bluuebunny/crossref_metadata_2025 huggingface dataset:
Musculoskeletal Ultrasound to Identify Subclinical Joint and Periarticular Involvement in Patients With Inflammatory Bowel Disease: A Systematic Literature Review
Authors: Sakellariou Garifallia , Schiepatti Annalisa , Scalvini Davide , Lusetti Francesca , Fazzino Erica , Biagi Federico , Montecucco Carlomaurizio
Published: May 2022

Background

Musculoskeletal ultrasonography identifies subclinical joint and entheseal inflammation, and it might be of value in patients with inflammatory bowel diseases (IBD), which are at higher risk of inflammatory arthropathy and disability. Our aim was to retrieve the evidence on the applications of ultrasound in patients with non-arthropathic IBD.

Methods

Studies enrolling patients with IBD without arthritis, undergoing ultrasound of joints, tendons or entheses were eligible. The outcomes of interest encompassed the frequency of ultrasound-detected lesions, their accuracy in diagnosing arthritis, their prognostic role and sensitivity to change. All study types, excluding case reports, case series and narrative reviews, were included. Search strategies were applied in PubMed and Embase. Abstract and full-texts were evaluated by pairs of reviewers. The risk of bias was evaluated through the Newcastle-Ottawa scale or the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 2. The protocol was registered in PROSPERO (CRD42021264972).

Results

Out of 2,304 records, eight studies were included, all reporting the frequency of lesions, while only three evaluated also the diagnostic accuracy. All studies had a cross-sectional design, with no evidence on prediction or follow-up. All studies evaluated the entheses, while only three the joints. The most common chronic lesions were entheseal thickening (up to 81.5%) and enthesophytes (67.9%), while entheseal erosions were present in 16%−17% of patients. Among inflammatory lesions, power Doppler was reported in 14%−67% of patients. There were no differences among Crohn's disease or ulcerative colitis and depending on disease activity, while there were contrasting results on different disease durations. When evaluating the diagnostic performance, the best specificity for a diagnosis if IBD was 0.88 (95%CI, 0.8–0.94) for joint abnormalities. Also, the best sensitivity was 0.88 (95%CI, 0.76–0.95) for entheseal lesions. No studies assessed of the combination of lesions. Due to the limited number of studies, meta-analyses were not performed.

Conclusions

Despite the possible value of ultrasound in IBD, there is limited evidence deriving from cross-sectional studies. Longitudinal studies are needed to clarify the role of this technique, while its current placement might be that of complementing clinical assessment, in particular in early intestinal disease.
Time Is of the Essence—Early Activation of the Mevalonate Pathway in Apple Challenged With Gray Mold Correlates With Reduced Susceptibility During Postharvest Storage
Authors: Naets Matthias , Van Hemelrijck Wendy , Gruyters Willem , Verboven Pieter , Nicolaï Bart , Keulemans Wannes , De Coninck Barbara , Geeraerd Annemie H.
Published: May 2022

Apple is typically stored under low temperature and controlled atmospheric conditions to ensure a year round supply of high quality fruit for the consumer. During storage, losses in quality and quantity occur due to spoilage by postharvest pathogens. One important postharvest pathogen of apple is Botrytis cinerea. The fungus is a broad host necrotroph with a large arsenal of infection strategies able to infect over 1,400 different plant species. We studied the apple-B. cinerea interaction to get a better understanding of the defense response in apple. We conducted an RNAseq experiment in which the transcriptome of inoculated and non-inoculated (control and mock) apples was analyzed at 0, 1, 12, and 28 h post inoculation. Our results show extensive reprogramming of the apple’s transcriptome with about 28.9% of expressed genes exhibiting significant differential regulation in the inoculated samples. We demonstrate the transcriptional activation of pathogen-triggered immunity and a reprogramming of the fruit’s metabolism. We demonstrate a clear transcriptional activation of secondary metabolism and a correlation between the early transcriptional activation of the mevalonate pathway and reduced susceptibility, expressed as a reduction in resulting lesion diameters. This pathway produces the building blocks for terpenoids, a large class of compounds with diverging functions including defense. 1-MCP and hot water dip treatment are used to further evidence the key role of terpenoids in the defense and demonstrate that ethylene modulates this response.
Unsalable Vegetables Ensiled With Sorghum Promote Heterofermentative Lactic Acid Bacteria and Improve in vitro Rumen Fermentation
Authors: Forwood Daniel L. , Holman Devin B. , Chaves Alex V. , Meale Sarah J.
Published: May 2022

This study characterized the nutritive and microbial profiles and the fermentation characteristics of silage with the following compositions on a dry matter (DM) basis: (1) 100% sorghum, (2) 70% sorghum + 30% carrot or pumpkin, and (3) 40% sorghum + 60% carrot or pumpkin. The treatments were further divided based on the addition or no addition of a probiotic inoculant. After 70 days of ensiling, the silage was incubated for 48 h using the in vitro batch culture technique. Crude protein and non-fiber carbohydrates in the silage increased (P ≤ 0.01) by 5.7 percent point (pp) and 9.6 pp, respectively, with pumpkin at 60% DM. The V4 region of the 16S rRNA gene was sequenced to profile pre-ensiled and ensiled archeal and bacterial communities. Silages containing carrot or pumpkin strongly influenced the microbial structure (PERMANOVA: R2 = 0.75; P < 0.001), despite the ensiled treatments being dominated by Lactobacillus spp., except for the control, which was dominated by Weissella and Pediococcus spp. (P < 0.01). Linear discriminant analysis indicated that carrot and pumpkin silages were responsible for the increased relative abundance of Lactobacillus and Acinetobacter spp. (log LDA score ≥ 2), respectively. After 48 h of incubation, carrot and pumpkin inclusion increased (P < 0.01) the in vitro DM digestibility by 22.5 and 31.3%, increased the total volatile fatty acids (VFAs) by 16 and 20.6% (P < 0.01), respectively, and showed a tendency (P = 0.07) to increase the gas production. Therefore, this study supports the use of carrot or pumpkin in sorghum silages to maximize feed digestibility and total VFA concentrations.
Multiple CRF01_AE/CRF07_BC Recombinants Enhanced the HIV-1 Epidemic Complexity Among MSM in Shenyang City, Northeast China
Authors: He Shan , Song Wei , Guo Gang , Li Qiang , An Minghui , Zhao Bin , Gao Yang , Tian Wen , Wang Lin , Shang Hong , Han Xiaoxu
Published: May 2022

The transmission of Unique Recombinant Forms (URFs) has complicated the molecular epidemic of HIV-1. This increasing genetic diversity has implications for prevention surveillance, diagnosis, and vaccine design. In this study, we characterized the HIV-1 URFs from 135 newly diagnosed HIV-1 infected cases between 2016 and 2020 in Shenyang, northeast China and analyzed the evolutionary relationship of them by phylogenetic and recombination approaches. Among 135 URFs, we found that the CRF01_AE/CRF07_BC recombinants were the most common (81.5%, 110/135), followed by CRF01_AE/B (11.9%, 16/135), B/C (3.7%, 5/135), and others (3.0%, 4/135). 94.8% (128/135) of patients infected by URFs were through homosexual contact. Among 110 URFs_0107, 60 (54.5%) formed 11 subclusters (branch support value = 1) and shared the consistent recombination structure, respectively. Four subclusters have caused small-scale spread among different high-risk populations. Although the recombination structures of URFs_0107 are various, the hotspots of recombinants gathered between position 2,508 and 2,627 (relative to the HXB2 position). Moreover, the CRF07_BC and CRF01AE fragments of URFs_0107 were mainly derived from the MSM population. In brief, our results reveal the complex recombinant modes and the high transmission risk of URFs_0107, which calls for more attention on the new URFs_0107 monitoring and strict control in the areas led by homosexual transmission route.
Altered Lipid Profile in COVID-19 Patients and Metabolic Reprogramming
Authors: Zhao Tie , Wang Chunhui , Duan Biyan , Yang Peipei , Wu Jianguo , Zhang Qiwei
Published: May 2022

Background

Coronavirus disease 2019 (COVID-19) is a global pandemic. Previous studies have reported dyslipidemia in patients with COVID-19. Herein, we conducted a retrospective study and a bioinformatics analysis to evaluate the essential data of the lipid profile as well as the possible mechanism in patients with COVID-19.

Methods

First of all, the retrospective study included three cohorts: patients with COVID-19, a healthy population, and patients with chronic obstructive pulmonary disease (COPD). For each subject, serum lipid profiles in the biochemical data were compared, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Furthermore, bioinformatics analyses were performed for exploring the biological or immunological mechanisms.

Results

In line with the biochemical data of the three cohorts, the statistical result displayed that patients with COVID-19 were more likely to have lower levels of TC and HDL-C as compared with healthy individuals. The differential proteins associated with COVID-19 are involved in the lipid pathway and can target and regulate cytokines and immune cells. Additionally, a heatmap revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were possibly involved in lipid metabolic reprogramming. The viral proteins, such as spike (S) and non-structural protein 2 (Nsp2) of SARS-CoV-2, may be involved in metabolic reprogramming.

Conclusion

The metabolic reprogramming after SARS-CoV-2 infections is probably associated with the immune and clinical phenotype of patients. Hence, metabolic reprogramming may be targeted for developing antivirals against COVID-19.
Absence of N-Acetylglucosamine Glycosylation on Listeria monocytogenes Wall Teichoic Acids Promotes Fatty Acid Tolerance by Repulsion From the Bacterial Surface
Authors: Thomasen Rikke S. S. , dos Santos Patricia T. , Sternkopf Lillebæk Eva M. , Skov Marianne N. , Kemp Michael , Kallipolitis Birgitte H.
Published: May 2022

Free fatty acids (FFAs) have strong antimicrobial properties against pathogenic bacteria and are known as natural protective agents against bacterial infections. Growth of the foodborne pathogen Listeria monocytogenes is highly affected by the presence of antimicrobial FFAs, however, the response of L. monocytogenes toward FFAs is not fully understood. Here, we explore how L. monocytogenes gains tolerance toward FFAs and present a novel mechanism conferring bacterial protection against FFA toxicity. Strains tolerant against the antimicrobial FFA palmitoleic acid were isolated and whole genome sequenced, and mutations were found in genes involved in wall teichoic acid (WTA) glycosylations. We show that mutation or deletion of lmo1079, which is essential for N-acetylglucosamine (GlcNAc) glycosylation of WTAs, confer tolerance against several antimicrobial FFAs. The FFA tolerant strains are lacking GlcNAc on their WTAs, which result in a more hydrophilic surface. In line with this, we observed a reduced binding of FFAs to the surface of the FFA tolerant strains. Additionally, lack of GlcNAc on WTAs confers tolerance toward acid stress. Altogether, these findings support that GlcNAc modification of WTA plays an important role in the response of L. monocytogenes toward stress conditions encountered during growth as a saprophyte and pathogen, including FFA-rich environments. Most importantly, our data revealed that L. monocytogenes strains lacking GlcNAc on their WTAs are protected against FFA toxicity, because the FFAs are repulsed from the bacterial surface of GlcNAc-deficient strains.
AI-2E Family Transporter Protein in Lactobacillus acidophilus Exhibits AI-2 Exporter Activity and Relate With Intestinal Juice Resistance of the Strain
Authors: Li Xiefei , Fan Xiankang , Shi Zihang , Xu Jue , Cao Yingying , Zhang Tao , Pan Daodong
Published: May 2022

The function of the autoinducer-2 exporters (AI-2E) family transporter protein of Lactobacillus acidophilus is still unclear. The phylogenetic analysis was used to analyze the relationship between the AI-2E protein of the L. acidophilus CICC 6074 strain and other AI-2E family members. Escherichia coli KNabc strain was used to verify whether the protein has Na+ (Li+)/H+ antiporter activity. The AI-2E protein overexpression strain was constructed by using the pMG36e expression vector, and the overexpression efficiency was determined by real-time quantitative PCR. The vitality and AI-2 activity of L. acidophilus CICC 6074 strains were determined. The results showed that the AI-2E protein of Lactobacillus formed a single branch on the phylogenetic tree and was closer to the AI-2E family members whose function was AI-2 exporter group I. The expression of AI-2E protein in the E. coli KNabc strain did not recover the resistance of the bacteria to the saline environment. Overexpression of AI-2E protein in L. acidophilus CICC 6074 could promote the AI-2 secretion of L. acidophilus CICC 6074 strain and enhance their survival ability in intestinal juice.
Identification and Validation of Apparent Imbalanced Epi-lncRNAs Prognostic Model Based on Multi-Omics Data in Pancreatic Cancer
Authors: Ke Mujing
Published: May 2022

Background: Globally, pancreatic adenocarcinoma is a recognized cause of pancreatic death (PAAD) associated with high mortality. Long non-coding RNAs (lncRNAs) play an important role in several biological processes in pancreatic cancer.

Methods: The gene expression profile of PAAD patients were obtained from The Cancer Genome Atlas (TCGA) database. The limma package was used to identify epigenetic disorders of lncRNAs and PCG. Subsequently, the genomic characteristics and landscape of lncRNAs were explored. The pancreatic cancer-related lncRNAs gene set from Lnc2Cancer v3.0 were collected and the difference between cancer samples and normal samples were analysed. A prognostic model consisting of five epigenetic lncRNA (epi-lncRNAs) was established by univariate and multivariate Cox proportional hazards regression analyses and was verified across different data sets. Finally, the expression of core epi-lncRNAs was identified by PCR experiment.

Results: A total of 2237 epi-lncRNAs, 11855 non-epi-lncRNAs, 13518 epi-PCGs, and 6097 non-epi-PCGs, were identified. The abnormal frequency of lncRNAs in pancreatic cancer was much lower than that in PCG, and 138 epi-lncRNAs were enriched in human cancer-related lncRNAs. Epi-lncRNAs had a higher number with longer lengths and a greater number of transcripts. Epi-lncRNAs associated with epigenetic disorders had a higher number of exons, gene length, and isomers as compared to non-epi-lncRNAs. Further, the five pancreatic cancer-specific epi-lncRNA genes (AL161431.1, LINC00663, LINC00941, SNHG10, and TM4SF1-AS1) were identified. Based on these five pancreatic cancer-specific epis-lncRNAs, a prognostic model for pancreatic cancer was established. The RT-PCR result confirmed that AL161431.1, LINC00663, LINC00941, and SNHG10 expressions in pancreatic cancer samples were higher as compared to normal pancreatic samples; the expression of TM4SF1-AS1 in pancreatic cancer cells was significantly lower than that in normal pancreatic samples.

Conclusions: Epigenetic abnormalities could promote abnormal lncRNA expression in pancreatic cancer and may play an important role in its progression.
Folic Acid Rescues Valproic Acid-Induced Morphogenesis Inhibition in Neural Rosettes Derived From Human Pluripotent Stem Cells
Authors: Zhang Xiao-zuo , Huo Hai-qin , Zhu Yu-qing , Feng Hao-yang , Jiao Jiao , Tan Jian-xin , Wang Yan , Hu Ping , Xu Zheng-feng
Published: May 2022

The ability of human pluripotent stem cells (hPSCs) to specialize in neuroepithelial tissue makes them ideal candidates for use in the disease models of neural tube defects. In this study, we cultured hPSCs in suspension with modified neural induction method, and immunostaining was applied to detect important markers associated with cell fate and morphogenesis to verify the establishment of the neural tube model in vitro. We carried out the drug experiments to further investigate the toxicity of valproic acid (VPA) exposure and the potential protective effect of folic acid (FA). The results demonstrated that neural rosette undergoes cell fate speciation and lumen formation accompanied by a spatiotemporal shift in the expression patterns of cadherin, indicating the model was successfully established. The results showed that VPA caused morphogenesis inhibition of lumen formation by altering cytoskeletal function and cell polarization, which could be rescued by FA supplement.
Reconstructive Endovascular Treatment of Basilar Trunk and Vertebrobasilar Junction Aneurysms: A Review of 77 Consecutive Cases
Authors: Peng Qichen , Zhou Yangyang , Li Wenqiang , Wang Chao , Dong Linggen , Mu Shiqing , Zhang Yisen
Published: May 2022

Background

Basilar trunk and vertebrobasilar junction (BTVBJ) aneurysms have a poor prognosis and are challenging to treat.

Objective

This study aimed to evaluate the efficacy of reconstructive endovascular treatment for BTVBJ aneurysms and explore a treatment selection paradigm.

Methods

Clinical and angiographic data from 77 patients with 80 BTVBJ aneurysms who underwent endovascular treatment with flow diverters (FDs) or conventional stent-assisted coiling between January 2016 and December 2020 were retrospectively analyzed. Aneurysm characteristics and treatment outcomes were compared between treatment groups.

Results

Among the 77 study patients, 34 (44.2%) were treated with FDs and 43 (55.8%) with conventional stent-assisted coiling. Overall, 72.7% of patients achieved favorable clinical outcome at follow-up. The rate of procedure-related complications was 23.4%. The aneurysm occlusion rate at last follow-up did not differ between the FD and conventional stent groups (79.2% vs. 77.1%, p = 0.854). Although the occlusion rate immediately after the procedure was lower in the FD group (29.4%), incidence of progressive occlusion was significantly higher (62.5 vs. 5.7%; p < 0.001). The proportion of patients with large and giant aneurysms (≥10 mm) was significantly higher in the FD group (70.6 vs. 34.8%; p = 0.002). In patients with large or giant aneurysms, favorable clinical outcome at last follow-up was achieved in 75% of patients in the FD group but only 43.8% of patients in the conventional stent group (p = 0.046). Moreover, the complication rate was lower in the FD group, but the difference was not significant (20.8 vs. 37.5%; p = 0.247). The same analyses were performed for patients with small aneurysms (<10 mm) but no significant differences between the two groups were observed.

Conclusion

Endovascular treatment of small BTVBJ aneurysms using either FDs or conventional stents was feasible and effective. In patients with large or giant aneurysms, treatment using FDs achieved higher rates of occlusion and favorable clinical outcome at last follow-up than conventional stent-assisted coiling.
Neuroscience Outside the Box: From the Laboratory to Discussing Drug Abuse at Schools
Authors: Machado do Vale Thereza Cristina , da Silva Chagas Luana , de Souza Pereira Helena , Giestal-de-Araujo Elizabeth , Arévalo Analía , Oliveira-Silva Bomfim Priscilla
Published: May 2022

One of the effects of the current COVID-19 pandemic is that low-income countries were pushed further into extreme poverty, exacerbating social inequalities and increasing susceptibility to drug use/abuse in people of all ages. The risks of drug abuse may not be fully understood by all members of society, partly because of the taboo nature of the subject, and partly because of the considerable gap between scientific production/understanding and communication of such knowledge to the public at large. Drug use is a major challenge to social development and a leading cause of school dropout rates worldwide. Some public policies adopted in several countries in recent decades failed to prevent drug use, especially because they focused on imposing combative or coercive measures, investing little or nothing in education and prevention. Here we highlight the role of neuroscience education as a valid approach in drug use education and prevention. We propose building a bridge between schools and scientists by promoting information, student engagement and honest dialogue, and show evidence that public policy regulators should be persuaded to support such science-based education programs in their efforts to effect important positive changes in society.
Local Label Point Correction for Edge Detection of Overlapping Cervical Cells
Authors: Liu Jiawei , Fan Huijie , Wang Qiang , Li Wentao , Tang Yandong , Wang Danbo , Zhou Mingyi , Chen Li
Published: May 2022

Accurate labeling is essential for supervised deep learning methods. However, it is almost impossible to accurately and manually annotate thousands of images, which results in many labeling errors for most datasets. We proposes a local label point correction (LLPC) method to improve annotation quality for edge detection and image segmentation tasks. Our algorithm contains three steps: gradient-guided point correction, point interpolation, and local point smoothing. We correct the labels of object contours by moving the annotated points to the pixel gradient peaks. This can improve the edge localization accuracy, but it also causes unsmooth contours due to the interference of image noise. Therefore, we design a point smoothing method based on local linear fitting to smooth the corrected edge. To verify the effectiveness of our LLPC, we construct a largest overlapping cervical cell edge detection dataset (CCEDD) with higher precision label corrected by our label correction method. Our LLPC only needs to set three parameters, but yields 30–40% average precision improvement on multiple networks. The qualitative and quantitative experimental results show that our LLPC can improve the quality of manual labels and the accuracy of overlapping cell edge detection. We hope that our study will give a strong boost to the development of the label correction for edge detection and image segmentation. We will release the dataset and code at: https://github.com/nachifur/LLPC.
Metabolomics in Primary Open Angle Glaucoma: A Systematic Review and Meta-Analysis
Authors: Tang Yizhen , Shah Simran , Cho Kin-Sang , Sun Xinghuai , Chen Dong Feng
Published: May 2022

Glaucoma is a leading cause of blindness worldwide. It is suggested that primary open angle glaucoma (POAG), the most common form of glaucoma, may be associated with significant metabolic alternations, but the systemic literature review and meta-analysis in the area have been missing. Altered metabolomic profiles in the aqueous humor and plasma may serve as possible biomarkers for early detection or treatment targets. In this article, we performed a systematic meta-analysis of the current literature surrounding the metabolomics of patients with POAG and metabolites associated with the disease. Results suggest several metabolites found to be specifically altered in patients with POAG, suggesting broad generalizability and pathways for future research.
Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study
Authors: Juarez-Martinez Erika L. , van Andel Dorinde M. , Sprengers Jan J. , Avramiea Arthur-Ervin , Oranje Bob , Scheepers Floortje E. , Jansen Floor E. , Mansvelder Huibert D. , Linkenkaer-Hansen Klaus , Bruining Hilgo
Published: May 2022

Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide—a chloride-regulating agent—improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8–21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC.

Clinical Trial Registration

EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.
Brain Gray Matter Atrophy and Functional Connectivity Remodeling in Patients With Chronic LHON
Authors: Tian Qin , Wang Ling , Zhang Yu , Fan Ke , Liang Meng , Shi Dapeng , Qin Wen , Ding Hao
Published: May 2022

Purpose

The aim of this study was to investigate the brain gray matter volume (GMV) and spontaneous functional connectivity (FC) changes in patients with chronic Leber's hereditary optic neuropathy (LHON), and their relations with clinical measures.

Methods

A total of 32 patients with chronic LHON and matched sighted healthy controls (HC) underwent neuro-ophthalmologic examinations and multimodel magnetic resonance imaging (MRI) scans. Voxel-based morphometry (VBM) was used to detect the GMV differences between the LHON and HC. Furthermore, resting-state FC analysis using the VBM-identified clusters as seeds was carried out to detect potential functional reorganization in the LHON. Finally, the associations between the neuroimaging and clinical measures were performed.

Results

The average peripapillary retinal nerve fiber layer (RNFL) thickness of the chronic LHON was significantly thinner (T = −16.421, p < 0.001), and the mean defect of the visual field was significantly higher (T = 11.28, p < 0.001) than the HC. VBM analysis demonstrated a significantly lower GMV of bilateral calcarine gyri (CGs) in the LHON than in the HC (p < 0.05). Moreover, in comparison with the HC, the LHON had significantly lower FC between the centroid of the identified left CG and ipsilateral superior occipital gyrus (SOG) and higher FC between this cluster and the ipsilateral posterior cingulate gyrus (p < 0.05, corrected). Finally, the GMV of the left CG was negatively correlated with the LHON duration (r = −0.535, p = 0.002), and the FC between the left CG and the ipsilateral posterior cingulate gyrus of the LHON was negatively correlated with the average peripapillary RNFL thickness (r = −0.522, p = 0.003).

Conclusion

The atrophied primary visual cortex of the chronic LHON may be caused by transneuronal degeneration following the retinal damage. Moreover, our findings suggest that the functional organization of the atrophied primary visual cortex has been reshaped in the chronic LHON.
Quantification of Intracranial Structures Volume in Fetuses Using 3-D Volumetric MRI: Normal Values at 19 to 37 Weeks' Gestation
Authors: Ren Jing-Ya , Zhu Ming , Wang Guanghai , Gui Yiding , Jiang Fan , Dong Su-Zhen
Published: May 2022

Objective

The purpose of this study is to establish a reference of intracranial structure volumes in normal fetuses ranging from 19 to 37 weeks' gestation (mean 27 weeks).

Materials and Methods

A retrospective analysis of 188 MRI examinations (1.5 T) of fetuses with a normal brain appearance (19–37 gestational weeks) from January 2018 to December 2021 was included in this study. Three dimensional (3-D) volumetric parameters from slice-to-volume reconstructed (SVR) images, such as total brain volume (TBV), cortical gray matter volume (GMV), subcortical brain tissue volume (SBV), intracranial cavity volume (ICV), lateral ventricles volume (VV), cerebellum volume (CBV), brainstem volume (BM), and extra-cerebrospinal fluid volume (e-CSFV), were quantified by manual segmentation from two experts. The mean, SD, minimum, maximum, median, and 25th and 75th quartiles for intracranial structures volume were calculated per gestational week. A linear regression analysis was used to determine the gestational weekly age-related change adjusted for sex. A t-test was used to compare the mean TBV and ICV values to previously reported values at each gestational week. The formulas to calculate intracranial structures volume derived from our data were created using a regression model. In addition, we compared the predicted mean TBV values derived by our formula with the expected mean TBV predicted by the previously reported Jarvis' formula at each time point. For intracranial volumes, the intraclass correlation coefficient (ICC) was calculated to convey association within and between observers.

Results

The intracranial volume data are shown in graphs and tabular summaries. The male fetuses had significantly larger VV compared with female fetuses (p = 0.01). Measured mean ICV values at 19 weeks are significantly different from those published in the literature (p < 0.05). Means were compared with the expected TBV generated by the previously reported formula, showing statistically differences at 22, 26, 29, and 30 weeks' gestational age (GA) (all p < 0.05). A comparison between our data-derived formula and the previously reported formula for TBV showed very similar values at every GA. The predicted TBV means derived from the previously reported formula were all within the 95% confidence interval (CI) of the predicted means of this study. Intra- and inter-observer agreement was high, with an intraclass correlation coefficient larger than 0.98.

Conclusion

We have shown that the intracranial structural volume of the fetal brain can be reliably quantified using 3-D volumetric MRI with a high degree of reproducibility and reinforces the existing data with more robust data in the earlier second and third stages of pregnancy.
Spatiotemporal Control of Neuronal Remodeling by Cell Adhesion Molecules: Insights From Drosophila
Authors: Meltzer Hagar , Schuldiner Oren
Published: May 2022

Developmental neuronal remodeling is required for shaping the precise connectivity of the mature nervous system. Remodeling involves pruning of exuberant neural connections, often followed by regrowth of adult-specific ones, as a strategy to refine neural circuits. Errors in remodeling are associated with neurodevelopmental disorders such as schizophrenia and autism. Despite its fundamental nature, our understanding of the mechanisms governing neuronal remodeling is far from complete. Specifically, how precise spatiotemporal control of remodeling and rewiring is achieved is largely unknown. In recent years, cell adhesion molecules (CAMs), and other cell surface and secreted proteins of various families, have been implicated in processes of neurite pruning and wiring specificity during circuit reassembly. Here, we review some of the known as well as speculated roles of CAMs in these processes, highlighting recent advances in uncovering spatiotemporal aspects of regulation. Our focus is on the fruit fly Drosophila, which is emerging as a powerful model in the field, due to the extensive, well-characterized and stereotypic remodeling events occurring throughout its nervous system during metamorphosis, combined with the wide and constantly growing toolkit to identify CAM binding and resulting cellular interactions in vivo. We believe that its many advantages pose Drosophila as a leading candidate for future breakthroughs in the field of neuronal remodeling in general, and spatiotemporal control by CAMs specifically.
Morphine-3-Glucuronide, Physiology and Behavior
Authors: Gabel Florian , Hovhannisyan Volodya , Berkati Abdel-Karim , Goumon Yannick
Published: May 2022

Morphine remains the gold standard painkiller available to date to relieve severe pain. Morphine metabolism leads to the production of two predominant metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). This metabolism involves uridine 5′-diphospho-glucuronosyltransferases (UGTs), which catalyze the addition of a glucuronide moiety onto the C3 or C6 position of morphine. Interestingly, M3G and M6G have been shown to be biologically active. On the one hand, M6G produces potent analgesia in rodents and humans. On the other hand, M3G provokes a state of strong excitation in rodents, characterized by thermal hyperalgesia and tactile allodynia. Its coadministration with morphine or M6G also reduces the resulting analgesia. Although these behavioral effects show quite consistency in rodents, M3G effects are much more debated in humans and the identity of the receptor(s) on which M3G acts remains unclear. Indeed, M3G has little affinity for mu opioid receptor (MOR) (on which morphine binds) and its effects are retained in the presence of naloxone or naltrexone, two non-selective MOR antagonists. Paradoxically, MOR seems to be essential to M3G effects. In contrast, several studies proposed that TLR4 could mediate M3G effects since this receptor also appears to be essential to M3G-induced hyperalgesia. This review summarizes M3G’s behavioral effects and potential targets in the central nervous system, as well as the mechanisms by which it might oppose analgesia.
Presynaptic Mitochondria Communicate With Release Sites for Spatio-Temporal Regulation of Exocytosis at the Motor Nerve Terminal
Authors: Lopez-Manzaneda Mario , Fuentes-Moliz Andrea , Tabares Lucia
Published: May 2022

Presynaptic Ca2+ regulation is critical for accurate neurotransmitter release, vesicle reloading of release sites, and plastic changes in response to electrical activity. One of the main players in the regulation of cytosolic Ca2+ in nerve terminals is mitochondria, which control the size and spread of the Ca2+ wave during sustained electrical activity. However, the role of mitochondria in Ca2+ signaling during high-frequency short bursts of action potentials (APs) is not well known. Here, we studied spatial and temporal relationships between mitochondrial Ca2+ (mCa2+) and exocytosis by live imaging and electrophysiology in adult motor nerve terminals of transgenic mice expressing synaptophysin-pHluorin (SypHy). Our results show that hot spots of exocytosis and mitochondria are organized in subsynaptic functional regions and that mitochondria start to uptake Ca2+ after a few APs. We also show that mitochondria contribute to the regulation of the mode of fusion (synchronous and asynchronous) and the kinetics of release and replenishment of the readily releasable pool (RRP) of vesicles. We propose that mitochondria modulate the timing and reliability of neurotransmission in motor nerve terminals during brief AP trains.
Preparation and Antioxidant Properties of Germinated Soybean Protein Hydrolysates
Authors: Qi Qianhui , Zhang Guohua , Wang Wei , Sadiq Faizan Ahmed , Zhang Yu , Li Xue , Chen Qihe , Xia Qile , Wang Xinquan , Li Yougui
Published: May 2022

In this study, soybeans during different germination stages were described and compared with regard to morphology, water content, protein, amino acids, and isoflavones. The optimal conditions for the hydrolysis of proteins obtained from germinated soybeans were determined using the response surface methodology. Gel filtration chromatography was used to separate germinated soybean protein hydrolysates after ultrafiltration, whereas 2,2-Diphenyl-1-picrylhydrazyl (DPPH), ABTS•+, and FRAP assays were used to assess the antioxidant activity of different fractions. Findings of this study revealed that protein and isoflavone contents were high in soybean at 24 h following germination (the bud was about 0.5–1 cm). The proteins from germinated soybeans were hydrolyzed and separated into five fractions (G1–G5) and evaluated in terms of their molecular weight and antioxidant activity. Interestingly, the antioxidant activity was found to be higher in germinated soybean protein hydrolysates than in other soybean protein hydrolysates derived from soybean meal protein. This suggests that germination can effectively improve the utilization rate of soybean proteins. The antioxidant activity of G3 was best among G1–G5. The results obtained in this study demonstrate that germination for 24 h when the bud length is about 0.5–1 cm can be applied as a special pretreatment of plant seeds in the development of germinated foods. These findings can be used to identify the structure of the potential antioxidative hydrolysates for their possible exploitation in functional foods.
Associations of Serum Biomarkers of Fruit and Vegetable Intake With the Risk of Cause–Specific Mortality and All–Cause Mortality: A National Prospective Cohort Study
Authors: Pu Liyuan , Zhang Ruijie , Wang Xiaojie , Zhao Tian , Sun Hongpeng , Han Liyuan
Published: May 2022

Objective

The purpose of this study was to evaluate the associations of serum biomarkers of fruit and vegetable intake (vitamin C and carotenoids) with cause–specific mortality and all–cause mortality in a nationally representative sample of US adults.

Methods

We analyzed data from 12,530 participants from the National Health and Nutrition Examination Survey III (1988–1994). The Cox proportional hazards models with restricted cubic spline were used for the analysis.

Results

During 246,027 person–years of follow–up, 4,511 deaths occurred, including 1,395 deaths from cardiovascular disease, 1,072 deaths from heart disease, 323 deaths from cerebral disease, and 954 deaths from cancer. The serum vitamin C was significantly associated with the cancer and all–cause mortality, with hazard ratios (HRs) (95% CIs) for each one SD of 0.80 (0.71–0.91) and 0.91 (0.86–0.96). The serum alpha–carotene was significantly associated with the cancer mortality, with HRs (95% CIs) of 0.70 (0.54–0.90), 0.68 (0.48–0.95), 0.64 (0.43–0.95), and 0.44 (0.33–0.60) for comparisons of groups 2–5 with group 1 in model 2, respectively. The change for each one SD in the composite biomarker score, equivalent to a 0.483 times/month difference in total fruits and vegetables intake, gave an HR of 0.79 (0.69–0.90) for cancer mortality.

Conclusion

Inverse associations were found between serum vitamin C, carotenoids, and composite biomarker score and outcomes expect for cerebral disease, heart disease, and cardiovascular disease mortality. This finding supports an increase in dietary fruit and vegetable intake as a primary prevention strategy for cancer and all–cause mortality.
Network Pharmacology and Transcriptomic Sequencing Analyses Reveal the Molecular Mechanism of Sanguisorba officinalis Against Colorectal Cancer
Authors: Zhang Weijia , Sang Shuyi , Peng Chang , Li George Q. , Ou Ling , Feng Zhong , Zou Yuanjing , Yuan Yuemei , Yao Meicun
Published: May 2022

Background

Colorectal cancer (CRC) is the most common malignant cancer worldwide. Sanguisorba officinalis has been shown to have anti-inflammatory, anti-bacterial, antioxidant, and anti-tumor effects, while its molecular mechanism against CRC remains unclear. The aim of this study is to explore the underlying mechanism of S. officinalis against CRC cell lines using network pharmacology and transcriptomic sequencing methods.

Method

Firstly, the active ingredients and potential targets of S. officinalis against CRC were screened from databases. Secondly, the networks of ingredient–target, ingredient–target–CRC and protein–protein interaction were constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of network pharmacology and transcriptomic sequencing were performed. Finally, the effect of S. officinalis against CRC was verified by in vitro experiments.

Results

In total, 14 active ingredients and 273 potential targets against CRC were identified in S. officinalis by network pharmacology. PI3K–Akt, HIF-1, and MAPK signaling pathways related to cell proliferation were regulated by S. officinalis in enrichment analyses and transcriptomic sequencing. In vitro, S. officinalis inhibited the proliferation and migration of CRC cells and arrested the cell cycle at the G0–G1 phase. The western blot showed that S. officinalis downregulated the expression of p-PI3K, p-Akt, HIF-1A, VEGFA, cyclin D1, c-Myc, and p-MAPK proteins in CRC cells.

Conclusion

In conclusion, network pharmacology and transcriptomic sequencing analyses, in combination with in vitro studies, have been successfully applied to study the underlying mechanism of S. officinalis against CRC cells. Our results demonstrate that S. officinalis suppresses the proliferation, survival, and migration of CRC cells through regulating the PI3K–Akt, HIF-1, and MAPK signaling pathways.
Ex Vivo Irradiation of Lung Cancer Stem Cells Identifies the Lowest Therapeutic Dose Needed for Tumor Growth Arrest and Mass Reduction In Vivo
Authors: Puglisi Caterina , Giuffrida Raffaella , Borzì Giuseppina , Illari Salvatore , Caronia Francesco Paolo , Di Mattia Paolo , Colarossi Cristina , Ferini Gianluca , Martorana Emanuele , Sette Giovanni , Eramo Adriana , Lorico Aurelio , Di Grazia Alfio , Forte Stefano
Published: May 2022

Radiotherapy represents a first-line treatment for many inoperable lung tumors. New technologies offer novel opportunities for the treatment of lung cancer with the administration of higher doses of radiation in smaller volumes. Because both therapeutic and toxic treatment effects are dose-dependent, it is important to identify a minimal dose protocol for each individual patient that maintains efficacy while decreasing toxicity. Cancer stem cells sustain tumor growth, promote metastatic dissemination, and may give rise to secondary resistance. The identification of effective protocols targeting these cells may improve disease-free survival of treated patients. In this work, we evaluated the existence of individual profiles of sensitivity to radiotherapy in patient-derived cancer stem cells (CSCs) using both in vitro and in vivo models. Both CSCs in vitro and mice implanted with CSCs were treated with radiotherapy at different dose intensities and rates. CSC response to different radiation doses greatly varied among patients. In vitro radiation sensitivity of CSCs corresponded to the therapeutic outcome in the corresponding mouse tumor model. On the other side, the dose administration rate did not affect the response. These findings suggest that in vitro evaluation of CSCs may potentially predict patients’ response, thus guiding clinical decision.
Statins Lower Lipid Synthesis But Promote Secretion of Cholesterol-Enriched Extracellular Vesicles and Particles
Authors: Chen Yundi , Xu Yongrui , Wang Jing , Prisinzano Peter , Yuan Yuhao , Lu Fake , Zheng Mingfeng , Mao Wenjun , Wan Yuan
Published: May 2022

Lipid droplets are lipid-rich cytosolic organelles that play roles in cell signaling, membrane trafficking, and many other cellular activities. Recent studies revealed that lipid droplets in cancer cells have various biological functions, such as energy production, membrane synthesis, and chemoresistance, thereby fostering cancer progression. Accordingly, the administration of antilipemic agents could improve anti-cancer treatment efficacy given hydrophobic chemotherapeutic drugs could be encapsulated into lipid droplets and then expelled to extracellular space. In this study, we investigated whether statins could promote treatment efficacy of lipid droplet-rich ovarian SKOV-3 cells and the potential influences on generation and composition of cell-derived extracellular vesicles and particles (EVP). Our studies indicate that statins can significantly lower lipid biosynthesis. Moreover, statins can inhibit proliferation, migration, and invasion of SKOV-3 cells and enhance chemosensitivity in vitro and in vivo. Furthermore, statins can lower EVP secretion but enforce the release of cholesterol-enriched EVPs, which can further lower lipid contents in parental cells. It is the first time that the influence of statins on EVP generation and EVP-lipid composition is observed. Overall, we demonstrated that statins could inhibit lipid production, expel cholesterol to extracellular space via EVPs, and improve chemosensitivity.
Development of Novel CD47-Specific ADCs Possessing High Potency Against Non-Small Cell Lung Cancer in vitro and in vivo
Authors: Chiang Zu-Chian , Fang Shubin , Shen Yang-kun , Cui Dongya , Weng Huanjiao , Wang Dawei , Zhao Yuxiang , Lin Jizhen , Chen Qi
Published: May 2022

Targeted therapies hold promise for efficiently and accurately delivering cytotoxic drugs directly to tumor tissue to exert anticancer effects. CD47 is a membrane protein expressed in a variety of malignant tumors and hematopoietic cells, which plays a key role in immune escape and tumor progression. Although CD47 immunocheckpoint therapy has been developed in recent years, many patients cannot benefit from it because of its low efficiency. To strengthen and extend the therapeutic efficacy of anti-CD47 monoclonal antibody (mAb), we used the newly developed 7DC2 and 7DC4 mAbs as the targeting payload adaptor and VCMMAE as the toxin payload to construct novel CD47-specific immunotoxin (7DC-VCMMAE) by engineering cysteine residues. These CD47-specific ADCs have the better cell penetration, excellent DAR, similar payload distribution and good antigen-binding affinity. In vitro, 7DC-VCMMAE treatment induced death of non-small cell lung cancer (NSCLC) cell lines 95D and SPC-A1, but not A549 that express low levels of CD47 on the cell membrane. This finding suggests that 7DC-VCMMAE may possess greater therapeutic effect on NSCLC tumors expressing a high level of CD47 antigen; however, 7DC-VCMMAE treatment also promoted phagocytosis of A549 cells by macrophages. In vivo, 7DC-VCMMAE treatment had remarkable antitumor effects in a NSCLC cell line-derived xenograft (CDX) mouse model based on nonobese diabetic/severe combined immunodeficient (NOD/SCID). In summary, this study combined VCMMAE with anti-CD47 mAbs, emphasizing a novel and promising immunotherapy method for direct killing of NSCLC, which provides a valuable new way to meet the needs of the cancer therapy field.