB appears to lack any neurocognitive control. In other words, MVPA appears to require neurocognitive effort, while SB may be the default behavioural pattern in adults.

Diabetic wounds significantly affect patient quality of life. Microneedles are a promising treatment to accelerate wound healing owing to their high drug-loading capacity and efficient drug delivery; however, few studies to date have comprehensively reviewed microneedles for diabetic wound healing. This up-to-date review summarizes the research progress in microneedles for diabetic wound healing, including manufacturing materials and techniques, structures, designs, release mechanisms, delivery substances, and their specific effects. This study showed that most microneedles designed for diabetic wounds are made of synthetic polymers and/or natural materials using polydimethylsiloxane micromolding. The geometric structure and design directly influence penetration ability and drug delivery capacity. Microneedles can deliver antibiotics, hypoglycemic agents, traditional Chinese medicines, metal ions, growth factors, exosomes, stem cells, and microorganisms, thus promoting diabetic wound healing through diverse mechanisms, such as antibacterial, anti-inflammatory, antioxidant, hypoglycemic, and angiogenic activities, at different stages of the healing process. In conclusion, microneedles are promising drug delivery systems for the treatment of diabetic wounds.

Abstract The osseous vascular endothelium encompasses a vast intricate framework that regulates bone remodeling. Osteoporosis, an age-associated systemic bone disease, is characterized by the degeneration of the vascular architecture. Nevertheless, the precise mechanisms underpinning the metamorphosis of endothelial cells (ECs) with advancing age remain predominantly enigmatic. In this study, we conducted a systematic analysis of differentially expressed genes (DEGs) and the associated pathways in juvenile and mature femoral ECs, utilizing data sourced from the Gene Expression Omnibus (GEO) repositories (GSE148804) and employing bioinformatics tools. Through this approach, we successfully discerned six pivotal genes, namely Adamts1, Adamts2, Adamts4, Adamts14, Col5a1, and Col5a2. Subsequently, we constructed a miRNA-mRNA network based on miRNAs displaying differential expression between CD31hiEMCNhi and CD31lowEMCNlow ECs, utilizing online repositories for prediction. The expression of miR-466i-3p and miR-466i-5p in bone marrow ECs exhibited an inverse correlation with age. Our in vivo experiments additionally unveiled miR-466i-5p as a pivotal regulator in osseous ECs and a promising therapeutic target for age-related osteoporosis.

Abstract Background Long non-coding RNAs (lncRNAs) play critical roles in various biological processes in plants. Extensive studies utilizing high-throughput RNA sequencing have revealed that many lncRNAs are involved in plant disease resistance. Oryza sativa RNase P protein 30 (OsRpp30) has been identified as a positive regulator of rice immunity against fungal and bacterial pathogens. Nevertheless, the specific functions of lncRNAs in relation to OsRpp30-mediated disease resistance in rice remain elusive. Results We conducted a comprehensive analysis of lncRNAs, miRNAs, and mRNAs expression patterns in wild type (WT), OsRpp30 overexpression (OsRpp30-OE), and OsRpp30 knockout (OsRpp30-KO) rice plants. In total, we identified 91 differentially expressed lncRNAs (DElncRNAs), 1671 differentially expressed mRNAs (DEmRNAs), and 41 differentially expressed miRNAs (DEmiRNAs) across the different rice lines. To gain further insights, we investigated the interaction between DElncRNAs and DEmRNAs, leading to the discovery of 10 trans- and 27 cis-targeting pairs specific to the OsRpp30-OE and OsRpp30-KO samples. In addition, we constructed a competing endogenous RNA (ceRNA) network comprising differentially expressed lncRNAs, miRNAs, and mRNAs to elucidate their intricate interplay in rice disease resistance. The ceRNA network analysis uncovered a set of gene targets regulated by lncRNAs and miRNAs, which were found to be involved in pathogen recognition, hormone pathways, transcription factor activation, and other biological processes related to plant immunity. Conclusions Our study provides a comprehensive expression profiling of lncRNAs, miRNAs, and mRNAs in a collection of defense mutants in rice. To decipher the putative functional significance of lncRNAs, we constructed trans- and cis-targeting networks involving differentially expressed lncRNAs and mRNAs, as well as a ceRNA network incorporating differentially expressed lncRNAs, miRNAs, and mRNAs. Together, the findings from this study provide compelling evidence supporting the pivotal roles of lncRNAs in OsRpp30-mediated disease resistance in rice.

Abstract The cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway has been a promising target for anticancer immunity, but rationally activating and enhancing this pathway in tumour cells is critical. Herein, a glutathione sensitive ZnFe2O4‐based nanosystem is developed to programmatically initiate and enhance the STING signalling pathway in tumour cells. The prepared ZnFe2O4 nanoparticles were coated with cancer cell membrane (CCM), which enabled the nanosystem target tumour cells. In tumour cells, ZnFe2O4 nanoparticles could be disintegrated by responding to high level glutathione, and the released Fe3+ generated reactive oxygen species to induce the DNA leakage into the cytoplasm to stimulate cGAS. Then Zn2+ promoted cGAS‐DNA phase separation to intensify the cGAS enzymatic activity. In addition, the low dose encapsulation of paclitaxel (PTX) acting as an antimitotic agent (ZnFe2O4‐PTX@CCM) ensured the sustained activation of cGAS/STING pathway. The in vitro and in vivo results confirmed that ZnFe2O4‐PTX@CCM elevated the cGAS/STING activity, promoted dendritic cell maturation, increased cytotoxic T lymphocyte and natural killer cells infiltration, eventually inhibiting the tumour progress and postoperative recurrence. This study provided feasible references on constructing STING activation nanosystem for tumour immunotherapy.

Peripheral arterial disease (PAD), characterized by atherosclerosis of the peripheral arteries or even amputation, has threatened public life and health. However, the underlying mechanism remains largely obscure. SUV39H1, a histone methyltransferase, could specifically methylate lysine 9 of histone H3 and act as a repressor in transcriptional activity. The study aimed to investigate the role of SUV39H1 in limb ischemia. C57BL/6 male mice were randomly divided into Sham or Model groups to investigate the expression of SUV39H1 in the ischemic limbs. Then, pharmaceutical inhibition or genetic deletion of SUV39H1 in the limb ischemia mice model was performed to confirm its effect on limb ischemia. The blood perfusion was quantified by laser speckle contrast imaging (LSCI). Capillary density and muscle edema were measured by CD31 immunohistochemical staining and HE staining. The expressions of SUV39H1 and Catalase were confirmed by western blot. Transcriptome sequencing of siSUV39H1 in human umbilical vein endothelial cells (HUVECs) was used to explore the regulation mechanism of SUV39H1 on angiogenesis. The results showed that SUV39H1 was highly expressed in the ischemic muscle tissue of the mice. Pharmaceutical inhibition or genetic deletion of SUV39H1 significantly improved blood perfusion, capillary density, and angiogenesis in ischemic muscle tissue. Cell experiments showed that SUV39H1 knockdown promoted cell migration, tube formation, and mitochondrial membrane potential in endothelial cells under oxidative stress. The transcriptome sequencing results unmasked mechanisms of the regulation of angiogenesis induced by SUV39H1. Finally, Salvianolic acid B and Astragaloside IV were identified as potential drug candidates for the improvement of endothelial function by repressing SUV39H1. Our study reveals a new mechanism in limb ischemia. Targeting SUV39H1 could improve endothelial dysfunction and thus prevent limb ischemia.

Abstract Long non-coding RNAs (lncRNAs) play an essential role in diverse biological processes and disease development. Accurate classification of lncRNAs and mRNAs is important for the identification of tissue- or disease-specific lncRNAs. Here, we present our tool LncDC (Long non-coding RNA detection) that is able to accurately predict lncRNAs with an XGBoost model using features extracted from RNA sequences, secondary structures, and translated proteins. Benchmarking experiments showed that LncDC consistently outperformed six state-of-the-art tools in distinguishing lncRNAs from mRNAs. Notably, the use of sequence and secondary structure (SASS) k-mer score features and flexible ORF features improved the classification capability of LncDC. We anticipate that LncDC will definitely promote the discovery of more and novel disease-specific lncRNAs. LncDC is implemented in Python and freely available at https://github.com/lim74/LncDC .

Abstract Background Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms. Methods Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer’s Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up). Discussion Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as “medicine” to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health. Trial registration ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016.

Background: Sorafenib is effective in treating hepatoma, but most patients develop resistance to it. STAT3 signaling has been implicated in sorafenib resistance. Artesunate (ART) and 20(R)-ginsenoside Rg3 (Rg3) have anti-hepatoma effects and can inhibit STAT3 signaling in cancer cells. This study aimed to evaluate the effects of Rg3 in combination with ART (Rg3-plus-ART) in overcoming sorafenib resistance, and to examine the involvement of STAT3 signaling in these effects. Methods: Sorafenib-resistant HepG2 cells (HepG2-SR) were used to evaluate the in vitro anti-hepatoma effects of Rg3-plus-ART. A HepG2-SR hepatoma-bearing BALB/c-nu/nu mouse model was used to assess the in vivo anti-hepatoma effects of Rg3-plus-ART. CCK-8 assays and Annexin V-FITC/PI double staining were used to examine cell proliferation and apoptosis, respectively. Immunoblotting was employed to examine protein levels. ROS generation was examined by measuring DCF-DA fluorescence. Results: Rg3-plus-ART synergistically reduced viability of, and evoked apoptosis in HepG2-SR cells, and suppressed HepG2-SR tumor growth in mice. Mechanistic studies revealed that Rg3-plus-ART inhibited activation/phosphorylation of Src and STAT3 in HepG2-SR cultures and tumors. The combination also decreased the STAT3 nuclear level and induced ROS production in HepG2-SR cultures. Furthermore, over-activation of STAT3 or removal of ROS diminished the anti-proliferative effects of Rg3-plus-ART, and removal of ROS diminished Rg3-plus-ART's inhibitory effects on STAT3 activation in HepG2-SR cells. Conclusions: Rg3-plus-ART overcomes sorafenib resistance in experimental models, and inhibition of Src/STAT3 signaling and modulation of ROS/STAT3 signaling contribute to the underlying mechanisms. This study provides a pharmacological basis for developing Rg3-plus-ART into a novel modality for treating sorafenib-resistant hepatoma.

Abstract Background The compound Danshen Dripping Pill (CDDP), which is a mixture of extracts from Radix Salviae and Panax notoginseng, is a patented traditional Chinese medicine that is widely used in multiple countries for relieving coronary heart disease (CHD), but its pharmacological mechanism has not been fully elucidated. In this study, we screened the key pharmacological pathways and targets of CDDP that act on CHD using a network pharmacology-based strategy, and the angiogenic activity of CDDP was directly visually investigated in zebrafish embryos in vivo. Methods The potential therapeutic targets and pathways were predicted through a bioinformatics analysis. The proangiogenic effects of CDDP were examined using vascular sprouting assays on subintestinal vessels (SIVs) and optic arteries (OAs) as well as injury assays on intersegmental vessels (ISVs). Pharmacological experiments were applied to confirm the pathway involved. Results Sixty-five potential therapeutic targets of CDDP on CHD were identified and enriched in the PI3K/AKT and VEGF/VEGFR pathways. An in vivo study revealed that CDDP promoted angiogenesis in SIVs and OAs in a dose-dependent manner and relieved the impairments in ISVs induced by lenvatinib, a VEGF receptor kinase inhibitor (VRI). In addition, Vegfaa and Kdrl expression were significantly upregulated after CDDP treatment. Furthermore, the proangiogenic effect of CDDP could be abolished by PI3K/AKT pathway inhibitors. Conclusions CDDP has a proangiogenic effect, the mechanism of which involves the VEGF/VEGFR and PI3K/AKT signaling pathways. These results suggest a new insight into the cardiovascular protective effect of CDDP.

When piglets are infected with intestinal virus, porcine intraepithelial lymphocytes undergo intra-and trans-epithelial migration promoted by chemokines from infected epithelial cells and produce an antiviral response.

Abstract Background Tea trees originated in southwest China 60 million or 70 million years ago. Written records show that Chinese ancestors had begun drinking tea over 3000 years ago. Nowadays, with the aging of populations worldwide and more people suffering from non-communicable diseases or poor health, tea beverages have become an inexpensive and fine complementary and alternative medicine (CAM) therapy. At present, there are 3 billion people who like to drink tea in the world, but few of them actually understand tea, especially on its development process and the spiritual and cultural connotations. Methods We searched PubMed, Google Scholar, Web of Science, CNKI, and other relevant platforms with the key word “tea”, and reviewed and analyzed tea-related literatures and pictures in the past 40 years about tea’s history, culture, customs, experimental studies, and markets. Results China is the hometown of tea, tea trees, tea drinking, and tea culture. China has the oldest wild and planted tea trees in the world, fossil of a tea leaf from 35,400,000 years ago, and abundant tea-related literatures and art works. Moreover, tea may be the first Chinese herbal medicine (CHM) used by Chinese people in ancient times. Tea drinking has many benefits to our physical health via its antioxidant, anti-inflammatory, immuno-regulatory, anticancer, cardiovascular-protective, anti-diabetic, and anti-obesity activities. At the moment, COVID-19 is wreaking havoc across the globe and causing severe damages to people’s health and lives. Tea has anti-COVID-19 functions via the enhancement of the innate immune response and inhibition of viral growth. Besides, drinking tea can allow people to acquire a peaceful, relaxed, refreshed and cheerful enjoyment, and even longevity. According to the meridian theory of traditional Chinese medicine, different kinds of tea can activate different meridian systems in the human body. At present, black tea (fermented tea) and green tea (non-fermented tea) are the most popular in the world. Black tea accounts for over 90% of all teas sold in western countries. The world’s top-grade black teas include Qi Men black in China, Darjeeling and Assam black tea in India, and Uva black tea in Sri Lanka. However, all top ten famous green teas in the world are produced in China, and Xi Hu Long Jing tea is the most famous among all green teas. More than 700 different kinds of components and 27 mineral elements can be found in tea. Tea polyphenols and theaflavin/thearubigins are considered to be the major bioactive components of black tea and green tea, respectively. Overly strong or overheated tea liquid should be avoided when drinking tea. Conclusions Today, CAM provides an array of treatment modalities for the health promotion in both developed and developing countries all over the world. Tea drinking, a simple herb-based CAM therapy, has become a popular man-made non-alcoholic beverage widely consumed worldwide, and it can improve the growth of economy as well. Tea can improve our physical and mental health and promote the harmonious development of society through its chemical and cultural elements.

Abstract The dysregulation of transposable elements (TEs) has been explored in a variety of cancers. However, TE activities in osteosarcoma (OS) have not been extensively studied yet. By integrative analysis of RNA-seq, whole-genome sequencing (WGS), and methylation data, we showed aberrant TE activities associated with dysregulations of TEs in OS tumors. Specifically, expression levels of LINE-1 and Alu of different evolutionary ages, as well as subfamilies of SVA and HERV-K, were significantly up-regulated in OS tumors, accompanied by enhanced DNA repair responses. We verified the characteristics of LINE-1 mediated TE insertions, including target site duplication (TSD) length (centered around 15 bp) and preferential insertions into intergenic and AT-rich regions as well as intronic regions of longer genes. By filtering polymorphic TE insertions reported in 1000 genome project (1KGP), besides 148 tumor-specific somatic TE insertions, we found most OS patient-specific TE insertions (3175 out of 3326) are germline insertions, which are associated with genes involved in neuronal processes or with transcription factors important for cancer development. In addition to 68 TE-affected cancer genes, we found recurrent germline TE insertions in 72 non-cancer genes with high frequencies among patients. We also found that +/− 500 bps flanking regions of transcription start sites (TSS) of LINE-1 (young) and Alu showed lower methylation levels in OS tumor samples than controls. Interestingly, by incorporating patient clinical data and focusing on TE activities in OS tumors, our data analysis suggested that higher TE insertions in OS tumors are associated with a longer event-free survival time.

Foot sole somatosensory impairment associated with peripheral neuropathy (PN) is prevalent and a strong independent risk factor for gait disturbance and falls in older adults. Walkasins, a lower-limb sensory prosthesis, has been shown to improve gait and mobility in people with PN by providing afferent input related to foot sole pressure distributions via lower-leg mechanical tactile stimulation. Given that gait and mobility are regulated by sensorimotor and cognitive brain networks, it is plausible improvements in gait and mobility from wearing the Walkasins may be associated with elicited neuroplastic changes in the brain. As such, this study aimed to examine changes in brain network connectivity after 26 weeks of daily use of the prosthesis among individuals with diagnosed PN and balance problems. In this exploratory investigation, assessments of participant characteristics, Functional Gait Assessment (FGA), and resting-state functional magnetic resonance imaging were completed at study baseline and 26 weeks follow-up. We found that among those who have completed the study (N = 8; mean age 73.7 years) we observed a five-point improvement in FGA performance as well as significant changes in network connectivity over the 26 weeks that were correlated with improved FGA performance. Specifically, greater improvement in FGA score over 26 weeks was associated with increased connectivity within the Default Mode Network (DMN; p

BackgroundWith the rapid advance in percutaneous coronary intervention (PCI) technology, patients absorb large volume of iodinated contrast media (ICM). Recent studies suggested that ICM may lead to hyperthyroidism, but the association between ICM volume and thyroid is still unclear. We sought to evaluate the long-term influence of ICM on thyroid dysfunction and disease in patients received PCI.MethodsThis single-center retrospective study included consecutive coronary artery disease (CAD) patients. A covariance (ANCOVA) model was performed to evaluate the change of serum TSH, FT3 and FT4 before and one-year after the PCI procedure. Restricted cubic splines and logistic regression were performed to evaluate the association between ICM volume and thyroid disease.Results2062 patients met inclusion criteria (1381 patients in the low-volume group and 681 patients in the high-volume group). The high-volume group was 0.238 ± 0.092 pmol/L higher than the low-volume group (P = 0.010) in the serum FT4. Restricted cubic splines show that there were linear dose-response relationships for ICM volume and composite endpoint and hyperthyroidism. In all models, there were significant differences in composite endpoint between the two groups. (OR 1.75, 95% CI (1.05, 2.92), P = 0.032, OR 1.73, 95% CI (1.01-2.96), P= 0.032 and OR 1.83, 95% CI (1.09-3.06), P= 0.022, respectively). The positive results were also showed for hyperthyroidism in all models (OR 2.35, 95% CI (1.14-4.84), P = 0.021, OR 10.36, 95% CI (1.20-89.00), P = 0.033 and OR 2.35, 95% CI (1.13-4.87), P = 0.022, respectively).ConclusionThe present analysis gives an overview that ICM volume is associated with an increased risk of thyroid dysfunction and thyroid disease.

The retinal pigment epithelium (RPE) exhibits a diverse range of plasticity across vertebrates and is a potential source of cells for the regeneration of retinal neurons. Embryonic amniotes possess a transitory ability to regenerate neural retina through the reprogramming of RPE cells in an FGF-dependent manner. Chicken RPE can regenerate neural retina at embryonic day 4 (E4), but RPE neural competence is lost by embryonic day 5 (E5). To identify mechanisms that underlie loss of regenerative competence, we performed RNA and ATAC sequencing using E4 and E5 chicken RPE, as well as at both stages following retinectomy and FGF2 treatment. We find that genes associated with neural retina fate remain FGF2-inducible in the non-regenerative E5 RPE. Coinciding with fate restriction, RPE cells stably exit the cell cycle and dampen the expression of cell cycle progression genes normally expressed during regeneration, including E2F1. E5 RPE exhibits progressive activation of gene pathways associated with mature function independently of retinectomy or FGF2 treatment, including retinal metabolism, pigmentation synthesis, and ion transport. Moreover, the E5 RPE fails to efficiently repress OTX2 expression in response to FGF2. Predicted OTX2 binding motifs undergo robust accessibility increases in E5 RPE, many of which coincide with putative regulatory elements for genes known to facilitate RPE differentiation and maturation. Together, these results uncover widespread alterations in gene regulation that culminate in the loss of RPE neural competence and implicate OTX2 as a key determinant in solidifying the RPE fate. These results yield valuable insight to the basis of RPE lineage restriction during early development and will be of importance in understanding the varying capacities for RPE-derived retinal regeneration observed among vertebrates.

Primary cardiac lymphoma (PCL) is a rare malignant lymphoma that is characteristically confined to the heart and/or pericardium. Here, the case of a 70-year-old male patient with complete atrioventricular block (AVB) associated with PCL is presented. The patient had a 10-month history of palpitation and electrocardiogram (ECG) showed a complete AVB. Additionally, transthoracic echocardiography indicated pericardial effusion where atypical lymphoid cells were identified by pericardiocentesis. Subsequent mediastinal lymph node biopsy revealed non-germinal centre diffuse large B-cell lymphoma. Therefore, a diagnosis of PCL was confirmed. As the patient’s vital signs were stable, he was prescribed chemotherapy without pacemaker implantation. After chemotherapy, the patient achieved remission and dynamic ECG demonstrated no recurrence of AVB. The present case demonstrates that although PCL initially manifesting as complete AVB is rare, this possibility should not be ignored when a new AVB without definite aetiology is encountered. In addition, if the vital signs of the patient are stable, pacemaker implantation may be postponed until the treatment effect of chemotherapy has been assessed.

Bupropion, an atypical anti-depressant and smoking cessation aid, attenuates complications arising from the activation of inflammatory and oxidative pathways. In this study, the effect of bupropion on an inflammatory and oxidative condition induced by carbon tetrachloride (CCl4) namely cirrhotic cardiomyopathy (CCM) was investigated in rats. CCM was induced by intraperitoneal injection of CCl4 (0.4 g/kg, i.p.). Bupropion was treated orally at doses 30 and 60 (mg/kg, p.o.) for 8 weeks. CCl4 treatment significantly lowered hepatic antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH) while enhanced Malondialdehyde (MDA). Elevations in serum nitric oxide (NO) metabolites nitrite/nitrate, and cardiac tumor necrosis factor alpha (TNF-α) and interleukin 1-beta (IL-1β) levels were observed. Cirrhosis also decreased contractility in response to isoproterenol (10−10 to 10−5 M). The spleen weight and intrasplenic pressure increased and QTc, QRS and RR intervals prolonged. Pathological damages in the liver for example focal necrosis, fibrosis and the hepatic blocking increased. On the other hand, bupropion increased GSH, CAT and SOD and lowered MDA. Bupropion reduced NO metabolites and TNF-α levels and decreased IL-1β. The cardiac contractile force improved at maximal effect (Rmax) 10-5 M by bupropion. The intrasplenic pressure was reduced by bupropion. Bupropion reduces QTc, QRS and RR intervals and the liver tissue damages. Bupropion played a cardioprotective role reducing inflammatory and oxidative factors. It may recover the impairment of cardiac contractility and hyperdynamic condition in CCM, and this effect could be mediated at least in part by a NO-dependent mechanism.

Cellular reprogramming resets the epigenetic landscape to drive shifts in transcriptional programmes and cell identity. The embryonic chick can regenerate a complete neural retina, after retinectomy, via retinal pigment epithelium (RPE) reprogramming in the presence of FGF2. In this study, we systematically analysed the reprogramming competent chick RPE prior to injury, and during different stages of reprogramming. In addition to changes in the expression of genes associated with epigenetic modifications during RPE reprogramming, we observed dynamic changes in histone marks associated with bivalent chromatin (H3K27me3/H3K4me3) and intermediates of the process of DNA demethylation including 5hmC and 5caC. Comprehensive analysis of the methylome by whole-genome bisulphite sequencing (WGBS) confirmed extensive rearrangements of DNA methylation patterns including differentially methylated regions (DMRs) found at promoters of genes associated with chromatin organization and fibroblast growth factor production. We also identified Tet methylcytosine dioxygenase 3 (TET3) as an important factor for DNA demethylation and retina regeneration, capable of reprogramming RPE in the absence of exogenous FGF2. In conclusion, we demonstrate that injury early in RPE reprogramming triggers genome-wide dynamic changes in chromatin, including bivalent chromatin and DNA methylation. In the presence of FGF2, these dynamic modifications are further sustained in the commitment to form a new retina. Our findings reveal active DNA demethylation as an important process that may be applied to remove the epigenetic barriers in order to regenerate retina in mammals. Abbreviations bp: Base pair; DMR: Differentially methylated region; DMC: Differentially methylated cytosines; GFP: Green fluorescent protein; PCR: Polymerase chain reaction. TET: Ten-eleven translocation; RPE: retinal pigment epithelium.

Abstract Background The red flour beetle Tribolium castaneum has emerged as an important model organism for the study of gene function in development and physiology, for ecological and evolutionary genomics, for pest control and a plethora of other topics. RNA interference (RNAi), transgenesis and genome editing are well established and the resources for genome-wide RNAi screening have become available in this model. All these techniques depend on a high quality genome assembly and precise gene models. However, the first version of the genome assembly was generated by Sanger sequencing, and with a small set of RNA sequence data limiting annotation quality. Results Here, we present an improved genome assembly (Tcas5.2) and an enhanced genome annotation resulting in a new official gene set (OGS3) for Tribolium castaneum, which significantly increase the quality of the genomic resources. By adding large-distance jumping library DNA sequencing to join scaffolds and fill small gaps, the gaps in the genome assembly were reduced and the N50 increased to 4753kbp. The precision of the gene models was enhanced by the use of a large body of RNA-Seq reads of different life history stages and tissue types, leading to the discovery of 1452 novel gene sequences. We also added new features such as alternative splicing, well defined UTRs and microRNA target predictions. For quality control, 399 gene models were evaluated by manual inspection. The current gene set was submitted to Genbank and accepted as a RefSeq genome by NCBI. Conclusions The new genome assembly (Tcas5.2) and the official gene set (OGS3) provide enhanced genomic resources for genetic work in Tribolium castaneum. The much improved information on transcription start sites supports transgenic and gene editing approaches. Further, novel types of information such as splice variants and microRNA target genes open additional possibilities for analysis.

Context Recent studies have shown compound Danshen dripping pills (CDDP) could improve microcirculation in ischemic/reperfusion injury and other microvascular disorders. The mechanism for CDDP’s role in microcirculation is not clear. Objective To explore the protective effects of CDDP on microvascular dysfunction. Materials and methods C57BL/6 male mice (6–8 weeks) were randomized into control, model and CDDP groups (n = 10), which were treated with normal saline or CDDP (105.30 mg/kg), respectively. Then, lipid emulsion and heparin were infused via mice jugular vein to establish systemic microvascular dysfunction model. Coronary flow reserve (CFR) and leukocytes adhesion on microvascular wall were measured. Relative CD11b and CD62L expression levels on neutrophils were measured by flow cytometric analysis. Expression level of forkhead box transcription factor O1 (FOXO1) mRNA was identified by real-time PCR. Results Lipid infusion significantly attenuated the CFR (1.84 ± 0.14 vs. 2.65 ± 0.02) and increased the number of leukocytes adherent to microvascular wall in cremaster (4067.00 ± 581.20 cells/mm2 vs. 10.67 ± 4.81 cells/mm2). The expression level of CD11b and FOXO1 in neutrophils was also up-regulated by lipid infusion. Pre-treatment with CDDP significantly improved CFR (2.57 ± 0.29 vs. 1.84 ± 0.14), decreased the number of leukocytes adherent to microvascular wall (2500.00 ± 288.70 cells/mm2 vs. 4067.00 ± 581.20 cells/mm2) and down-regulated CD11b and FOXO1 expression. Discussion and conclusions: Pre-treatment with CDDP could prevent lipid infusion-induced systemic microvascular disorder including coronary and peripheral microvascular dysfunction. Down-regulated FOXO1 and decreased leukocyte adhesion might play an important role in the mechanisms of CDDP’s efficacy.

Objective Using stratified analyses, we examined the cost-effectiveness of the Otago Exercise Programme (OEP), from a health care system perspective, among older women and men who have previously fallen. Methods This study was a secondary stratified analysis (by women and men), of a 12-month prospective economic evaluation of a randomized clinical trial (OEP compared with usual care). Three hundred and forty four community-dwelling older adults (≥70; 172 OEP (110 women; 62 men), 172 usual care (119 women; 53 men)) who sustained a fall in the past 12 months and received a baseline assessment at the Vancouver Falls Prevention Clinic, Canada were included. A gender by OEP/usual care interaction was examined for the falls incidence rate ratio (IRR). Outcome measures stratified by gender included: falls IRR, incremental cost-per fall prevented (ICER), incremental cost per quality adjusted life year (QALY, ICUR) gained, and mean total health care resource utilization costs. Results Men were frailer than women at baseline. Men incurred higher mean total healthcare costs $6794 (SD: $11906)). There was no significant gender by OEP/usual care interaction on falls IRR. The efficacy of the OEP did not vary by gender. The adjusted IRR for the OEP group demonstrated a 39% (IRR: 0.61, CI: 0.40–0.93) significant reduction in falls among men but not women (32% reduction (IRR: 0.69, CI: 0.47–1.02)). The ICER showed the OEP was effective in preventing falls and less costly for men, while it was costlier for women by $42. The ICUR showed the OEP did not impact quality of life. Conclusion Future studies should explore gender factors (i.e., health seeking behaviours, gender related frailty) that may explain observed variation in the cost-effectiveness of the OEP as a secondary falls prevention strategy. Trial registrations ClinicalTrials.gov Protocol Registration System Identifier: NCT01029171; URL: https://clinicaltrials.gov/ct2/show/NCT01029171 Identifier: NCT00323596; URL: https://clinicaltrials.gov/ct2/show/NCT00323596

White matter hyperintensities (WMH) are a prominent feature of cerebral small vessel disease and are associated with cognitive impairment. These deficits in cognition may be caused by the disruption of large-scale functional networks due to the presence of WMHs. However, knowledge regarding the relevance of these lesions on functional networks remains inconclusive. These inconsistencies may derive from issues with interpreting functional imaging data from clinical populations. Lesion network mapping is a technique that allows the overlaying of lesions from a patient population to the functional connectivity of a human connectome derived from healthy adults. This allows researchers to identify functional networks that would be disrupted in a healthy population should the WMHs seen in cerebral small vessel disease be present. We hypothesized that the extent to which these functional networks are disrupted by WMHs is associated with cognitive performance in older adults with cerebral small vessel disease.This cross-sectional study combined baseline data from four studies to create a total sample of 164 older adults (aged ≥55) from metropolitan Vancouver with cerebral small vessel disease. Using lesion network mapping, we assessed the percentage overlap between voxels functionally connected with both the WMHs (lesion network) and five common functional networks: (1) visual; (2) dorsal attention; (3) ventral attention; (4) sensorimotor; and (5) frontoparietal. Cognition was assessed using: (1) Montreal Cognitive Assessment (MoCA); (2) Stroop Colour Word Test (3–2); (3) Trail Making Tests (Part B-A); and (4) Digit Symbol Substitution Test. A One-Way ANOVA and Tukey post-hoc tests were performed to identify the functional networks with greatest percentage overlap with the lesion network. Partial correlations controlling for age were used to analyse whether the extent of the overlap between the lesion and functional networks was associated with poorer cognition.The visual, ventral attention, and frontoparietal networks had significantly greater overlap with the lesion network. After controlling for multiple comparisons, level of lesion network overlap with both the sensorimotor network (p

Background: To determine whether intracoronary pro-urokinase or tirofiban improves myocardial reperfusion during primary percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI).Methods: The study included patients with acute STEMI presenting within 12 h of symptoms at 11 hospitals in China between November 2015 and July 2017. Patients were randomized to receive selective intracoronary infusion of recombinant pro-urokinase (20 mg), tirofiban (10 μg/kg), or saline (20 mL) proximal to the infarct-related lesion over a 3-min period before stent implantation during primary PCI. The primary outcome was final corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) after PCI.Results: This study included 345 patients. Initial angiography identified a high-grade thrombus (TIMI 4–5) in 80% of patients. Final CTFC after PCI was significantly lower in the pro-urokinase (P < 0.001) and tirofiban (P < 0.001) groups than in the saline group and similar between the pro-urokinase and tirofiban groups (P > 0.05). The pro-urokinase (P = 0.008) and tirofiban groups (P = 0.022) had more complete ST-segment resolution at 2 h and lower peak creatine kinase-MB levels after PCI than the saline group (P = 0.006 and P = 0.023). The 30-day incidence of major adverse cardiac events was 4.5% in the pro-urokinase group, 3.4% in the tirofiban group, and 2.6% in the saline group. The incidence of in-hospital TIMI major bleeding events was low and comparable between groups.Conclusions: Adjunctive intracoronary pro-urokinase or tirofiban given before stent implantation during primary PCI improves myocardial reperfusion without increasing the incidence of major bleeding events.

Abstract Background Despite a number of different transgenes that can mediate DNA deletion in the developing lens, each has unique features that can make a given transgenic line more or less appropriate for particular studies. The purpose of this work encompasses both a review of transgenes that lead to the expression of Cre recombinase in the lens and a comparative analysis of currently available transgenic lines with a particular emphasis on the Le-Cre and P0-3.9GFPCre lines that can mediate DNA deletion in the lens placode. Although both of these transgenes are driven by elements of the Pax6 P0 promoter, the Le-Cre transgene consistently leads to ocular abnormalities in homozygous state and can lead to ocular defects on some genetic backgrounds when hemizygous. Result Although both P0-3.9GFPCre and Le-Cre hemizygous transgenic mice undergo normal eye development on an FVB/N genetic background, Le-Cre homozygotes uniquely exhibit microphthalmia. Examination of the expression patterns of these two transgenes revealed similar expression in the developing eye and pancreas. However, lineage tracing revealed widespread non-ocular CRE reporter gene expression in the P0-3.9GFPCre transgenic mice that results from stochastic CRE expression in the P0-3.9GFPCre embryos prior to lens placode formation. Postnatal hemizygous Le-Cre transgenic lenses express higher levels of CRE transcript and protein than the hemizygous lenses of P0-3.9GFPCre mice. Transcriptome analysis revealed that Le-Cre hemizygous lenses deregulated the expression of 15 murine genes, several of which are associated with apoptosis. In contrast, P0-3.9GFPCre hemizygous lenses only deregulated two murine genes. No known PAX6-responsive genes or genes directly associated with lens differentiation were deregulated in the hemizygous Le-Cre lenses. Conclusions Although P0-3.9GFPCre transgenic mice appear free from ocular abnormalities, extensive non-ocular CRE expression represents a potential problem for conditional gene deletion studies using this transgene. The higher level of CRE expression in Le-Cre lenses versus P0-3.9GFPCre lenses may explain abnormal lens development in homozygous Le-Cre mice. Given the lack of deregulation of PAX6-responsive transcripts, we suggest that abnormal eye development in Le-Cre transgenic mice stems from CRE toxicity. Our studies reinforce the requirement for appropriate CRE-only expressing controls when using CRE as a driver of conditional gene targeting strategies.

Flexible pressure sensors are essential components for wearable smart devices and intelligent systems. Significant progress has been made in this area, reporting on excellent sensor performance and fascinating sensor functionalities. Nevertheless, geometrical and morphological engineering of pressure sensors is usually neglected, which, however, is significant for practical application. Here, we present a digitized manufacturing methodology to construct a new class of iontronic pressure sensors with optionally defined configurations and widely modulated performance. These pressure sensors are composed of self-defined electrode patterns prepared by a screen printing method and highly tunable pressure-sensitive microstructures fabricated using 3D printed templates. Importantly, the iontronic pressure sensors employ an iontronic capacitive sensing mechanism based on mechanically regulating the electrical double layer at the electrolyte/electrode interfaces. The resultant pressure sensors exhibit high sensitivity (58 kPa−1), fast response/recovery time (45 ms/75 ms), low detectability (6.64 Pa), and good repeatability (2000 cycles). Moreover, our pressure sensors show remarkable tunability and adaptability in device configuration and performance, which is challenging to achieve via conventional manufacturing processes. The promising applications of these iontronic pressure sensors in monitoring various human physiological activities, fabricating flexible electronic skin, and resolving the force variation during manipulation of an object with a robotic hand are successfully demonstrated.

Background: Falls in older adults are a major public health problem. White matter hyperintensities (WMHs) are highly prevalent in older adults and are a risk factor for falls. In the absence of a cure for WMHs, identifying potential strategies to counteract the risk of WMHs on falls are of great importance. Physical activity (PA) is a promising countermeasure to reduce both WMHs and falls risk. However, no study has yet investigated whether PA attenuates the association of WMHs with falls risk. We hypothesized that PA moderates the association between WMHs and falls risk.Methods: Seventy-six community-dwelling older adults aged 70–80 years old were included in this cross-sectional study. We indexed PA using the Physical Activity Score for the Elderly (PASE) Questionnaire. Falls risk was assessed using the Physiological Profile Assessment (PPA), and WMH volume (mm3) was determined by an experienced radiologist on T2-weighted and PD-weighted MRI scans. We first examined the independent associations of WMH volume and PASE score with PPA. Subsequently, we examined whether PASE moderated the relationship between WMH volume and PPA. We plotted simple slopes to interpret the interaction effects. Age, sex, and Montreal Cognitive Assessment (MoCA) score were included as covariates in all models.Results: Participants had a mean age of 74 years (SD = 3 years) and 54 (74%) were female. Forty-nine participants (66%) had a Fazekas score of 1, 19 (26%) had a score of 2, and 6 (8%) a score of 3. Both PASE (β = −0.26 ± 0.11; p = 0.022) and WMH volume (β = 0.23 ± 0.11; p = 0.043) were each independently associated with PPA score. The interaction model indicated that PASE score moderated the association between WMH volume and PPA (β = −0.27 ± 0.12; p = 0.030), whereby higher PASE score attenuated the association between WMHs and falls risk.Conclusion: PA is an important moderator of falls risk. Importantly, older adults with WMH can reduce their risk of falls by increasing their PA.

Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors have been shown to decrease the adverse cardiac events and risks of cardiovascular mortality among patients with or without diabetes, which has made these drugs promising treatment options for patients with chronic heart failure. Cardiac dysfunction is a common and severe side effect induced by cancer chemotherapies, which seriously affects the prognosis and life quality of tumor patients. However, it is not clear whether SGLT2 inhibitors have cardiovascular benefits in patients with cancer chemotherapy–related cardiac dysfunction. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role against sunitinib (SNT)-induced cardiac dysfunction in a mouse model.Methods: Male C57BL/6J mice were randomized into control (control, n = 8), empagliflozin (EMPA, n = 8), sunitinib (SNT, n = 12), or sunitinib and empagliflozin coadministration (SNT + EMPA, n = 12) groups. EMPA, SNT, or SNT-combined EMPA was given via oral gavage for consecutive 28 days. Cardiovascular functions and pathological changes were examined, and the underlying mechanisms of EMPA’s effects were investigated in H9c2 cardiomyocytes.Results: Mice in the SNT group exhibited dramatically elevated blood pressure (systolic blood pressure [SBP] 134.30 ± 6.455 mmHg vs. 114.85 ± 6.30 mmHg) and impaired left ventricular function (left ventricular ejection fraction [LVEF] 50.24 ± 3.06% vs. 84.92 ± 2.02%), as compared with those of the control group. However, EMPA could ameliorate SNT-induced cardiotoxicity, both in terms of SBP (117.51 ± 5.28 mmHg vs. 134.30 ± 6.455 mmHg) and LVEF (76.18 ± 5.16% vs. 50.24 ± 3.06 %). In H9c2 cardiomyocytes, SNT-induced cardiomyocyte death and cell viability loss as well as dysfunction of adenosine 5’-monophosphate–activated protein kinase–mammalian target of rapamycin (AMPK-mTOR) signaling–mediated autophagy were restored by EMPA. However, these favorable effects mediated by EMPA were blocked by the inhibition of AMPK or autophagy.Conclusion: EMPA could ameliorate SNT-induced cardiac dysfunction via regulating cardiomyocyte autophagy, which was mediated by the AMPK-mTOR signaling pathway. These findings supported that SGLT2 inhibitor therapy could be a potential cardioprotective approach for cardiovascular complications among patients receiving SNT. However, these favorable effects still need to be validated in clinical trials.

Autism spectrum disorder (ASD) is very heterogeneous, particularly in language. Studies have suggested that language impairment is linked to auditory-brainstem dysfunction in ASD. However, not all ASD children have these deficits, which suggests potential subtypes of ASD. We classified ASD children into two subtypes according to their speech-evoked auditory brainstem response (speech-ABR) and explored the neural substrates for possible subtypes. Twenty-nine children with ASD and 25 typically developing (TD) peers were enrolled to undergo speech-ABR testing and structural magnetic resonance imaging (sMRI). There were significant differences between the ASD group and TD group in surface area, cortical volume and cortical thickness. According to speech-ABR results, ASD participants were divided into the ASD-typical (ASD-T) group and ASD-atypical (ASD-A) group. Compared with the ASD-T group, the ASD-A group had a lower score in language of the Gesell Developmental Diagnosis Scale (GDDS), increased left rostral middle frontal gyrus (lRMFG) area and decreased local gyrification index of the right superior temporal gyrus. GDDS-language and surface area of lRMFG were correlated to the wave-A amplitude in ASD. Surface area of lRMFG had an indirect effect on language performance via alteration of the wave-V amplitude. Thus, cortical deficits may impair language ability in children with ASD by causing subcortical dysfunction at preschool age. These evidences support dysfunction of the auditory brainstem as a potential subtype of ASD. Besides, this subtype-based method may be useful for various clinical applications.

Primary cilia are microtubule-based, antenna-like organelles, which are formed in G0 phase and resorbed as cells re-enter the cell cycle. It has been reported that primary cilia can influence the timing of cell cycle progression. However, the molecular links between ciliogenesis and cell cycle progression are not well understood. The Fibroblast Growth Factor Receptor 1 Oncogene Partner (FOP) has been implicated in ciliogenesis, but its function in ciliogenesis is not clear. Here, we show that FOP plays a negative role in ciliogenesis. Knockdown of FOP promotes cilia elongation and suppresses cilia disassembly. In contrast, ectopic expression of FOP induces defects in primary cilia formation, which can be rescued by either pharmacological or genetic inhibition of Aurora kinase A which promotes cilia disassembly. Moreover, knockdown of FOP delays cell cycle re-entry of quiescent cells following serum re-stimulation, and this can be reversed by silencing Intraflagellar Transport 20 (IFT20), an intraflagellar transport member essential for ciliogenesis. Collectively, these results suggest that FOP negatively regulates ciliogenesis and can promote cell cycle re-entry by facilitating cilia disassembly.

Cochlear implants (CI) are widely used in children and adults to restore hearing function. However, CI outcomes are vary widely. The affected factors have not been well understood. It is well known that the right and left hemispheres play different roles in auditory perception in adult normal hearing listeners. It is unknown how the implantation side may affect the outcomes of CIs. In this study, the effect of the implantation side on how the brain processes frequency changes within a sound was examined in 12 right-handed adult CI users. The outcomes of CIs were assessed with behaviorally measured frequency change detection threshold (FCDT), which has been reported to significantly affect CI speech performance. The brain activation and regions were also examined using acoustic change complex (ACC, a type of cortical potential evoked by acoustic changes within a stimulus), on which the waveform analysis and the standardized low-resolution brain electromagnetic tomography (sLORETA) were performed. CI users showed activation in the temporal lobe and non-temporal areas, such as the frontal lobe. Right-ear CIs could more efficiently activate the contralateral hemisphere compared to left-ear CIs. For right-ear CIs, the increased activation in the contralateral temporal lobe together with the decreased activation in the contralateral frontal lobe was correlated with good performance of frequency change detection (lower FCDTs). Such a trend was not found in left-ear CIs. These results suggest that the implantation side may significantly affect neuroplasticity patterns in adults.

IntroductionMost cochlear implant (CI) users have difficulty in listening tasks that rely strongly on perception of frequency changes (e.g., speech perception in noise, musical melody perception, etc.). Some previous studies using behavioral or subjective assessments have shown that short-term music training can benefit CI users’ perception of music and speech. Electroencephalographic (EEG) recordings may reveal the neural basis for music training benefits in CI users.ObjectiveTo examine the effects of short-term music training on CI hearing outcomes using a comprehensive test battery of subjective evaluation, behavioral tests, and EEG measures.DesignTwelve adult CI users were recruited for a home-based music training program that focused on attentive listening to music genres and materials that have an emphasis on melody. The participants used a music streaming program (i.e., Pandora) downloaded onto personal electronic devices for training. The participants attentively listened to music through a direct audio cable or through Bluetooth streaming. The training schedule was 40 min/session/day, 5 days/week, for either 4 or 8 weeks. The pre-training and post-training tests included: hearing thresholds, Speech, Spatial and Qualities of Hearing Scale (SSQ12) questionnaire, psychoacoustic tests of frequency change detection threshold (FCDT), speech recognition tests (CNC words, AzBio sentences, and QuickSIN), and EEG responses to tones that contained different magnitudes of frequency changes.ResultsAll participants except one finished the 4- or 8-week training, resulting in a dropout rate of 8.33%. Eleven participants performed all tests except for two who did not participate in EEG tests. Results showed a significant improvement in the FCDTs as well as performance on CNC and QuickSIN after training (p < 0.05), but no significant improvement in SSQ scores (p > 0.05). Results of the EEG tests showed larger post-training cortical auditory evoked potentials (CAEPs) in seven of the nine participants, suggesting a better cortical processing of both stimulus onset and within-stimulus frequency changes.ConclusionThese preliminary data suggest that extensive, focused music listening can improve frequency perception and speech perception in CI users. Further studies that include a larger sample size and control groups are warranted to determine the efficacy of short-term music training in CI users.

The breakdown of polymer insulators at a nanosecond scale is a serious problem for high-voltage devices and pulsed power systems. This paper reviews recent developments in research on the mechanisms and characteristics of the breakdown of polymers at a nanosecond scale at the Northwest Institute of Nuclear Technology. An improved avalanche breakdown model is proposed, and a formula for the strength of the electric breakdown (EBD) is formulated based on it. The formative time lag of the avalanche breakdown model is then developed to verify it. Two research groups were formed to study the characteristics of the breakdown. One focused on the characteristics of single-pulse breakdown, such as the effects of size, polymer type, electrode, pulse width, and pulse polarity on EBD, with the aim of deriving expressions for EBD. The other research group examined cumulative (multi-pulse) characteristics of the breakdown with the aim of deriving a formula for the lifetime of the polymer. A method to design solid insulation structures is finally proposed.

Summary: Eukaryotic DNA replication licensing is a prerequisite for, and plays a role in, regulating genome duplication that occurs exactly once per cell cycle. ORC (origin recognition complex) binds to and marks replication origins throughout the cell cycle and loads other replication-initiation proteins onto replication origins to form pre-replicative complexes (pre-RCs), completing replication licensing. However, how an asymmetric single-heterohexameric ORC structure loads the symmetric MCM (minichromosome maintenance) double hexamers is controversial, and importantly, it remains unknown when and how ORC proteins associate with the newly replicated origins to protect them from invasion by histones. Here, we report an essential and cell-cycle-dependent ORC “dimerization cycle” that plays three fundamental roles in the regulation of DNA replication: providing a symmetric platform to load the symmetric pre-RCs, marking and protecting the nascent sister replication origins for the next licensing, and playing a crucial role to prevent origin re-licensing within the same cell cycle. : Amin et al. provide in vivo evidence for an essential, cell-cycle-dependent, and likely semi-conservative ORC dimerization cycle that regulates eukaryotic chromosomal DNA replication. ORC dimers provide symmetric platforms to load the symmetric pre-RCs at replication origins. ORC de-dimerization produces two single hexamers to bind and protect the two nascent origins. Keywords: DNA replication, replication licensing, pre-RC formation, cell-cycle control, ORC dimerization

Digenic Connexin26 (Cx26, GJB2) and Cx30 (GJB6) heterozygous mutations are the second most frequent cause of recessive deafness in humans. However, the underlying deafness mechanism remains unclear. In this study, we created different double Cx26 and Cx30 heterozygous (Cx26+/−/Cx30+/−) mouse models to investigate the underlying pathological changes and deafness mechanism. We found that double Cx26+/−/Cx30+/− heterozygous mice had hearing loss. Endocochlear potential (EP), which is a driving force for hair cells producing auditory receptor current, was reduced. However, unlike Cx26 homozygous knockout (Cx26−/−) mice, the cochlea in Cx26+/−/Cx30+/− mice displayed normal development and had no apparent hair cell degeneration. Gap junctions (GJs) in the cochlea form two independent networks: the epithelial cell GJ network in the organ of Corti and the connective tissue GJ network in the cochlear lateral wall. We further found that double heterozygous deletion of Cx26 and Cx30 in the epithelial cells did not reduce EP and had normal hearing, suggesting that Cx26+/−/Cx30+/− may mainly impair gap junctional functions in the cochlear lateral wall and lead to EP reduction and hearing loss. Most of Cx26 and Cx30 in the cochlear lateral wall co-expressed in the same gap junctional plaques. Moreover, sole Cx26+/− or Cx30+/− heterozygous mice had no hearing loss. These data further suggest that digenic Cx26 and Cx30 mutations may impair heterozygous coupling of Cx26 and Cx30 in the cochlear lateral wall to reduce EP, thereby leading to hearing loss.