bluuebunny/crossref_metadata_2025 huggingface dataset:
New Insights Into the Antibacterial Mechanism of Cryptotanshinone, a Representative Diterpenoid Quinone From Salvia miltiorrhiza Bunge
Authors: Chen Bo-Chen , Ding Zhi-Shan , Dai Jian-Sheng , Chen Ni-Pi , Gong Xing-Wen , Ma Lie-Feng , Qian Chao-Dong
Published: February 2021

The rapid rise of antibiotic resistance causes an urgent need for new antimicrobial agents with unique and different mechanisms of action. The respiratory chain is one such target involved in the redox balance and energy metabolism. As a natural quinone compound isolated from the root of Salvia miltiorrhiza Bunge, cryptotanshinone (CT) has been previously demonstrated against a wide range of Gram-positive bacteria including multidrug-resistant pathogens. Although superoxide radicals induced by CT are proposed to play an important role in the antibacterial effect of this agent, its mechanism of action is still unclear. In this study, we have shown that CT is a bacteriostatic agent rather than a bactericidal agent. Metabolome analysis suggested that CT might act as an antibacterial agent targeting the cell membrane. CT did not cause severe damage to the bacterial membrane but rapidly dissipated membrane potential, implying that this compound could be a respiratory chain inhibitor. Oxygen consumption analysis in staphylococcal membrane vesicles implied that CT acted as respiratory chain inhibitor probably by targeting type II NADH:quinone dehydrogenase (NDH-2). Molecular docking study suggested that the compound would competitively inhibit the binding of quinone to NDH-2. Consistent with the hypothesis, the antimicrobial activity of CT was blocked by menaquinone, and the combination of CT with thioridazine but not 2-n-heptyl-4-hydroxyquinoline-N-oxide exerted synergistic activity against Staphylococcus aureus. Additionally, combinations of CT with other inhibitors targeting different components of the bacterial respiratory chain exhibit potent synergistic activities against S. aureus, suggesting a promising role in combination therapies.
In vitro Antibacterial Activity of an FDA-Approved H+-ATPase Inhibitor, Bedaquiline, Against Streptococcus mutans in Acidic Milieus
Authors: Zhang Meng , Yu Wenqian , Zhou Shujing , Zhang Bing , Lo Edward Chin Man , Xu Xin , Zhang Dongjiao
Published: February 2021

Background

Dental caries is an acid-related disease. Current anti-caries agents mainly focus on the bacteriostatic effect in a neutral environment and do not target acid-resistant microorganisms related to caries in acidic milieus.

Objectives

To assess thein vitroantibacterial activities of bedaquiline against oral pathogens in acidic milieus.

Methods

Streptococcus mutans,Streptococcus sanguinis, andStreptococcus salivariuswere used to prepare the mono-/multiple suspension and biofilm. The MIC and IC50of bedaquiline againstS. mutanswere determined by the broth microdilution method. Bedaquiline was compared regarding (i) the inhibitory activity in pH 4–7 and at different time points against planktonic and biofilm; (ii) the effect on the production of lactic acid, extracellular polysaccharide, and pH ofS. mutansbiofilm; (iii) the cytotoxicity effects; and (iv) the activity on H+-ATPase enzyme ofS. mutans.

Results

In pH 5 BHI, 2.5 mg/L (IC50) and 4 mg/L (MIC) of bedaquiline inhibited the proliferation and biofilm generation ofS. mutansand Mix in a dose-dependent and time-dependent manner, but it was invalid in a neutral environment. The lactic acid production, polysaccharide production, and pH drop range reduced with the incorporation of bedaquiline in a pH 5 environment. Its inhibitory effect (>56 mg/L) against H+-ATPase enzyme inS. mutansand its non-toxic effect (<10 mg/L) on periodontal ligament stem cells were also confirmed.

Conclusion

Bedaquiline is efficient in inhibiting the proliferation and biofilm generation ofS. mutansand other oral pathogens in an acidic environment. Its high targeting property and non-cytotoxicity also promote its clinical application potential in preventing caries. Further investigation of its specific action sites and drug modification are warranted.
Reduced Superficial Capillary Density in Cerebral Infarction Is Inversely Correlated With the NIHSS Score
Authors: Kwapong William Robert , Yan Yuying , Hao Zilong , Wu Bo
Published: February 2021

Purpose: The retina and the brain share similar neuronal and microvascular features, therein we aimed to assess the structural and microvascular changes in the macula and choriocapillaris (CC) in patients with cerebral infarction when compared with healthy controls using optical coherence tomography angiography (OCTA).

Methods: OCTA was used to image and measure the capillary density in the radial peripapillary capillaries (RPC), superficial capillary plexus (SCP), deep capillary plexus (DCP), choriocapillaris (CC), and mean area of the foveal avascular zone (FAZ) in all participants. Twenty-two cerebral infarction patients based on their magnetic resonance imaging (MRI) and 25 healthy controls were included in our study.

Results: Density of the RPC (P < 0.001), SCP (P = 0.001), DCP (P < 0.001) and CC (P < 0.001) were significantly reduced in cerebral infarction patients when compared with healthy controls, respectively. Retinal thickness measurements (P < 0.05) were significantly reduced in cerebral infarction patients when compared with healthy controls. The mean FAZ area was significantly larger (P = 0.012) in cerebral infarction patients when compared with healthy controls. National Institute of HealthStroke Scale (NIHSS) inversely correlated with SCP density in cerebral infarction patients (Rho = −0.409, P = 0.001). Receiver operating characteristics curve analysis showed that the blood flow of the choriocapillaris had the highest index [area under the receiver operatingcharacteristic (AUROC) = 0.964] to discriminate cerebral infarction patients from the healthy controls.

Conclusions: Our study suggests that cerebral microcirculation dysfunction which occurs in cerebral infarction is mirrored in the macula and choroidal microcirculation. OCTA has the potential to non-invasively characterize the macula and choroidal changes in cerebral infarction in vivo.
TNFRSF1B Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer's Disease
Authors: Pillai Jagan A. , Bebek Gurkan , Khrestian Maria , Bena James , Bergmann Cornelia C. , Bush William S. , Leverenz James B. , Bekris Lynn M.
Published: February 2021

Tumor necrosis factor receptor 2 (TNFR2) promotes neuronal survival downstream. This longitudinal study evaluated whether the TNFRSF1B gene encoding TNFR2 and levels of its soluble form (sTNFR2) affect Alzheimer disease (AD) biomarkers and clinical outcomes. Data analyzed included 188 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had mild cognitive impairment (MCI) and AD dementia. Further, a replication study was performed in 48 patients with MCI with positive AD biomarkers who were treated at a memory clinic. Cerebrospinal fluid (CSF) sTNFR2 levels along with two related TNFRSF1B gene single nucleotide polymorphisms (SNPs) rs976881 and rs1061622 were assessed. General linear models were used to evaluate the effect of CSF sTNFR2 levels and each SNP in relationship to CSF t-tau and p-tau, cognitive domains, MRI brain measures, and longitudinal cognitive changes after adjustments were made for covariates such as APOE ε4 status. In the ADNI cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF t-tau and p-tau levels; hippocampal and whole brain volumes; and Digit Span Forwards subtest scores. In the replication cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF p-tau. A significant interaction between rs976881 and CSF sTNFR2 also impacts Clinical Dementia Rating Sum of Boxes scores over 12 months in the ADNI cohort. The interaction between TNFRSF1B variant rs976881 and CSF sTNFR2 levels was noted to modulate multiple AD-associated severity markers and cognitive domains. This interaction impacts resilience-related clinical outcomes in AD and lends support to sTNFR2 as a promising candidate for therapeutic targeting to improve clinical outcomes of interest.
The Role of the Cerebellum in Social and Non-Social Action Sequences: A Preliminary LF-rTMS Study
Authors: Heleven Elien , van Dun Kim , De Witte Sara , Baeken Chris , Van Overwalle Frank
Published: February 2021

An increasing number of studies demonstrated the involvement of the cerebellum in (social) sequence processing. The current preliminary study is the first to investigate the causal involvement of the cerebellum in sequence generation, using low-frequency repetitive transcranial magnetic stimulation (LF-rTMS). By targeting the posterior cerebellum, we hypothesized that the induced neuro-excitability modulation would lead to altered performance on a Picture and Story sequencing task, which involve the generation of the correct chronological order of various social and non-social stories depicted in cartoons or sentences. Our results indicate that participants receiving LF-rTMS over the cerebellum, as compared to sham participants, showed a stronger learning effect from pre to post stimulation for both tasks and for all types of sequences (i.e. mechanical, social scripts, false belief, true belief). No differences between sequence types were observed. Our results suggest a positive effect of LF-rTMS on sequence generation. We conclude that the cerebellum is causally involved in the generation of sequences of social and nonsocial events. Our discussion focuses on recommendations for future studies.
Quercetin-Conjugated Superparamagnetic Iron Oxide Nanoparticles Protect AlCl3-Induced Neurotoxicity in a Rat Model of Alzheimer’s Disease via Antioxidant Genes, APP Gene, and miRNA-101
Authors: Amanzadeh Jajin Elnaz , Esmaeili Abolghasem , Rahgozar Soheila , Noorbakhshnia Maryam
Published: February 2021

Alzheimer’s disease (AD) is a neurodegenerative disease with cognitive impairment. Oxidative stress in neurons is considered as a reason for development of AD. Antioxidant agents such as quercetin slow down AD progression, but the usage of this flavonoid has limitations because of its low bioavailability. We hypothesized that quercetin-conjugated superparamagnetic iron oxide nanoparticles (QT-SPIONs) have a better neuroprotective effect on AD than free quercetin and regulates the antioxidant, apoptotic, and APP gene, and miRNA-101. In this study, male Wistar rats were subjected to AlCl3, AlCl3 + QT, AlCl3 + SPION, and AlCl3 + QT-SPION for 42 consecutive days. Behavioral tests and qPCR were used to evaluate the efficiency of treatments. Results of behavioral tests revealed that the intensity of cognitive impairment was decelerated at both the middle and end of the treatment period. The effect of QT-SPIONs on learning and memory deficits were closely similar to the control group. The increase in expression levels of APP gene and the decrease in mir101 led to the development of AD symptoms in rats treated with AlCl3 while these results were reversed in the AlCl3 + QT-SPIONs group. This group showed similar results with the control group. QT-SPION also decreased the expression levels of antioxidant enzymes along with increases in expression levels of anti-apoptotic genes. Accordingly, the antioxidant effect of QT-SPION inhibited progression of cognitive impairment via sustaining the balance of antioxidant enzymes in the hippocampus of AD model rats.
Tracking Eye Movements During Sleep in Mice
Authors: Meng Qingshuo , Tan Xinrong , Jiang Chengyong , Xiong Yanyu , Yan Biao , Zhang Jiayi
Published: February 2021

Eye movement is not only for adjusting the visual field and maintaining the stability of visual information on the retina, but also provides an external manifestation of the cognitive status of the brain. Recent studies showed similarity in eye movement patterns between wakefulness and rapid eye movement (REM) sleep, indicating that the brain status of REM sleep likely resembles that of awake status. REM sleep in humans could be divided into phasic REM and tonic REM sleep according to the difference in eye movement frequencies. Mice are the most commonly used animal model for studying neuronal and molecular mechanisms underlying sleep. However, there was a lack of details for eye movement patterns during REM sleep, hence it remains unknown whether REM sleep can be further divided into different stages in mice. Here we developed a device combining electroencephalogram (EEG), electromyogram (EMG) as well as eye movements recording in mice to study the eye movement patterns during sleep. We implanted a magnet beneath the conjunctiva of eye and tracked eye movements using a magnetic sensor. The magnetic signals showed strong correlation with video-oculography in head-fixed mice, indicating that the magnetic signals reflect the direction and magnitude of eye movement. We also found that the magnet implanted beneath the conjunctiva exhibited good biocompatibility. Finally, we examined eye movement in sleep–wake cycle, and discriminated tonic REM and phasic REM according to the frequency of eye movements, finding that compared to tonic REM, phasic REM exhibited higher oscillation power at 0.50 Hz, and lower oscillation power at 1.50–7.25 Hz and 9.50–12.00 Hz. Our device allowed to simultaneously record EEG, EMG, and eye movements during sleep and wakefulness, providing a convenient and high temporal-spatial resolution tool for studying eye movements in sleep and other researches in mice.
The F-Box Protein CG5003 Regulates Axon Pruning and the Integrity of the Drosophila Mushroom Body
Authors: Yang Mengying , Guo Yige , Wang Shuran , Chen Changyan , Chang Yung-Heng , Ho Margaret Su-chun
Published: February 2021

Protein homeostasis serves as an important step in regulating diverse cellular processes underlying the function and development of the nervous system. In particular, the ubiquitination proteasome system (UPS), a universal pathway mediating protein degradation, contributes to the development of numerous synaptic structures, including theDrosophilaolfactory-associative learning center mushroom body (MB), thereby affecting associated function. Here, we describe the function of a newly characterizedDrosophilaF-box protein CG5003, an adaptor for the RING-domain type E3 ligase (SCF complex), in MB development. Lacking CG5003 ubiquitously causes MB γ axon pruning defects and selectiveCG5003expression in pan-neurons leads to both γ axon and α/β lobe abnormalities. Interestingly, change inCG5003expression in MB neurons does not cause any abnormalities in axons, suggesting that CG5003 functions in cells extrinsic to MB to regulate its development. Mass spectrum analysis indicates that silencingCG5003expression in all neurons affects expression levels of proteins in the cell and structural morphogenesis, transcription regulator activity, and catalytic activity. Our findings reinforce the importance of UPS and identify a new factor in regulating neuronal development as exemplified by the synaptic structure MB.
Neuroligin1 Contributes to Neuropathic Pain by Promoting Phosphorylation of Cofilin in Excitatory Neurons
Authors: Ouyang Junlin , Chen Xiaping , Su Shanchun , Li Xiaohui , Xu Xueqin , Yu Xinhua , Ke Changbin , Zhu Xiaohu
Published: February 2021

Neuropathic pain is a kind of chronic pain that remains difficult to treat due to its complicated underlying mechanisms. Accumulating evidence has indicated that enhanced synaptic plasticity of nociceptive interneurons in the superficial spinal dorsal horn contributes to the development of neuropathic pain. Neuroligin1 (NL1) is a type of excitatory postsynaptic adhesion molecule, which can mediate excitatory synaptic activity, hence promoting neuronal activation. Vglut2 is the most common marker of excitatory glutamatergic neurons. To explore the role of NL1 in excitatory neurons in nociceptive regulation, we used transgenic mice with cre recombinase expression driven by the Vglut2 promoter combined with viral vectors to knockdown the expression of NL1 in excitatory neurons in the spinal dorsal horn. We found that NL1 was upregulated in the L4–L6 spinal dorsal horn in Vglut2-cre+/– mouse subjected to spared nerve injury (SNI). Meanwhile, the expression of phosphorylated cofilin (p-cofilin) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) was also increased. Spinal microinjection of a cre-dependent NL1-targeting RNAi in Vglut2-cre+/– mouse alleviated the neuropathic pain-induced mechanical hypersensitivity and reduced the increase in p-cofilin and GluR1 caused by SNI. Taken together, NL1 in excitatory neurons regulates neuropathic pain by promoting the SNI-dependent increase in p-cofilin and GluR1 in the spinal dorsal horn. Our study provides a better understanding of the role of NL1 in excitatory neurons, which might represent a possible therapeutic target for alleviating neuropathic pain.
Lung Cancer Attributed Mortality Among 316,336 Early Stage Breast Cancer Cases Treated by Radiotherapy and/or Chemotherapy, 2000–2015: Evidence From the SEER Database
Authors: Abera Semaw Ferede , Mikolajczyk Rafael T. , Kantelhardt Eva Johanna , Efremov Ljupcho , Bedir Ahmed , Ostheimer Christian , Glowka André , Vordermark Dirk , Medenwald Daniel
Published: February 2021

Objective

To estimate the risk of death from lung cancer in patients treated for breast cancer (BC) in relation to the general population.

Methods

BC data, covering 2000 to 2015, were extracted from the Surveillance, Epidemiology and End Results-18 (SEER-18) cancer registry database. A comparison of lung cancer attributed mortality between BC patients and the general population was performed using standardized mortality ratios (SMRs) and SMRs conditional on survival length (cSMRs). Prognostic factors of lung cancer mortality were identified using flexible parametric modelling. Our model adjusts the effect of downstream (histopathological BC tumor grade and hormone receptor status) and upstream (age at diagnosis, ethnicity, and marital status) factors.

Results

The median follow-up was 6.4 years (interquartile range, 3.0–10.3 years). BC cases who received only radiotherapy (cSMR = 0.93; 95%CI: 0.77–1.13), only chemotherapy (cSMR = 0.91; 0.62–1.33), and radio-and chemotherapy (cSMR = 1.04; 0.77–1.39) had no evidence of increased lung cancer mortality relative to the general population. The adjusted model identified that lung cancer mortality was higher for women who were older at diagnosis compared to those <50 years (ranging from HR50-59 = 3.41 [95%CI: 2.72–4.28] to HR70-79 = 10.53 [95%CI: 8.44–13.13]) and for cases with negative estrogen and progesterone receptors (HR =1.38; 95% CI: 1.21–1.57). Compared to married cases, widowed, divorced, single or others had a 76%, 45%, and 25% higher hazard of lung cancer mortality, respectively. Lung cancer mortality was lower for American Indian/Alaska Native and Asian/Pacific Islander ethnicities (HR = 0.51; 95% CI: 0.40–0.64) compared to BC cases with white ethnic background.

Conclusions

There is no evidence for a higher lung cancer mortality in BC patients when compared to the general population.
Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6
Authors: Li Dong-Mei , Chen Qiu-Dan , Wei Gui-Ning , Wei Jie , Yin Jian-Xing , He Jun-Hui , Ge Xin , Shi Zhu-Mei
Published: February 2021

Purpose

Glioblastoma multiforme (GBM) is one of the deadliest tumors, which is involved in numerous dysregulated microRNAs including miR-137. However, the mechanism of how miR-137 suppression associated with cancer progression and chemoresistance still remains to be elucidated.

Methods

Quantitative reverse transcriptase-PCR (qRT-PCR), DNA methylation analysis, cell proliferation assay, flow cytometric analysis, invasion assay, in situ tumor formation experiment were performed to test the expression levels and functions of miR-137 in GBM. Bioinformatics analysis, luciferase reporter assay, qRT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry assay were used to identify and verify the target of miR-137.

Results

We found that miR-137 was downregulated in primary and recurrent GBM compared with normal brain tissues. Overexpression of miR-137 inhibited cell invasion and enhanced cell chemosensitivity to temozolomide (TMZ) by directly targeting low-density lipoprotein receptor-related protein 6 (LRP6) in GBM. Forced expression of LRP6 cDNA without its 3’-UTR region partly restored the effects of miR-137 in vitro and in vivo. Hypoxia-induced miR-137 methylation was responsible for the miR-137 suppression, leading to the cell chemoresistance and poor prognosis of GBM.

Conclusions

These findings demonstrated the detailed molecular mechanism of miR-137 in regulating GBM growth and chemoresistance in hypoxia microenvironment, suggesting the potentiality of miR-137 as a therapeutic target for GBM.
The Impact of m6A RNA Modification in Therapy Resistance of Cancer: Implication in Chemotherapy, Radiotherapy, and Immunotherapy
Authors: Shriwas Omprakash , Mohapatra Pallavi , Mohanty Sibasish , Dash Rupesh
Published: February 2021

m6A RNA methylation, which serves as a critical regulator of transcript expression, has gathered tremendous scientific interest in recent years. From RNA processing to nuclear export, RNA translation to decay, m6A modification has been studied to affect various aspects of RNA metabolism, and it is now considered as one of the most abundant epitranscriptomic modification. RNA methyltransferases (writer), m6A-binding proteins (readers), and demethylases (erasers) proteins are frequently upregulated in several neoplasms, thereby regulating oncoprotein expression, augmenting tumor initiation, enhancing cancer cell proliferation, progression, and metastasis. Though the potential role of m6A methylation in growth and proliferation of cancer cells has been well documented, its potential role in development of therapy resistance in cancer is not clear. In this review, we focus on m6A-associated regulation, mechanisms, and functions in acquired chemoresistance, radioresistance, and resistance to immunotherapy in cancer.
Comparison of the Gross Target Volumes Based on Diagnostic PET/CT for Primary Esophageal Cancer
Authors: Shi Jingzhen , Li Jianbin , Li Fengxiang , Zhang Yingjie , Guo Yanluan , Wang Wei , Wang Jinzhi
Published: February 2021

Background

Clinically, many esophageal cancer patients who planned for radiation therapy have already undergone diagnostic Positron-emission tomography/computed tomography (PET/CT) imaging, but it remains unclear whether these imaging results can be used to delineate the gross target volume (GTV) of the primary tumor for thoracic esophageal cancer (EC).

Methods

Seventy-two patients diagnosed with thoracic EC had undergone prior PET/CT for diagnosis and three-dimensional CT (3DCT) for simulation. The GTV3D was contoured on the 3DCT image without referencing the PET/CT image. The GTVPET-ref was contoured on the 3DCT image referencing the PET/CT image. The GTVPET-reg was contoured on the deformed registration image derived from 3DCT and PET/CT. Differences in the position, volume, length, conformity index (CI), and degree of inclusion (DI) among the target volumes were determined.

Results

The centroid distance in the three directions between two different GTVs showed no significant difference (P > 0.05). No significant difference was found among the groups in the tumor volume (P > 0.05). The median DI values of the GTVPET-reg and GTVPET-ref in the GTV3D were 0.82 and 0.86, respectively (P = 0.006). The median CI values of the GTV3D in the GTVPET-reg and GTVPET-ref were 0.68 and 0.72, respectively (P = 0.006).

Conclusions

PET/CT can be used to optimize the definition of the target volume in EC. However, no significant difference was found between the GTVs delineated based on visual referencing or deformable registration whether using the volume or position. So, in the absence of planning PET–CT images, it is also feasible to delineate the GTV of primary thoracic EC with reference to the diagnostic PET–CT image.
PAFAH1B3 Expression Is Correlated With Gastric Cancer Cell Proliferation and Immune Infiltration
Authors: Xie Tianyu , Guo Xin , Wu Di , Li Shuo , Lu Yixun , Wang Xinxin , Chen Lin
Published: February 2021

Background

Platelet activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3) is associated with a variety of human diseases. However, its function in gastric cancer remains uncertain.

Methods

PAFAH1B3 expression was analyzed in The Cancer Genome Atlas (TCGA) and genotype-tissue expression pan-cancer data. The association between PAFAH1B3 expression and patient prognosis was evaluated using TCGA clinical survival data. Enrichment analysis of PAFAH1B3 was performed using the clusterProfiler R software package. Moreover, the correlation between PAFAH1B3 expression and immune cell infiltration were evaluated by analyzing TCGA database. CCK8 assay and colony-formation assay were performed to assess the effect of PAFAH1B3 on the proliferation of gastric cancer cells. Transwell assay was used to evaluate the impact of PAFAH1B3 on gastric cancer cell migration. Western blot was performed to evaluate the role of PAFAH1B3 on signaling pathways in gastric cancer cells.

Results

PAFAH1B3 was highly expressed in many types of tumors including gastric cancer. High PAFAH1B3 expression was significantly correlated with proliferation-related gene sets involved in DNA replication, the cell cycle, and cell cycle checkpoints. Further analysis showed that high PAFAH1B3 expression was associated with high M1 macrophage and CD8-positive T cell infiltration scores. PAFAH1B3 knockdown inhibited the proliferation, migration, and the activation of oncogenic signaling in gastric cancer cells.

Conclusions

Our findings suggest that PAFAH1B3 may be an oncogene in gastric cancer.
FOXA2-Interacting FOXP2 Prevents Epithelial-Mesenchymal Transition of Breast Cancer Cells by Stimulating E-Cadherin and PHF2 Transcription
Authors: Liu Yuxiang , Chen Taolin , Guo Mingyue , Li Yu , Zhang Qian , Tan Guixiang , Yu Li , Tan Yongjun
Published: February 2021

FOXP2, a member of forkhead box transcription factor family, was first identified as a language-related gene that played an important role in language learning and facial movement. In addition, FOXP2 was also suggested regulating the progression of cancer cells. In previous studies, we found that FOXA2 inhibited epithelial-mesenchymal transition (EMT) in breast cancer cells. In this study, by identifying FOXA2-interacting proteins from FOXA2-pull-down cell lysates with Mass Spectrometry Analysis, we found that FOXP2 interacted with FOXA2. After confirming the interaction between FOXP2 and FOXA2 through Co-IP and immunofluorescence assays, we showed a correlated expression of FOXP2 and FOXA2 existing in clinical breast cancer samples. The overexpression of FOXP2 attenuated the mesenchymal phenotype whereas the stable knockdown of FOXP2 promoted EMT in breast cancer cells. Even though FOXP2 was believed to act as a transcriptional repressor in most cases, we found that FOXP2 could activate the expression of tumor suppressor PHF2. Meanwhile, we also found that FOXP2 could endogenously bind to the promoter of E-cadherin and activate its transcription. This transcriptional activity of FOXP2 relied on its interaction with FOXA2. Furthermore, the stable knockdown of FOXP2 enhanced the metastatic capacity of breast cancer cells in vivo. Together, the results suggested that FOXP2 could inhibit EMT by activating the transcription of certain genes, such as E-cadherin and PHF2, in concert with FOXA2 in breast cancer cells.
Fragile Gene WWOX Guides TFAP2A/TFAP2C-Dependent Actions Against Tumor Progression in Grade II Bladder Cancer
Authors: Kołat Damian , Kałuzińska Żaneta , Bednarek Andrzej K. , Płuciennik Elżbieta
Published: February 2021

Introduction

The presence of common fragile sites is associated with no-accidental chromosomal instability which occurs prior to carcinogenesis. TheWWOXgene spans the second most active fragile site: FRA16D. Chromosomal breakage at this site is more common in bladder cancer patients who are tobacco smokers which suggests the importance ofWWOXgene loss regarding bladder carcinogenesis. Tryptophan domains of WWOX are known to recognize motifs of other proteins such as AP-2α and AP-2γ allowing protein-protein interactions. While the roles of both AP-2 transcription factors are important for bladder carcinogenesis, their nature is different. Based on the literature, AP-2γ appears to be oncogenic, whereas AP-2α mainly exhibits tumor suppressor character. Presumably, the interaction between WWOX and both transcription factors regulates thousands of genes, hence the aim of the present study was to determine WWOX, AP-2α, and AP-2γ function in modulating biological processes of bladder cancer.

Methods

RT-112 cell line (grade II bladder cancer) was subjected to two stable lentiviral transductions. Overall, this resulted in six variants to investigate distinct WWOX, AP-2α, or AP-2γ function as well as WWOX in collaboration with a particular transcription factor. Cellular models were examined with immunocytochemical staining and in terms of differences in biological processes using assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, migration, activity of metalloproteinases and 3D culture growth.

Results

WWOX overexpression increased apoptosis but decreased cell viability, migration and large spatial colonies. AP-2α overexpression decreased tumor cell viability, migratory potential, matrix metalloproteinase-2 activity and clonogenicity. AP-2γ overexpression decreased matrix metalloproteinase-2 activity but increased wound healing, adhesion, clonogenicity and spatial colony formation. WWOX and AP-2α overexpression induced apoptosis but decreased cell viability, adhesion, matrix metalloproteinase-2 activity, overall number of cultured colonies and migration rate. WWOX and AP-2γ overexpression decreased tumor cell viability, proliferation potential, adhesion, clonogenicity and the ability to create spatial structures, but also increased apoptosis or migration rate.

Conclusion

Co-overexpression of WWOX with AP-2α or WWOX with AP-2γ resulted in a net anti-tumor effect. However, considering this research findings and the difference between AP-2α and AP-2γ, we suggest that this similarity is due to a divergent behavior of WWOX.
LRIG3 Suppresses Angiogenesis by Regulating the PI3K/AKT/VEGFA Signaling Pathway in Glioma
Authors: Peng Chenghao , Chen Hanmin , Li Youwei , Yang Hang , Qin Peizhong , Ma Baojun , Duan Qiuhong , Wang Baofeng , Mao Feng , Guo Dongsheng
Published: February 2021

High levels of microvessel density (MVD) indicate poor prognosis in patients with malignant glioma. Leucine-rich repeats and immunoglobulin-like domains (LRIG) 3, a potential tumor suppressor, plays an important role in tumor progression and may serve as a biomarker in many human cancers. However, its role and underlying mechanism of action in glioma angiogenesis remain unclear. In the present study, we used loss- and gain-of-function assays to show that LRIG3 significantly suppressed glioma-induced angiogenesis, both in vitro and in vivo. Mechanistically, LRIG3 inhibited activation of the PI3K/AKT signaling pathway, downregulating vascular endothelial growth factor A (VEGFA) in glioma cells, thereby inhibiting angiogenesis. Notably, LRIG3 had a significant negative correlation with VEGFA expression in glioma tissues. Taken together, our results suggest that LRIG3 is a novel regulator of glioma angiogenesis and may be a promising option for developing anti-angiogenic therapy.
MR-Guided Adaptive Radiotherapy for Bladder Cancer
Authors: Hijab Adham , Tocco Boris , Hanson Ian , Meijer Hanneke , Nyborg Christina Junker , Bertelsen Anders Smedegaard , Smeenk Robert Jan , Smith Gillian , Michalski Jeff , Baumann Brian C. , Hafeez Shaista
Published: February 2021

Radiotherapy has an important role in the curative and palliative treatment settings for bladder cancer. As a target for radiotherapy the bladder presents a number of technical challenges. These include poor tumor visualization and the variability in bladder size and position both between and during treatment delivery. Evidence favors the use of magnetic resonance imaging (MRI) as an important means of tumor visualization and local staging. The availability of hybrid systems incorporating both MRI scanning capabilities with the linear accelerator (MR-Linac) offers opportunity for in-room and real-time MRI scanning with ability of plan adaption at each fraction while the patient is on the treatment couch. This has a number of potential advantages for bladder cancer patients. In this article, we examine the technical challenges of bladder radiotherapy and explore how magnetic resonance (MR) guided radiotherapy (MRgRT) could be leveraged with the aim of improving bladder cancer patient outcomes. However, before routine clinical implementation robust evidence base to establish whether MRgRT translates into improved patient outcomes should be ascertained.
Case Report: Clinical Description of a Patient Carrying a 12.48 Mb Microdeletion Involving the 10p13–15.3 Region
Authors: Pan Yu-qing , Fu Jian-hua
Published: February 2021

Partial deletion of 10p chromosome is a rare chromosomal aberration. Submicroscopic deletion of 10p15.3 is mainly related to cognitive deficits, speech disorders, motor delay, and hypotonia with the deleted region ranging from 0.15 to 4 Mb. The clinical phenotype is mainly determined by the ZMYND11 and DIP2C genes. Here, we report a rare case of feeding difficulties, hypocalcemia, and psychomotor retardation. Our patient has a 12.48 Mb deletion in 10p15.3–10p13, which is the second case of large 10p deletion among reported cases thus far.
Differences in Importance Attached to Drug Effects Between Patients With Type 2 Diabetes From the Netherlands and Turkey: A Preference Study
Authors: Roldan Munoz Sonia , Postmus Douwe , de Vries Sieta T. , Arnardottir Arna H. , Dolu İlknur , Hillege Hans , Mol Peter G. M.
Published: February 2021

Objective: The aim of this study was to compare the importance that patients with type 2 diabetes mellitus from the Netherlands and Turkey attach to certain drug effects of oral anti-diabetic drugs.

Methods: Data were collected through a cross-sectional survey containing demographic questions and a discrete choice experiment assessing preferences for oral anti-diabetic drugs. Adults from the Netherlands and Turkey were included if they had type 2 diabetes mellitus and had received a prescription of an oral anti-diabetic drug in the last 4 months. The oral anti-diabetic drugs in the discrete choice experiment were described in terms of six attributes: effects on HbA1c, cardiovascular diseases, weight change, gastrointestinal adverse drug events hypoglycemic events, and bladder cancer. Multinomial logit models with country as an interaction factor were fitted.

Results: In total, 381 patients were included, 199 from the Netherlands and 182 from Turkey. Patients’ preferences toward drug effects varied between the countries. Turkish patients attached the highest importance to reducing the risk of cardiovascular diseases (relative weight: 0.51, 95% CI 0.45–0.55), followed by reducing hypoglycemic events (relative weight: 0.16, 95% CI 0.11–0.22), and reducing gastrointestinal adverse drug events (relative weight: 0.11, 95% CI 0.07–0.18). Patients from the Netherlands attached the highest importance to gastrointestinal ADEs (relative weight: 0.22, 95% CI 0.14–0.39), followed by reducing hypoglycemic events (relative weight: 0.22, 95% CI 0.16–0.25), and reducing the risk of cardiovascular diseases (relative weight: 0.20, 95% CI 0.13–0.23).

Conclusion: Patient preferences may differ across countries. Such differences should be acknowledged in regulatory decisions and clinical practice.
Maternal Methadone Destabilizes Neonatal Breathing and Desensitizes Neonates to Opioid-Induced Respiratory Frequency Depression
Authors: Hocker Austin D. , Morrison Nina R. , Selby Matthew L. , Huxtable Adrianne G.
Published: February 2021

Pregnant women and developing infants are understudied populations in the opioid crisis, despite the rise in opioid use during pregnancy. Maternal opioid use results in diverse negative outcomes for the fetus/newborn, including death; however, the effects of perinatal (maternal and neonatal) opioids on developing respiratory circuitry are not well understood. Given the profound depressive effects of opioids on central respiratory networks controlling breathing, we tested the hypothesis that perinatal opioid exposure impairs respiratory neural circuitry, creating breathing instability. Our data demonstrate maternal opioids increase apneas and destabilize neonatal breathing. Maternal opioids also blunted opioid-induced respiratory frequency depression acutely in neonates; a unique finding since adult respiratory circuity does not desensitize to opioids. This desensitization normalized rapidly between postnatal days 1 and 2 (P1 and P2), the same age quantal slowing emerged in respiratory rhythm. These data suggest significant reorganization of respiratory rhythm generating circuits at P1–2, the same time as the preBötzinger Complex (key site of respiratory rhythm generation) becomes the dominant respiratory rhythm generator. Thus, these studies provide critical insight relevant to the normal developmental trajectory of respiratory circuits and suggest changes to mutual coupling between respiratory oscillators, while also highlighting how maternal opioids alter these developing circuits. In conclusion, the results presented demonstrate neurorespiratory disruption by maternal opioids and blunted opioid-induced respiratory frequency depression with neonatal opioids, which will be important for understanding and treating the increasing population of neonates exposed to gestational opioids.
Characterization of the Common Genetic Basis Underlying Seed Hilum Size, Yield, and Quality Traits in Soybean
Authors: Zhao Qingsong , Shi Xiaolei , Yan Long , Yang Chunyan , Liu Cong , Feng Yan , Zhang Mengchen , Yang Yongqing , Liao Hong
Published: February 2021

Developing high yielding cultivars with outstanding quality traits are perpetual objectives throughout crop breeding operations. Confoundingly, both of these breeding objectives typically involve working with complex quantitative traits that can be affected by genetic and environmental factors. Establishing correlations of these complex traits with more easily identifiable and highly heritable traits can simplify breeding processes. In this study, two parental soybean genotypes contrasting in seed hilum size, yield, and seed quality, as well as 175 F9 recombinant inbred lines (RILs) derived from these parents, were grown in 3 years. The h2b of four hilum size, two quality and two yield traits, ranged from 0.72 to 0.87. The four observed hilum size traits exhibited significant correlation (P < 0.05) with most of seed yield and quality traits, as indicated by correlation coefficients varying from -0.35 to 0.42, which suggests that hilum size could be considered as a proxy trait for soybean yield and quality. Interestingly, among 53 significant quantitative trait loci (QTLs) with logarithm of odds (LOD) values ranging from 2.51 to 6.69 and accounting for 6.40–16.10% of genetic variation, three loci encoding hilum size, qSH6.2, qSH8, and qSH10, colocated with QTLs for seed yield and quality traits, demonstrating that genes impacting seed hilum size colocalize in part with genes acting on soybean yield and quality. As a result of the breeding efforts and field observations described in this work, it is reasonable to conclude that optimizing hilum size through selection focused on a few QTLs may be useful for breeding new high yielding soybean varieties with favorable quality characteristics.
Grafting Delays Watermel on Fruit Ripening by Altering Gene Expression of ABA Centric Phytohormone Signaling
Authors: Guo Shaogui , Sun Honghe , Tian Jiaxing , Zhang Guoyu , Gong Guoyi , Ren Yi , Zhang Jie , Li Maoying , Zhang Haiying , Li Haizhen , Xu Yong
Published: February 2021

Grafting cultivation is implemented worldwide mainly to resist abiotic and biotic stresses and is an effective method to improve watermelon production. However, grafting may affect fruit development and quality. In our experiment, pumpkin-grafted (PG) watermelon fruits developed slower and the ripening period was extended compared to self-grafted (SG) fruits. We found that the concentrations of abscisic acid (ABA) among endogenous phytohormones were dramatically reduced by pumpkin grafting. In order to understand these changes at the gene expression level, we performed a comprehensive analysis of the fruit flesh transcriptomes between PG and SG during fruit development and ripening. A total of 1,675 and 4,102 differentially expressed genes (DEGs) were identified between PG and SG. Further functional enrichment analysis revealed that these DEGs were associated with carbohydrate biosynthesis, phytohormone signaling transmission, and cell wall metabolism categories. ABA centric phytohormone signaling and fruit quality-related genes including ABA receptor, PP2C proteins, AP2-EREBP transcription factors, sucrose transporter, and carotenoid isomerase were co-expressed with fruit ripening. These results provide the valuable resource for understanding the mechanism of pumpkin grafting effect on watermelon fruit ripening and quality development.
Auxin-Mediated Regulation of Dorsal Vascular Cell Development May Be Responsible for Sucrose Phloem Unloading in Large Panicle Rice
Authors: Deng Yao , Yu Yongchao , Hu Yuxiang , Ma Li , Lin Yan , Wu Yue , Wang Zhen , Wang Ziteng , Bai Jiaqi , Ding Yanfeng , Chen Lin
Published: February 2021

Large panicle rice cultivars often fail to fulfill their high-yield potential due to the poor grain filling of inferior spikelets (IS), which appears as initially stagnant development and low final seed weight. Understanding the mechanism of the initial stagnancy is important to improve IS grain filling. In this study, superior spikelets (SS) were removed from two homozygous japonica rice varieties (W1844 and CJ03) with the same sink capacity in an attempt to force photosynthate transport to the IS. The results showed that SS removal increased the grain weight, sucrose content, starch accumulation, and endogenous IAA levels of IS during the initial grain-filling stage. SS removal also improved the patterns of vascular cells in the dorsal pericarp and the expression levels of genes involved in sucrose transport (OsSUTs and OsSWEETs) and IAA metabolism (OsYUCs and OsPINs). Exogenous IAA application advanced the initiation of grain filling by increasing the sucrose content and the gene expression levels of sucrose transporters. These results indicate that auxin may act like a signal substance and play a vital role in initial grain filling by regulating dorsal vascular cell development and sucrose phloem unloading into caryopsis.
Multi-Locus Genome-Wide Association Studies Reveal Fruit Quality Hotspots in Peach Genome
Authors: da Silva Linge Cassia , Cai Lichun , Fu Wanfang , Clark John , Worthington Margaret , Rawandoozi Zena , Byrne David H. , Gasic Ksenija
Published: February 2021

Peach is one of the most important fruit crops in the world, with the global annual production about 24.6 million tons. The United States is the fourth-largest producer after China, Spain, and Italy. Peach consumption has decreased over the last decade, most likely due to inconsistent quality of the fruit on the market. Thus, marker-assisted selection for fruit quality traits is highly desired in fresh market peach breeding programs and one of the major goals of the RosBREED project. The ability to use DNA information to select for desirable traits would enable peach breeders to efficiently plan crosses and select seedlings with desired quality traits early in the selection process before fruiting. Therefore, we assembled a multi-locus genome wide association study (GWAS) of 620 individuals from three public fresh market peach breeding programs (Arkansas, Texas, and South Carolina). The material was genotyped using 9K SNP array and the traits were phenotyped for three phenological (bloom date, ripening date, and days after bloom) and 11 fruit quality-related traits (blush, fruit diameter, fruit weight, adherence, fruit firmness, redness around pit, fruit texture, pit weight, soluble solid concentration, titratable acidity, and pH) over three seasons (2010, 2011, and 2012). Multi-locus association analyses, carried out using mrMLM 4.0 and FarmCPU R packages, revealed a total of 967 and 180 quantitative trait nucleotides (QTNs), respectively. Among the 88 consistently reliable QTNs detected using multiple multi-locus GWAS methods and/or at least two seasons, 44 were detected for the first time. Fruit quality hotspots were identified on chromosomes 1, 3, 4, 5, 6, and 8. Out of 566 candidate genes detected in the genomic regions harboring the QTN clusters, 435 were functionally annotated. Gene enrichment analyses revealed 68 different gene ontology (GO) terms associated with fruit quality traits. Data reported here advance our understanding of genetic mechanisms underlying important fruit quality traits and further support the development of DNA tools for breeding.
Negative Affectivity, Authoritarianism, and Anxiety of Infection Explain Early Maladjusted Behavior During the COVID-19 Outbreak
Authors: Bochicchio Vincenzo , Winsler Adam , Pagliaro Stefano , Pacilli Maria Giuseppina , Dolce Pasquale , Scandurra Cristiano
Published: February 2021

During the first phase of the COVID-19 outbreak, Italy experienced problems of public order and maladjusted behavior. This study assessed the role of negative affectivity, right-wing authoritarianism, and anxiety of COVID-19 infection in explaining a variety of the maladjusted behaviors (i.e., “China-phobic” discrimination, panic buying) observed with an Italian sample. Specifically, we examined the effect of Negative Affectivity and Right-Wing Authoritarianism on maladjusted behaviors, and the moderating role of anxiety of infection. Seven hundred and fifty-seven Italian participants completed an online survey between March 3rd to the 7th 2020, which was immediately before the lockdown. A moderated-mediation model was tested using a structural equation modeling approach. Results indicated that both Negative Affectivity and Right-Wing Authoritarianism were positively associated with COVID-19-related maladjusted behavior, and that Right-Wing Authoritarianism mediated the relationship between Negative Affectivity and maladjusted behavior. Furthermore, the effect of Right-Wing Authoritarianism on maladjusted behavior was greater for those with high anxiety of infection, and the indirect effect of Negative Affectivity on maladjusted behavior through Right-Wing Authoritarianism was moderated by infection anxiety. Findings highlight potential psychological paths that may inform communication strategies and public health initiatives aimed at promoting healthy behavior during an outbreak.