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Introduction The transplantation of dental pulp stem cells (DPSCs) has emerged as a novel strategy for the regeneration of lost dental pulp after pulpitis and trauma. Dental pulp regeneration of the young permanent tooth with a wide tooth apical foramen has achieved significant progress in the clinical trials. However, because of the narrow apical foramen, dental pulp regeneration in adult teeth using stem cells remains difficult in the clinic. Finding out how to promote vascular reconstitution is essential for the survival of stem cells and the regeneration of dental pulp after transplantation into the adult tooth. Methods Adipose tissue–derived microvascular fragments (ad-MVFs) were isolated from human adipose tissues. The apoptosis and senescence of DPSCs cultured in conditioned media were evaluated to explore the effects of ad-MVFs on DPSCs. DPSCs combined with ad-MVFs were inserted into the human tooth root segments and implanted subcutaneously into immunodeficient mice. Regenerated pulplike tissues were analyzed by hematoxylin and eosin and immunohistochemistry. The vessels in regenerated tissues were analyzed by Micro-CT and immunofluorescence. Results The isolated ad-MVFs contained endothelial cells and pericytes. ad-MVFs effectively prevented the apoptosis and senescence of the transplanted DPSCs both in vivo and in vitro. Combined with DPSCs, ad-MVFs obviously facilitated the formation of vascular networks in the transplants. DPSCs combined with ad-MVFs formed dental pulp–like tissues with abundant cells and matrix after 4 weeks of implantation. The supplementation of ad-MVFs led to more odontoblastlike cells and increased the formation of mineralized substance around the root canal. Conclusions Cotransplantation with ad-MVFs promotes the angiogenesis and revascularization of transplanted DPSC aggregates, leading to robust regeneration of dental pulp.

Background The low survival rate or dysfunction of extracellular matrix (ECM)-based engineered organs caused by the adverse effects of unfavourable local microenvironments on seed cell viability and stemness, especially the effects of excessive reactive oxygen species (ROS), prompted us to examine the importance of controlling oxidative damage for tissue transplantation and regeneration. We sought to improve the tolerance of seed cells to the transplant microenvironment via antioxidant pathways, thus promoting transplant efficiency and achieving better tissue regeneration. Methods We improved the antioxidative properties of ECM-based bioroots with higher glutathione contents in dental follicle stem cells (DFCs) by pretreating cells or loading scaffolds with the antioxidant NAC. Additionally, we developed an in situ rat alveolar fossa implantation model to evaluate the long-term therapeutic effects of NAC in bioroot transplantation. Results The results showed that NAC decreased H2O2-induced cellular damage and maintained the differentiation potential of DFCs. The transplantation experiments further verified that NAC protected the biological properties of DFCs by repressing replacement resorption or ankylosis, thus facilitating bioroot regeneration. Conclusions The following findings suggest that NAC could significantly protect stem cell viability and stemness during oxidative stress and exert better and prolonged effects in bioroot intragrafts.

Introduction Vital pulp therapy aims at preserving pulp vitality and regenerating dentin. Therefore, the purpose of this study was to explore the effects of a combination of treated dentin matrix (TDM) proteins and dental pulp cell (DPC)-derived small extracellular vesicles (sEVs) on pulp-dentin complex repair. Methods We prepared TDM by chemical demineralization and mechanical disruption of teeth to a powder preparation. The sEVs were isolated from culture supernatants of DPCs and identified by nanoparticle tracking analysis, Western blotting, and transmission electron microscopy. The effect of a combination of TDM proteins and DPC-derived sEVs on DPC proliferation, migration, and odontogenic differentiation was evaluated in vitro. A minipig model of pulp injury was used to compare the clinical outcomes and tissue responses attributed to 4 materials including TDM, sEV-TDM, sEVs, and mineral trioxide aggregate. Results The sEV isolated from the cell supernatant promoted DPC proliferation and migration. The combination of TDM extracts and sEV synergistically promoted the migration of DPCs but suppressed their proliferation. Real-time polymerase chain reaction and Western blot revealed that sEV-TDM enhanced the odontoblast-related protein expressions in DPCs. In in vivo studies, TDM and sEV-TDM promoted the formation of continuous reparative dentin. Furthermore, odontoblastlike high columnar cells were observed on the pulp side of the dentin bridge. Conclusions The sEV-TDM complex exhibits intrinsic biological activities, which has potential applications as a bioactive pulp-capping material.

Deep caries, trauma, and severe periodontitis result in pulpitis, pulp necrosis, and eventually pulp loss. However, no clinical therapy can regenerate lost pulp. A novel pulp regeneration strategy for clinical application is urgently needed. Signaling transduction plays an essential role in regulating the regenerative potentials of dental stem cells. Cytokines or growth factors, such as stromal cell-derived factor (SDF), fibroblast growth factor (FGF), bone morphogenetic protein (BMP), vascular endothelial growth factor (VEGF), WNT, can promote the migration, proliferation, odontogenic differentiation, pro-angiogenesis, and pro-neurogenesis potentials of dental stem cells respectively. Using the methods of signaling modulation including growth factors delivery, genetic modification, and physical stimulation has been applied in multiple preclinical studies of pulp regeneration based on cell transplantation or cell homing. Transplanting dental stem cells and growth factors encapsulated into scaffold regenerated vascularized pulp-like tissue in the root canal. Also, injecting a flowable scaffold only with chemokines recruited endogenous stem/progenitor cells for pulp regeneration. Notably, dental pulp regeneration has gradually developed into the clinical phase. These findings enlightened us on a novel strategy for structural and functional pulp regeneration through elaborate modulation of signaling transduction spatially and temporally via clinically applicable growth factors delivery. But challenges, such as the adverse effects of unphysiological signaling activation, the controlled drug release system, and the safety of gene modulation, are necessary to be tested in future works for promoting the clinical translation of pulp regeneration.

RNF40 (OMIM: 607700) is a really interesting new gene (RING) finger E3 ubiquitin ligase containing multiple coiled-coil domains and a C-terminal RING finger motif, which engage in protein–DNA and protein–protein interactions. RNF40 encodes a polypeptide of 1001 amino acids with a predicted molecular mass of 113,678 Da. RNF40 and its paralog RNF20 form a stable heterodimer complex that can monoubiquitylate histone H2B at lysine 120 as well as other nonhistone proteins. Cancer is a major public health problem and the second leading cause of death. Through its protein ubiquitylation activity, RNF40 acts as a tumor suppressor or oncogene to play major epigenetic roles in cancer development, progression, and metastasis, highlighting the essential function of RNF40 and the importance of studying it. In this review, we summarize current knowledge about RNF40 gene structure and the role of RNF40 in histone H2B monoubiquitylation, DNA damage repair, apoptosis, cancer development, and metastasis. We also underscore challenges in applying this information to cancer prognosis and prevention and highlight the urgent need for additional investigations of RNF40 as a potential target for cancer therapeutics.

Purpose To analyze networks of social interactions between the residents of a therapeutic community (TC) for women and the way, in which such interactions predict the discussion of issues that arise in treatment. Design/methodology/approach In total, 50 residents of a corrections-based TC for women were surveyed on the peers with whom they socialized informally, shared meals, shared letters from home and discussed issues that arose in treatment over a 12 h period. The data were analyzed using exponential random graph models (ERGM). Findings Reciprocity occurred in all networks while transitivity (a tendency of two residents who are connected to both connect to a third peer) occurred in all networks measuring informal social interactions. When controlling for reciprocity and transitivity, residents avoided spending social time or sharing meals with the same peers. There was no evidence of homophily by race, age or years of education. Homophily by entrance time and case manager occurred in social time. Case manager homophily occurred in the discussion of treatment issues but disappeared when controlling for social time and sharing letters from home. Research limitations/implications Social networks in this TC arise from factors endogenous to the TC itself. It should be possible to determine the characteristics of optimal social networks in TCs. External validity is limited. Practical implications It should be possible to intervene to optimize the social networks of TC residents. Originality/value This is the first ERGM analysis of both informal and formal interactions in a TC.

To observe the effects of laurocapram and borneol as transdermal penetration enhancers applied to herbal cake-partitioned moxibustion on liver lipids, hormone-sensitive lipase (HSL) and hydroxymethylglutaryl CoA (HMG-CoA) reductase in hyperlipidemia rabbits. Forty New-Zealand rabbits were randomly divided into 5 groups using the random number table method, with 8 rats in each group. Rabbits in the blank group were fed routinely with a normal diet; rabbits in the other groups were fed with high-fat diet for 12 weeks to establish the hyperlipidemia model. Rabbits in the blank and the model groups were not given any intervention. After the model was prepared successfully, rabbits in the non-transdermal penetration enhancer group received herbal cake-partitioned moxibustion without transdermal penetration enhancers; rabbits in the laurocapram group and the borneol group received herbal cake-partitioned moxibustion with laurocapram or borneol respectively. After 4 weeks of treatment, the serum was isolated and enzyme-linked immunosorbent assay (ELISA) was applied for the detection of HSL and HMG-CoA reductase. The liver tissues were isolated, and total cholesterol (TC) and triglycerides (TG) were measured by enzymatic methods. One-step method was applied for high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) detection, and transmission turbidimetry was for apolipoprotein A1 (Apo-A1) and apolipoprotein B (Apo-B) detection. The serum concentrations of the drugs in the laurocapram and the borneol groups were significantly higher than those in the non-transdermal penetration enhancer group (both P

Background: Very-low-birth-weight (VLBW) infants have a high risk of postdischarge growth retardation (GR). Continued GR might exert negative long-term effects on their health. This study examined the prevalence and the risk factors for postdischarge GR among VLBW infants in Taiwan. Methods: Nationwide data from the Taiwan Premature Infant Follow-up Network between 2007 and 2011 were analyzed. Infants with a gestational age (GA)

Objective: To observe the lipid-lowering effect of different transdermal absorption enhancers applied to the herbal cake-partitioned moxibustion in hyperlipidemia model rabbits, and to explore the possible mechanism. Methods: Forty New-Zealand rabbits were randomly divided into 5 groups using the random number table method, with 8 rats in each group. Rabbits in the blank group were fed routinely with normal diet; rabbits in the other groups were fed with high-fat diet for 12 weeks to establish the hyperlipidemia model. Rabbits in the blank and the model groups were not treated. After the model was prepared, rabbits in the non-transdermal absorption enhancer group received herbal cake-partitioned moxibustion without transdermal absorption enhancer; rabbits in the laurocapram group and the borneol group received herbal cake-partitioned moxibustion with laurocapram or borneol respectively. After 4 weeks of treatment, serum was collected for enzyme-linked immunosorbent assay (ELISA), and the liver tissues were isolated for immunohistochemistry, quantitative polymerase chain reaction (qPCR) and Western-blotting (WB) detection. Results: Serum ELISA results showed that leptin was significantly decreased in the model group compared with the blank group (P 0.05). The qPCR results of rabbit liver tissues showed that the mRNA expressions of leptin, Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) in the model group were significantly lower than those in the blank group (all P

BackgroundComorbidity is the phenomenon of two or more diseases occurring simultaneously not by random chance and presents great challenges to accurate diagnosis and treatment. As an effort toward better understanding the genetic causes of comorbidity, in this work, we have developed a computational method to predict comorbid diseases. Two diseases sharing common genes tend to increase their comorbidity. Previous work shows that after mapping the associated genes onto the human interactome the distance between the two disease modules (subgraphs) is correlated with comorbidity.MethodsTo fully incorporate structural characteristics of interactome as features into prediction of comorbidity, our method embeds the human interactome into a high dimensional geometric space with weights assigned to the network edges and uses the projection onto different dimension to “fingerprint” disease modules. A supervised machine learning classifier is then trained to discriminate comorbid diseases versus non-comorbid diseases.ResultsIn cross-validation using a benchmark dataset of more than 10,000 disease pairs, we report that our model achieves remarkable performance of ROC score = 0.90 for comorbidity threshold at relative risk RR = 0 and 0.76 for comorbidity threshold at RR = 1, and significantly outperforms the previous method and the interactome generated by annotated data. To further incorporate prior knowledge pathways association with diseases, we weight the protein-protein interaction network edges according to their frequency of occurring in those pathways in such a way that edges with higher frequency will more likely be selected in the minimum spanning tree for geometric embedding. Such weighted embedding is shown to lead to further improvement of comorbid disease prediction.ConclusionThe work demonstrates that embedding the two-dimension planar graph of human interactome into a high dimensional geometric space allows for characterizing and capturing disease modules (subgraphs formed by the disease associated genes) from multiple perspectives, and hence provides enriched features for a supervised classifier to discriminate comorbid disease pairs from non-comorbid disease pairs more accurately than based on simply the module separation.

The complete plastid genome of Stenotaphrum subulatum Trin. was determined and analyzed in this work. The plastid genome was 139,282 bp in length with 82,220 bp of the large single-copy (LSC) regio...

Chrysopogon aciculatus (Retz.) Trin. is one of the most important warm-season turfgrass and one of the distribution centers in China, widely distributed in tropical regions of South China. In this ...

Background To estimate the prevalence of elevated blood glucose level (EBG, including type 2 diabetes mellitus and impaired fasting glucose), and its association with non-valvular atrial fibrillation (NVAF) in Guangzhou, China. Methods The population-based follow-up Guangzhou Heart Study collected baseline data from July 2015 to August 2017 among 12,013 permanent residents aged > 35 from 4 Guangzhou districts. Two streets (Dadong and Baiyun) in the Yuexiu District, and one street (Xiaoguwei) and two towns (Xinzao and Nancun) in the Panyu District were chosen as representative of urban and rural areas, respectively. Each participant completed a comprehensive questionnaire, and underwent physical examination, blood sample collection for laboratory testing, electrocardiography, and other evaluations. Multivariable logistic regression analyses were used to estimate the independent association between hyperglycemia and NVAF prevalence. Results The prevalence of EBG in overall study population was 29.9%. Compared with residents without EBG, the odds ratio (OR) for AF among residents with EBG was significantly higher (1.94, 95% confidence interval [CI]: 1.40–2.70, P P = 0.007), and driven by women (OR = 1.80, 95% CI: 1.12–2.91, P = 0.016). Conclusions In Guangzhou, China, prevalence of EBG is high among residents aged > 35 years and associated with a multivariate adjusted increase in prevalence of NVAF overall and in women.

Hemagglutinin (HA) is the major surface antigen of influenza virus and the most promising influenza vaccine immunogen. In 2013, the devastating H7N9 influenza virus was identified in China, which induced high mortality. The HA of this virus (H7) is relatively unstable, making it challenging to produce an effective vaccine. To improve the stability of HA protein from H7N9 influenza virus for better vaccine antigens without impairing immunogenicity, we recombined the HA from H7N9 (H7) with a more stable HA from H3N2 (H3) by structure-guided recombination, resulting in six chimeric HAs, FrA-FrF. Two of these chimeric HAs, FrB and FrC, exhibited proper hemagglutination activity and presented improved thermal stability compared to the original H7. Mice immunized with FrB and FrC elicited H7-specific antibodies comparable to those induced by parental H7, and the antisera collected from these immunized mice successfully inhibited H7N9 infection in a microneutralization assay. These results suggest that our structural-recombination approach can create stabilizing chimeric antigens while maintaining proper immunogenicity, which may not only benefit the construction of more stable HA vaccines to fight against H7N9 infection, but also facilitate effective vaccine improvements for other influenza viruses or infectious pathogens. In addition, this study also demonstrates the potential for better engineering of multimeric protein complexes like HA to achieve improved function, which are often immunologically or pharmaceutically important but difficult to modify.

Background Growing evidence indicates that high phosphoserine phosphatase (PSPH) expression is associated with tumor prognosis in many types of cancers. However, the role of PSPH in non-small cell lung cancer (NSCLC) is unclear. The purpose of this study was to investigate the clinical significance of PSPH in NSCLC. Methods One hundred forty-three patients with histologically confirmed NSCLC who underwent surgery were included. Quantitative real-time PCR and Western blot were used to assess PSPH expression in paired tumor and corresponding adjacent non-tumorous tissues. The role of PSPH in invasion and cell growth was investigated in vitro. Results Compared to adjacent normal lung tissues, PSPH messenger RNA and protein levels were significantly higher in NSCLC tissues, and the PSPH expression level was positively related to clinical stage, metastasis, and recurrence. High PSPH expression was predictive of poor overall survival. A549 cells transfected with small interfering-PSPH showed inhibited cell migration, invasion, and proliferation. We further demonstrated that PSPH might promote the invasive capabilities of NSCLC cells through the AKT/AMPK signaling pathway. Conclusion Our results indicate that PSPH may act as a putative oncogene in NSCLC, and may be a vital molecular marker for the metastasis and proliferation of NSCLC cells by regulating the AKT/AMPK signaling pathway.

The pathogenesis of rhegmatogenous retinal detachment depends on three factors, namely, retinal rupture, vitreous liquefaction and traction causing the retina to separate from the pigment epithelium, among which retinal rupture is the most important. Retinopathy is caused by a gap between the neurosensory retina and the retinal pigment epithelium, which severely damages the visual function of the patient. Therefore, early clinical discovery, prevention and selection of an appropriate treatment are important. This article reviews progress in the treatment of retinal detachment.

Epidermal growth factor receptor (EGFR) mutations are associated with leptomeningeal metastases (LM) of nonsmall cell lung cancer and sensitivity to tyrosine kinase inhibitor (TKI) treatment. Owing to the difficulty of obtaining carcinomatous meningeal tissue for analysis, cerebrospinal fluid (CSF) might be an alternative.To investigate the EGFR mutation detection in the CSF of lung adenocarcinoma patients with LM.Twenty-five lung adenocarcinoma patients with LM diagnosed by CSF cytology were retrospectively evaluated. The results of EGFR mutation detection in CSF, the treatment plan, and clinical outcome information were recorded.Nineteen patients had a known EGFR status in their primary tumors. Twenty patients received EGFR mutation analysis in CSF after LM diagnosis and 14 of them with a known EGFR mutation status of both primary tumors and CSF. Ten (71.4%) had the same EGFR gene status. In primary tumors, no T790M mutations were detected, whereas in CSF, 2 L858R cases and 1 19del case had T790M mutations at the same time. The detection rate of T790M mutations in CSF was 18.1% (2 of 11) in all cases with EGFR-sensitive mutations in the primary lesion.EGFR mutation detection in CSF of lung adenocarcinoma patients with LM might be an alternative when leptomeningeal biopsy cannot be applied and may help to guide TKI treatments.

Little is known about the survival and effect of rapid climate warming on Pseudoalteromonas in the Arctic, although it is abundant and important in this ecosystem. Here, we investigated a cold-adapted Pseudoalteromonas fuliginea BSW20308 from the Arctic Ocean, from the genome to its transcriptomic responses towards temperature changes. It contained two circular chromosomes, with the second chromosome probably evolved from an ancestral plasmid. The evolution of multipartite genomes may be advantageous for its survival under changing environments. RNA-seq analysis revealed the extensive involvement of sRNome in response to temperature stress for the first time, especially tmRNA and a novel Pf1 sRNA strongly induced under heat stress. The present study makes significant contributions towards the understanding of Pseudoalteromonas in two aspects: the genome structure and evolution of its two chromosomes, and the important discovery of the sRNome in response to temperature stress.

Axonopus compressus also known as carpet grass is a robust, stoloniferous grass that can grow in minimal fertilization and resists well to abiotic and biotic stresses including low nitrogen (LN) stress. This study aimed at characterizing the agro-morphological and metabolome responses to LN in carpet grass leaves. Under LN stress, carpet grass increased yellowness of leaves and root dry matter while reduced turf quality and shoot dry weight. The metabolome comparison between samples from optimum and LN conditions indicated 304 differentially accumulated metabolites (DAMs), which could be classified into 12 major and 31 subclasses. The results revealed that the leaf tissues accumulated more anthocyanins and other flavonoid metabolites under LN stress. Conversely, amino acids, nucleic acids and their derivatives were reduced in response to LN stress. The overall evaluation of individual metabolites and pathways, and previous studies on metabolomes indicated that carpet grass reduced its energy consumption in leaves and increased the level of organic acid metabolism and secondary metabolism in order to resist LN stress conditions.

Therapeutic guidance in non-small cell lung cancer (NSCLC) tumors that are positive for anaplastic lymphoma kinase (ALK) fluorescent in situ hybridization (FISH), but negative for ALK immunohistochemistry, is still challenging. Parallel routine screening of 4588 NSCLC cases identified 22 discordant cases. We rechecked these samples using ALK antibodies and selected reaction monitoring (SRM) quantitative multiplexed proteomics screening multiple protein targets, including ALK and MET for the ALK tyrosine kinase inhibitor (TKI), and FR-alpha, hENT1, RRM1, TUBB3, ERCC1, and XRCC1 for chemotherapy. The presence of ALK (31.8%), MET (36.4%), FR-alpha (72.7%), hENT1 (18.2%), RRM1 (31.8%), TUBB3 (72.9%), ERCC1 (4.5%), and a low level of XRCC1 (54.4%) correlated with clinical outcomes. SRM was more sensitive than the ALK D5F3 assay. Among the eight cases receiving ALK TKI, four cases with ALK or MET detected by SRM had complete or partial responses, whereas four cases without ALK or MET showed progression. Twenty-seven treatment outcomes from 20 cases were assessed and cases expressing more than half of the specific predictive proteins were sensitive to matching therapeutic agents and showed longer progression-free survival than the other cases (p &lt, 0.001). SRM showed a potential role in therapeutic decision making in NSCLC patients with ambiguous ALK test results.

Quercetin is the major representative of the flavonoid subgroup of flavones, with good pharmacological activities for the treatment of liver diseases, including liver steatosis, fatty hepatitis, liver fibrosis, and liver cancer. It can significantly influence the development of liver diseases via multiple targets and multiple pathways via antifat accumulation, anti-inflammatory, and antioxidant activity, as well as the inhibition of cellular apoptosis and proliferation. Despite extensive research on understanding the mechanism of quercetin in the treatment of liver diseases, there are still no targeted therapies available. Thus, we have comprehensively searched and summarized the different targets of quercetin in different stages of liver diseases and concluded that quercetin inhibited inflammation of the liver mainly through NF-κB/TLR/NLRP3, reduced PI3K/Nrf2-mediated oxidative stress, mTOR activation in autophagy, and inhibited the expression of apoptotic factors associated with the development of liver diseases. In addition, quercetin showed different mechanisms of action at different stages of liver diseases, including the regulation of PPAR, UCP, and PLIN2-related factors via brown fat activation in liver steatosis. The compound inhibited stromal ECM deposition at the liver fibrosis stage, affecting TGF1β, endoplasmic reticulum stress (ERs), and apoptosis. While at the final liver cancer stage, inhibiting cancer cell proliferation and spread via the hTERT, MEK1/ERK1/2, Notch, and Wnt/β-catenin-related signaling pathways. In conclusion, quercetin is an effective liver protectant. We hope to explore the pathogenesis of quercetin in different stages of liver diseases through the review, so as to provide more accurate targets and theoretical basis for further research of quercetin in the treatment of liver diseases.

Ultrasound-guided perineural dextrose injection (PDI) has been reported effective for carpal tunnel syndrome (CTS). Higher volume of injectate may reduce adhesion of median nerve from other tissues, but volume-dependent effects of PDI in CTS remain unknown. We aimed to investigate whether PDI with different injectate volumes had different effects for CTS participants. In this randomized, double-blinded, three-arm trial, 63 wrists diagnosed with CTS were randomized into three groups that received ultrasound-guided PDI with either 1, 2 or 4 ml of 5% dextrose water. All participants finished this study. Primary outcome as visual analog scale (VAS) and secondary outcomes including Boston Carpal Tunnel Questionnaire (BCTQ), Disability of the Arm, Shoulder and Hand score (QuickDASH), electrophysiological studies and cross-sectional area (CSA) of the median nerve at carpal tunnel inlet were assessed before and after PDI at the 1st, 4th, 12th and 24th weeks. For within-group analysis, all three groups (21 participants, each) revealed significant improvement from baseline in VAS, BCTQ and QuickDASH at the 1st, 4th, 12th and 24th weeks. For between-group analysis, 4 ml-group yielded better VAS reduction at the 4th and 12th weeks as well as improvement of BCTQ and QuickDASH at the 1st, 4th, and 12th weeks, compared to other groups. No significant between-group differences were observed in electrophysiological studies or median nerve CSA at any follow-up time points. There were no severe complications in this trial, and transient minor adverse effects occurred equally in the three groups. In conclusion, ultrasound-guided PDI with 4 ml of 5% dextrose provided better efficacy than with 1 and 2 ml based on symptom relief and functional improvement for CTS at the 1st, 4th, and 12th week post-injection, with no reports of severe adverse effects. There was no significant difference between the three groups at the 24th-week post-injection follow-up.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT03598322.

In this paper, we present a novel training method based on Baum-Welch algorithm for hidden Markov models (HMM), named as Comprehensive HMM (CompHMM), which changes the traditional approach of training HMM from positive examples only to be able to utilize both positive and negative examples in training HMMs. By comparison, our method outperformed the standard Baum-Welch method and another HMM discriminative training method significantly through both synthetic and real data in membership prediction task.

Background: Mesenchymal stem cells-conditioned medium (MSC-CM) provides a promising cell-free therapy for Alzheimer’s disease (AD) mainly due to the paracrine of MSCs, but the precise mechanisms remain unclear. Studies suggests that mitochondrial dysfunction precedes the accumulation of amyloid-β plaques and neurofibrillary tangles, and involves in the onset and development of AD. Objective: In the present study, we evaluated the protective effects and explored the related-mitochondrial mechanisms of human umbilical cord derived MSC-CM (hucMSC-CM) in an AD model in vitro. Methods: To this end, an AD cellular model was firstly established by okadaic acid (OA)-treated SH-SY5Y cells, and then treated by hucMSC-CM to assess the oxidative stress, mitochondrial function, apoptosis, AD-related genes, and signaling pathways. Results: hucMSC-CM significantly deceased tau phosphorylated at Thr181 (p181-tau) level, which was increased in AD. hucMSC-CM also alleviated intracellular and mitochondrial oxidative stress in OA-treated SH-SY5Y cells. In addition, hucMSC-CM suppressed apoptosis and improved mitochondrial function in OA-treated SH-SY5Y cells. Flow cytometric analysis indicated that hucMSC-CM exerted the protective effects relying on or partly extracellular vesicle (EV) mitochondrial transfer from hucMSCs to OA-treated SH-SY5Y cells. Moreover, RNA sequencing data further demonstrated that hucMSC-CM regulated many AD-related genes, signaling pathways and mitochondrial function. Conclusion: These results indicated that MSC-CM or MSC-EVs containing abundant mitochondria may provide a novel potential therapeutic approach for AD.

Background TIFY is a plant-specific protein family with a diversity of functions in plant development and responses to stress and hormones, which contains JASMONATE ZIM-domain (JAZ), TIFY, PPD and ZML subfamilies. Despite extensive studies of TIFY family in many other species, TIFY has not yet been characterized in Brassica napus. Results In this study, we identified 77, 36 and 39 TIFY family genes in the genome of B. napus, B. rapa and B. oleracea, respectively. Results of the phylogenetic analysis indicated the 170 TIFY proteins from Arabidopsis, B. napus, B. rapa and B. oleracea could be divided into 11 groups: seven JAZ groups, one PPD group, one TIFY group, and two ZIM/ZML groups. The molecular evolutionary analysis showed that TIFY genes were conserved in Brassicaceae species. Gene expression profiling and qRT-PCR revealed that different groups of BnaTIFY members have distinct spatiotemporal expression patterns in normal conditions or following treatment with different abiotic/biotic stresses and hormones. The BnaJAZ subfamily genes were predominantly expressed in roots and up-regulated by NaCl, PEG, freezing, methyl jasmonate (MeJA), salicylic acid (SA) and Sclerotinia sclerotiorum in leaves, suggesting that they have a vital role in hormone signaling to regulate multiple stress tolerance in B. napus. Conclusions The extensive annotation and expression analysis of the BnaTIFY genes contributes to our understanding of the functions of these genes in multiple stress responses and phytohormone crosstalk in B. napus.

Inflammation is a common pathological phenomenon when homeostasis is seriously disturbed. Phillygenin (PHI), a lignin component isolated from Forsythiae Fructus, has shown a good anti-inflammatory effect. However, the mechanisms of PHI on anti-inflammation have not yet been systematically elucidated. In this study, the lipopolysaccharide (LPS) - induced RAW264.7 cell inflammation model was established to investigate mechanisms of PHI on inflammation. The effect of PHI on the release of IL-1β and PGE2 inflammatory factors induced by LPS was detected by ELISA, and the mRNA expressions of IL-1β, IL-6 and TNF-α were detected by RT-qPCR. Proteomics studied the signaling pathways that might be affected by PHI and molecular docking technology was subsequently used to study the possible targets on proteomic screened pathways. Western blot was performed ultimately to detect progressive changes in protein expression on the related pathway. Our research showed that PHI significantly inhibited the robust increase of IL-1β and PGE2 and lowered the transcriptional level of inflammatory genes including IL-6, IL-1β and PGE2 in LPS-stimulated RAW264.7 cells. Proteomics results indicated that PHI was involved in the regulation of multiple signaling pathways. Molecular docking results indicated that PHI had an affinity for most proteins in NF-κB pathway. Western blot analysis proved that PHI inhibited LPS-induced NF-κB pathway activation. On the whole, PHI inhibited the activation of NF-κB pathway, thereby inhibiting the expression of related inflammatory genes and the release of cytokines, and showed a remarkable anti-inflammatory effect.

Apoptosis is a universal and continuous event during tissue development, restoration, repair, and regeneration. Mounting evidence has demonstrated that apoptosis is essential for the activation of tissue regeneration. However, the underlying mechanism remains elusive. A striking development in recent years comes from research on extracellular vesicles (EVs) derived from apoptotic cells. During apoptosis, cells secrete vesicles of various sizes containing various components. Apoptotic cell-derived EVs (ApoEVs) have been found to transit to neighboring cells or cells in distant tissues through the circulation. These vesicles could act as containers to transmit the nucleic acid, protein, and lipid signals to target cells. ApoEVs have been shown to promote regeneration in the cardiovascular system, skin, bone, muscle, kidney, etc. Moreover, several specific signaling pathways mediating the anabolic effects of ApoEVs have been classified. In this review, we comprehensively discussed the latest findings on the function of ApoEVs in tissue regeneration and disease prevention. These findings may reveal unexpected clues regarding the regulatory network between cell death and tissue regeneration and suggest novel targets for regenerative medicine. The findings discussed here also raise the question whether and to what extent ApoEVs contribute to embryonic development. This question is all the more urgent because the exact functions of apoptotic events during numerous developmental processes are still largely unclear.

This article aims to explore the underlying molecular mechanisms and prognosis‐related genes in pancreatic cancer metastasis. Pancreatic cancer metastasis‐related gene chip data were downloaded from GENE EXPRESSION OMNIBUS(GEO)database. Differentially expressed genes were screened after R‐package pre‐treatment. Functional annotations and related signalling pathways were analysed using DAVID software. GEPIA (Gene Expression Profiling Interactive Analysis) was used to perform prognostic analysis, and differential genes associated with prognosis were screened and validated using data from GEO. We screened 40 healthy patients, 40 primary pancreatic cancer and 40 metastatic pancreatic cancer patients, collected serum, designed primers and used qPCR to test the expression of prognosis‐related genes in each group. 109 differentially expressed genes related with pancreatic cancer metastasis were screened, of which 49 were up‐regulated and 60 were down‐regulated. Functional annotation and pathway analysis revealed differentially expressed genes were mainly concentrated in protein activation cascade, extracellular matrix construction, decomposition, etc In the biological process, it is mainly involved in signalling pathways such as PPAR, PI3K‐Akt and ECM receptor interaction. Prognostic analysis showed the expression levels of four genes were significantly correlated with the overall survival time of patients with pancreatic cancer, namely SCG5, CRYBA2, CPE and CHGB. qPCR experiments showed the expression of these four genes was decreased in both the primary pancreatic cancer group and the metastatic pancreatic cancer group, and the latter was more significantly reduced. Pancreatic cancer metastasis is closely related to the activation of PPAR pathway, PI3K‐Akt pathway and ECM receptor interaction. SCG5, CRYBA2, CPE and CHGB genes are associated with the prognosis of pancreatic cancer, and their low expression suggests a poor prognosis.

In the present study, anti-inflammatory activity of the methanol extracts of soymilk and soymilk fermented with Streptococcus salivarius subsp. thermophilus CCRC 14805 alone or in conjunction with Bificobacterium infantis CCRC 14603 was evaluated. It was found that extracts of soymilk and the prepared fermented soymilk dose-dependently suppress nitric oxide (NO) production of lipopolysaccharide (LPS)-induced macrophages, with soymilk showing the highest inhibition ability followed by S. thermophilus-fermented soymilk. Extracts of soymilk and fermented soymilk did not affect the activity of inducible nitric oxide synthase (iNOS). The extracts of the fermented soymilk inhibited the protein expression of iNOS in LPS-induced macrophages, but soymilk did not. Moreover, these extracts did not show obvious inhibition on cyclooxygenase-2 (COX-2) protein expression, while all showed the inhibitory effect on LPS-induced pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β and prostaglandin E2 (PGE2) produced by RAW 264.7 macrophages.

Due to the current COVID-19 pandemic, colleges and universities have implemented network teaching. E-learning engagement is the most important concern of educators and parents because this will directly affect student academic performance. Hence, this study focuses on students’ perceived family support and their e-learning engagement and analyzes the effects of e-learning normative consciousness and behaviors and self-efficacy on the relationship between family support and e-learning engagement in college students. Prior to this study, the relationship between these variables was unknown. Four structural equation models revealed the multiple mediating roles of e-learning normative consciousness and behaviors and self-efficacy in the relationship between family support and e-learning engagement. A total of 1,317 college students (mean age=19.51; 52.2% freshman) voluntarily participated in our study. The results showed that e-learning normative consciousness and behaviors and self-efficacy played significant and mediating roles between students’ perceived family support and e-learning engagement. Specifically, these two individual variables fully mediated the relationship between students’ perceived family support and e-learning engagement. The multiple mediation model showed that family members can increase family support of their children by creating a household environment conducive to learning, displaying positive emotions, demonstrating the capability to assist their children, advocating the significance of learning normative consciousness and behaviors, and encouraging dedicated and efficient learning. The findings complement and extend the understanding of factors influencing student e-learning engagement.

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Subcellular localization plays important roles in protein’s functioning. In this paper, we developed a hidden Markov model to detect de novo signals in protein sequences that target at a particular cellular location: plasmodesmata. We also developed a support vector machine to classify plasmodesmata located proteins (PDLPs) in Arabidopsis, and devised a decision-tree approach to combine the SVM and HMM for better classification performance. The methods achieved high performance with ROC score 0.99 in cross-validation test on a set of 360 type I transmembrane proteins in Arabidopsis. The predicted PD targeting signals in one PDLP have been experimentally verified.

Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer. Significance: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors. See related commentary by Koleilat and Kwong, p. 1094. This article is highlighted in the In This Issue feature, p. 1079

Background. Chinese oral herbal paste has been widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the treatment effects of herbal paste were controversial and lack evidence to support its clinical use. This study aims to systematically assess the efficacy and safety of Chinese oral herbal paste for the treatment of stable COPD. Methods. PubMed, Web of Science, CENTRAL, EMBASE, CNKI, VIP, CBM, and WANFANG database in addition to two websites of clinical trial registry were searched from respective inception to August 2019. Only randomized controlled trials (RCTs) studying Chinese herbal paste for the treatment of stable COPD were included. Methodological quality was assessed based on Cochrane risk of bias and GRADE approach. Data were analyzed using RevMan 5.3. Results. A total of 19 RCTs with 1303 individuals compared Chinese oral herbal paste and Western medicine (WM) with WM alone were included for meta-analysis. The review showed compared with WM alone, the combination of herbal paste and WM reduced exacerbation frequency. Subgroup analyses showed that after two to three months of treatment, compared with WM alone, Chinese herbal paste plus WM significantly decreased the St George’s Respiratory Questionnaire (SGRQ) scores, COPD assessment test (CAT) scores, and scores of traditional Chinese medicine (TCM) syndrome, and improved clinical effective rates, lung function, and 6-minute walk distance. No serious adverse events related to herbal paste were reported. Conclusion. Current evidence showed that Chinese oral herbal paste may be an effective and well-tolerated adjuvant therapy for stable COPD. Considering the risks of bias and heterogeneity, more high-quality, well-designed RCTs are still needed.

Objective To perform a meta-analysis to quantitatively assess functional magnetic resonance imaging (MRI) in the diagnosis of locally recurrent prostate cancer. Materials and methods A comprehensive search of the PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted from January 1, 1995 to December 31, 2016. Diagnostic accuracy was quantitatively pooled for all studies by using hierarchical logistic regression modeling, including bivariate modeling and hierarchical summary receiver operating characteristic (HSROC) curves (AUCs). The Z test was used to determine whether adding functional MRI to T2-weighted imaging (T2WI) results in significantly increased diagnostic sensitivity and specificity. Results Meta-analysis of 13 studies involving 826 patients who underwent radical prostatectomy showed a pooled sensitivity and specificity of 91%, and the AUC was 0.96. Meta-analysis of 7 studies involving 329 patients who underwent radiotherapy showed a pooled sensitivity of 80% and specificity of 81%, and the AUC was 0.88. Meta-analysis of 11 studies reporting 1669 sextant biopsies from patients who underwent radiotherapy showed a pooled sensitivity of 54% and specificity of 91%, and the AUC was 0.85. Sensitivity after radiotherapy was significantly higher when diffusion-weighted MRI data were combined with T2WI than when only T2WI results were used. This was true when meta-analysis was performed on a per-patient basis (p = 0.027) or per sextant biopsy (p = 0.046). A similar result was found when 1H-magnetic resonance spectroscopy (1H-MRS) data were combined with T2WI and sextant biopsy was the unit of analysis (p = 0.036). Conclusion Functional MRI data may not strengthen the ability of T2WI to detect locally recurrent prostate cancer in patients who have undergone radical prostatectomy. By contrast, diffusion-weight MRI and 1H-MRS data may improve the sensitivity of T2WI for patients who have undergone radiotherapy.

The increasing prevalence of low pI non-mAb therapeutics as well as current challenges in mAb-aggregate separations and low recoveries motivate further development in the multimodal anion exchange (MM AEX) space. In this work, linear salt gradient experiments at pH 7 were used to evaluate the retention of model proteins (with pI from 3.4 to 6.8) in 17 novel MM AEX prototype systems. The ligands were organized into three series. Series 1 extended previous work in multimodal ligand design and included a hydroxyl variant and linker length variants. Series 2 and 3 investigated the nature of hydrophobicity in MM AEX systems by adding hydrophobic (series 2) or fluorine (series 3) substituents to a solvent exposed phenyl ring. Compared to the commercial resin Capto Adhere, the series 1 and 3 ligands exhibited weaker binding, while some of the series 2 aliphatic prototypes showed dramatically increased retention and unique selectivities. Within series 1, the model proteins eluted earlier in the gradient as the charge-hydrophobic group distance on the ligand was increased from 4.9 A to 8.5 A. For the aliphatic variants in series 2, proteins that eluted early in the salt gradient were not affected by the increase in ligand hydrophobicity, while the later eluting proteins bound stronger as the length of the aliphatic substituent increased. The series 3 variants indicated that phenyl ring fluorination created subtle changes in protein elution in these MM AEX systems. Retention data from the three series was used to generate a partial least squares QSAR model based on both protein and ligand descriptors which accurately predicted protein retention with a training R 2 of 0.81 and a test R 2 of 0.76. The retention characteristics of some prototypes such as the earlier elution and unique selectivities compared to Capto Adhere suggest that they could potentially provide unique selectivities and increased recovery for the downstream processing of both mAb and non-mAb biotherapeutics.

Background and Aims Esophageal stricture is a common adverse event after endoscopic submucosal dissection (ESD) when it involves the entire circumference of the esophagus. We aimed to assess the effectiveness and safety of endoscopic transplantation of autologous esophageal mucosa in preventing stricture formation after circumferential ESD. Methods Nine patients who underwent circumferential ESD for early esophageal cancer were enrolled. After the patients underwent ESD, autologous esophageal mucosal patches were attached to the ulcer surface by using hemoclips and were then fixed with a covered metal mesh stent. The stent was removed 7 days after the procedure. The patients were followed up with endoscopy at scheduled times. Results Epithelialization occurred within a median of 7.1 days, with a graft survival rate of 96.5%. Strictures occurred at a mean of 24.7 days (range 18-34 days) after the procedure. The median number of endoscopic balloon dilatation sessions was 2.7 (range 0-6). Conclusions Transplantation of autologous esophageal mucosa could be a safe way of relieving the severity of esophageal stricture after circumferential ESD.

Effective legume-rhizobia symbiosis depends on efficient nutrient exchange. Rhizobia need to synthesize iron-containing proteins for symbiotic nitrogen fixation (SNF) in nodules, which depends on host plant-mediated iron uptake into the symbiosome. We functionally investigated a pair of vacuolar iron transporter like (VTL) genes, GmVTL1a/b, in soybean (Glycine max) and evaluated their contributions to SNF, including investigations of gene expression patterns, subcellular localization, and mutant phenotypes. Though both GmVTL1a/b genes were specifically expressed in the fixation zone of the nodule, GmVTL1a was the lone member to be localized at the tonoplast of tobacco protoplasts, and shown to facilitate ferrous iron transport in yeast. GmVTL1a targets the symbiosome in infected cells, as verified by in situ immunostaining. Two vtl1 knockout mutants had lower iron concentrations in nodule cell sap and peribacteroid units than in wild-type plants, suggesting that GmVTL1 knockout inhibited iron import into symbiosomes. Furthermore, GmVTL1 knockout minimally affected soybean growth under nonsymbiotic conditions, but dramatically impaired nodule development and SNF activity under nitrogen-limited and rhizobia-inoculation conditions, which eventually led to growth retardation. Taken together, these results demonstrate that GmVTL1a is indispensable for SNF in nodules as a transporter of ferrous iron from the infected root cell cytosol to the symbiosome.

The number of people with dementia is increasing rapidly worldwide. Developing strategies to improve quality of life for those with dementia is crucial and is receiving more attention. Natural environments are known for their healing effects on most people. This pilot study aimed to understand the benefits that natural environments, such as gardens, can provide for people with dementia. In total, 42 staff members in nine dementia care facilities were recruited as participants in this study and answered a semistructured questionnaire. One-way analysis of variance with repeated measures and the Mann–Whitney U test were used to compare the effects of garden visits on evaluated characteristics and the differences in evaluated characteristics between free garden use and unfree garden use groups. Data from open-ended questions underwent text analysis to obtain the principal beliefs of the participants. The staff members reported that garden visits had positive effects on mood, social interaction, depression, and agitation in people with dementia because of the multisensory, gentle stimuli of the natural environment. Of the evaluated cognitive characteristics, attention and orientation to time were improved the most after residents with dementia had spent time in a garden. Additionally, staff members in the free garden use group scored the effects of garden visits on the mood, long-term memory, language abilities, spatial ability, aggression, and agitation of patients with dementia as significantly higher than staff members in the unfree garden use group. Recommendations for future studies are discussed.

Background and purpose We hypothesized that a plan’s robustness to anatomical changes can be improved by optimizing with multiple CT scans of a patient. The purpose of this study was to determine whether an intensity modulated proton therapy (IMPT) plan could be developed to meet dose criteria on both planning and adaptive CT plans. Material and methods Eight lung cancer patients who underwent adaptive IMPT were retrospectively selected. Each patient had two CTs: a primary planning CT (PCT) and an adaptive planning CT (ACT), and IMPT plans associated with the scans. PCT and ACT were then used in combination to optimize one plan (MCT plan). The doses to the target and organs at risk from the PCT plan, ACT plan, P-ACT plan (PCT plan calculated on ACT data), and MCT plans calculated on both CTs were compared. Results The MCT plan maintained the D 95% on both CTs (mean, 65.99 Gy on PCT and 66.02 Gy on ACT). Target dose coverage on ACT was significantly better with the MCT plan than with the P-ACT plan ( p = 0.01). MCT plans had slightly higher lung V 20 (0.6%, p = 0.02) than did PCT plans. The various plans showed no statistically significant difference in heart and spinal cord dose. Conclusions The results of this study indicate that an IMPT plan can meet the dose criteria on both PCT and ACT, and that MCT optimization can improve the plan’s robustness to anatomical change.

Ke-Li Liao,1 Song Huang,1 Yu-Peng Wu2 1Department of Neurosurgery, ZigongFirst People’s Hospital, Zigong, Sichuan, People’s Republic of China; 2Department of Neurosurgery, TheSecond Hospital of Hebei MedicalUniversity, Shijiazhuang, Hebei, People’s Republic of China Background: A combination of temozolomide (TMZ) and radiotherapy and subsequent adjuvant chemotherapy is the gold standard of treatment for glioblastoma (GB). Bevacizumab (BEV), a humanized monoclonal antibody that blocks the effects of vascular endothelial growth factor A, has produced impressive response rates for recurrent GB and has been approved as second-line therapy. The efficacy and safety of BEV in newly diagnosed GB are not known. Aim: This systematic meta-analysis was undertaken to evaluate the value of combination therapy involving BEV in newly diagnosed GB. Methods: Electronic databases were searched for eligible literature up to October 2017. Randomized controlled trials assessing the efficacy and safety of BEV in patients with newly diagnosed GB were included, of which the main outcomes were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). All the data were pooled with the corresponding 95% confidence intervals (CIs) using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. Results: A total of six randomized controlled trials were included in this analysis. The experimental BEV group had significantly improved the overall PFS (OR =0.46, 95% CI =0.26–0.81, P=0.007), as well as PFS at 6months (OR =3.47, 95% CI =2.85–4.22, P

Lipoprotein lipase (LPL) is a rate-limiting enzyme that catalyzes hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins including chylomicrons (CM), low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). A variety of parenchymal cells can synthesize and secrete LPL. Recent studies have demonstrated that complicated processes are involved in LPL biosynthesis, secretion and transport. The enzyme activity of LPL is regulated by many factors, such as apolipoproteins, angiopoietins, hormones and miRNAs. In this article, we also reviewed the roles of LPL in atherosclerosis, coronary heart disease, cerebrovascular accident, Alzheimer disease and chronic lymphocytic leukemia. LPL in different tissues exerts differential physiological functions. The role of LPL in atherosclerosis is still controversial as reported in the literature. Here, we focused on the properties of LPL derived from macrophages, endothelial cells and smooth muscle cells in the vascular wall. We also explore the existence of crosstalk between LPL and those cells when the molecule mainly plays a proatherogenic role. This review will provide insightful knowledge of LPL and open new therapeutic perspectives.

Background Protein-protein interaction (PPI) prediction remains a central task in systems biology to achieve a better and holistic understanding of cellular and intracellular processes. Recently, an increasing number of computational methods have shifted from pair-wise prediction to network level prediction. Many of the existing network level methods predict PPIs under the assumption that the training network should be connected. However, this assumption greatly affects the prediction power and limits the application area because the current golden standard PPI networks are usually very sparse and disconnected. Therefore, how to effectively predict PPIs based on a training network that is sparse and disconnected remains a challenge. Results In this work, we developed a novel PPI prediction method based on deep learning neural network and regularized Laplacian kernel. We use a neural network with an autoencoder-like architecture to implicitly simulate the evolutionary processes of a PPI network. Neurons of the output layer correspond to proteins and are labeled with values (1 for interaction and 0 for otherwise) from the adjacency matrix of a sparse disconnected training PPI network. Unlike autoencoder, neurons at the input layer are given all zero input, reflecting an assumption of no a priori knowledge about PPIs, and hidden layers of smaller sizes mimic ancient interactome at different times during evolution. After the training step, an evolved PPI network whose rows are outputs of the neural network can be obtained. We then predict PPIs by applying the regularized Laplacian kernel to the transition matrix that is built upon the evolved PPI network. The results from cross-validation experiments show that the PPI prediction accuracies for yeast data and human data measured as AUC are increased by up to 8.4 and 14.9% respectively, as compared to the baseline. Moreover, the evolved PPI network can also help us leverage complementary information from the disconnected training network and multiple heterogeneous data sources. Tested by the yeast data with six heterogeneous feature kernels, the results show our method can further improve the prediction performance by up to 2%, which is very close to an upper bound that is obtained by an Approximate Bayesian Computation based sampling method. Conclusions The proposed evolution deep neural network, coupled with regularized Laplacian kernel, is an effective tool in completing sparse and disconnected PPI networks and in facilitating integration of heterogeneous data sources.

Rational: Senescence of mesenchymal stem cells (MSCs) and the related functional decline of osteogenesis have emerged as the critical pathogenesis of osteoporosis in aging. Resveratrol (RESV), a small molecular compound that safely mimics the effects of dietary restriction, has been well documented to extend lifespan in lower organisms and improve health in aging rodents. However, whether RESV promotes function of senescent stem cells in alleviating age-related phenotypes remains largely unknown. Here, we intend to investigate whether RESV counteracts senescence-associated bone loss via osteogenic improvement of MSCs and the underlying mechanism. Methods: MSCs derived from bone marrow (BMMSCs) and the bone-specific, senescence-accelerated, osteoblastogenesis/osteogenesis-defective mice (the SAMP6 strain) were used as experimental models. In vivo application of RESV was performed at 100 mg/kg intraperitoneally once every other day for 2 months, and in vitro application of RESV was performed at 10 μM. Bone mass, bone formation rates and osteogenic differentiation of BMMSCs were primarily evaluated. Metabolic statuses of BMMSCs and the mitochondrial activity, transcription and morphology were also examined. Mitofilin expression was assessed at both mRNA and protein levels, and short hairpin RNA (shRNA)-based gene knockdown was applied for mechanistic experiments. Results: Chronic intermittent application of RESV enhances bone formation and counteracts accelerated bone loss, with RESV improving osteogenic differentiation of senescent BMMSCs. Furthermore, in rescuing osteogenic decline under BMMSC senescence, RESV restores cellular metabolism through mitochondrial functional recovery via facilitating mitochondrial autonomous gene transcription. Molecularly, in alleviating senescence-associated mitochondrial disorders of BMMSCs, particularly the mitochondrial morphological alterations, RESV upregulates Mitofilin, also known as inner membrane protein of mitochondria (Immt) or Mic60, which is the core component of the mitochondrial contact site and cristae organizing system (MICOS). Moreover, Mitofilin is revealed to be indispensable for mitochondrial homeostasis and osteogenesis of BMMSCs, and that insufficiency of Mitofilin leads to BMMSC senescence and bone loss. More importantly, Mitofilin mediates resveratrol-induced mitochondrial and osteogenic improvements of BMMSCs in senescence. Conclusion: Our findings uncover osteogenic functional improvements of senescent MSCs as critical impacts in anti-osteoporotic practice of RESV, and unravel Mitofilin as a novel mechanism mediating RESV promotion on mitochondrial function in stem cell senescence.

// Junbao Wei 1, * , Hengzong Zhu 2, * and Xiaoli Liao 3 1 Department of Therapeutic Radiology, Guangxi Autonomous Regional Cancer Hospital & Cancer Hospital of Guangxi Medical University, Nanning, 530021, China 2 Department of General Medicine, Longan Hospital of Traditional Chinese Medicine, Nanning, 532700, China 3 The Oncology Department, Guangxi Autonomous Regional Cancer Hospital & Cancer Hospital of Guangxi Medical University, Nanning, 530021, China * These authors contributed equally to this work Correspondence to: Xiaoli Liao, email: 121021866@qq.com Keywords: prostate cancer; recurrence; choline PET/CT; PSA; meta-analysis Received: July 27, 2017 Accepted: December 13, 2017 Epub: January 24, 2018 Published: March 06, 2018 ABSTRACT Purpose: To assess the relationship between the diagnostic accuracy of Choline positron emission tomography/computed tomography (PET/CT) and the trigger prostate-specific antigen (PSA) level in patients with a biochemical recurrence of prostate cancer. Materials and Methods: A meta-analysis was conducted to synthesize data across multiple studies. Results: The pooled sensitivity and specificity of choline PET/CT were 82% (95% Confidence Interval (CI):80–84%) and 92% (95%CI: 90–93%), respectively. The pooled sensitivity and specificity of 18 F-choline PET/CT were 81% (95%CI: 78–84%) and 90% (95%CI: 85–93%), respectively. The pooled sensitivity and specificity of 11 C-choline PET/CT were 83% (95% CI: 80–86%) and 92% (95% CI: 90–94%), respectively. The pooled detection rate of 18 F-choline PET/CT and 11 C-choline PET/CT were 58% (95% CI: 48–68%) and 58% (95%CI: 49–68%), respectively. Conclusions: Trigger PSA is an important risk factor for positive findings of Choline PET/CT and the detection rate of Choline PET/CT for recurrent prostate cancer increased in parallel with raises in PSA-values. Choline PET/CT got higher detection rate while the trigger PSA > 2ng/ml.

Bone marrow-derived mesenchymal stem cell (BMSC) cytotherapy has emerged as a promising treatment strategy for refractory immune diseases; however, the influence of the pathologic conditions of donors on the immunomodulatory properties of BMSCs is still poorly understand. Here, we found that BMSCs that were derived from donors with osteoporosis were ineffective as cytotherapy for patients with experimental colitis and graft- vs.-host disease (GVHD). In vivo and in vitro assays revealed that the capacity of osteoporotic BMSCs to induce T-cell apoptosis declined as a result of decreased Fas and FasL protein. Additional analysis revealed that let-7a, a microRNA induced by TNF-α in osteoporosis, inhibited the expression of the Fas/FasL system via post-transcriptional regulation. By knocking down let-7a expression, we successfully recovered the immunosuppressive capacity of osteoporotic BMSCs and improved their therapy for experimental colitis and GVHD. Taken together, our study demonstrates that the immunomodulatory properties of BMSCs are suppressed in osteoporosis and illustrates the molecular mechanism that underlies this suppression. These findings might have important implications for the development of targeted strategies to improve BMSC cytotherapy.-Liao, L., Yu, Y., Shao, B., Su, X., Wang, H., Kuang, H., Jing, H., Shuai, Y., Yang, D., Jin, Y. Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis.

Approximately 90% of patients diagnosed with non-small cell lung cancer (NSCLC) die due to distant metastases. However, the complicated molecular and cellular mechanisms involved in lung cancer metastasis remain poorly understood. Copine III (CPNE3), a member of a Ca2+-dependent phospholipid-binding protein family, was identified as a novel metastasis-associated protein in NSCLC in our previous study, however, its function in metastasis remains unclear. Here, we found that CPNE3 was expressed at high levels in NSCLC tissues and advanced TNM stages and was significantly associated with poor prognosis. In addition, CPNE3 interacted with phosphorylated erb-b2 receptor tyrosine kinase 2 (pErbB2) and receptor of activated protein C kinase 1 (RACK1) and activated the focal adhesion (FA) signaling pathway in NSCLC cells. Moreover, knockdown of RACK1 inhibited cell motility in the CPNE3-overexpressed NSCLC cells. These findings offer mechanistic insights into the oncogenic roles of CPNE3 and the pivotal effects of CPNE3 as a biomarker and therapeutic target for NSCLC metastasis.

Aeromicrobium sp. A1–2, a putative new species isolated from marine sediments in the King George Island, Antarctica, was completely sequenced. The genome data showed biosynthetic potential of new natural products and clues for environmental adaptation of this actinobacterium.

PA forms a biofilm resistant to antibiotics, hindering antibiotics efficacy and preventing the eradication of PA, has attracted much attention for its biofilm. In this study, we first established and validated an efficient and sensitive gas chromatography-mass spectrometry (GC–MS) method for the quantification of metabolites in biofilm. Decanoic acid was used as the internal standard. The separation of Palmitic acid, stearic acid and Decanoic acid was conducted on an Elite-5 MS column (30 m × 0.25 mm, 0.25 μm) using gradient elution condition at a flow rate of 1 mL/min. Palmitic acid, stearic acid and Decanoic acid were determined under the positive ionization mode, respectively. The calibration curve of Palmitic acid and stearic acid were established in the range of 4 to 128 μg/mL (r2 = 0.999). The recovery of palmitic acid and stearic acid were between 98.76% and 113.91%, RSD ＜ 5%. The well validated method was used to detect the metabolites of Pseudomonas aeruginosa biofilm. 54 metabolites were isolated and identified from biofilm samples, and 7 important signal pathways were identified by KEGG enrichment analysis. ABC transporters and bacterial chemotaxis signaling pathways have an important impact on the growth of PA biofilm among these metabolic pathways. This study provides valuable references for the further study of PA biofilm, especially the change of metabolite content and the search for biomarkers.

Sea ice in the polar oceans is a dynamic and challenging environment for life to survive, with extreme gradients of temperature, salinity and nutrients etc., as well as formation of ice crystals. Bacteria surviving in sea ice attract broad attention from academia and industry, due to fascinating mechanisms for adaptation. Here we described the complete genome sequence of Marinomonas arctica BSI20414, isolated from Arctic sea ice. The strain tolerated high salinity and low temperature. Genetic features commonly related to adaptation to oxidative stress, osmotic stress and cold stress were detected in the genome. In addition, a large adhesion protein containing a putative antifreeze protein (AFP) domain was detected in the genome, similar with the giant AFP MpIBP from M. primoryensis. The presence of the putative AFP could facilitate M. arctica BSI20414 to bind to sea ice for favorable conditions and protect it from freezing. The genome sequence and the AFP reported here can provide insights into adaptation to sea ice and can be explored further for biotechnological applications.