bluuebunny/crossref_metadata_2025 huggingface dataset:
International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder
Authors: Amin Sam , Monaghan Marie , Aledo-Serrano Angel , Bahi-Buisson Nadia , Chin Richard F. , Clarke Angus J. , Cross J. Helen , Demarest Scott , Devinsky Orrin , Downs Jenny , Pestana Knight Elia M. , Olson Heather , Partridge Carol-Anne , Stuart Graham , Trivisano Marina , Zuberi Sameer , Benke Tim A.
Published: June 2022

CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ~ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer impairments affecting cognitive, motor, visual, sleep, gastrointestinal and other functions. Here we present the recommendations of international healthcare professionals, experienced in CDD management, to address the multisystem and holistic needs of these individuals. Using a Delphi method, an anonymous survey was administered electronically to an international and multidisciplinary panel of expert clinicians and researchers. To provide summary recommendations, consensus was set, a priori, as >70% agreement for responses. In the absence of large, population-based studies to provide definitive evidence for treatment, we propose recommendations for clinical management, influenced by this proposed threshold for consensus. We believe these recommendations will help standardize, guide and improve the medical care received by individuals with CDD.
Using Large-Scale Sensor Data to Test Factors Predictive of Perseverance in Home Movement Rehabilitation: Optimal Challenge and Steady Engagement
Authors: Ramos Muñoz Edgar De Jesus , Swanson Veronica Ann , Johnson Christopher , Anderson Raeda K. , Rabinowitz Amanda R. , Zondervan Daniel K. , Collier George H. , Reinkensmeyer David J.
Published: June 2022

Persevering with home rehabilitation exercise is a struggle for millions of people in the US each year. A key factor that may influence motivation to engage with rehabilitation exercise is the challenge level of the assigned exercises, but this hypothesis is currently supported only by subjective, self-report. Here, we studied the relationship between challenge level and perseverance using long-term, self-determined exercise patterns of a large number of individuals (N = 2,581) engaging in home rehabilitation with a sensor-based exercise system without formal supervision. FitMi is comprised of two puck-like sensors and a library of 40 gamified exercises for the hands, arms, trunk, and legs that are designed for people recovering from a stroke. We found that individuals showed the greatest perseverance with the system over a 2-month period if they had (1) a moderate level of motor impairment and (2) high but not perfect success during the 1st week at completing the exercise game. Further, a steady usage pattern (vs. accelerating or decelerating use) was associated with more overall exercise, and declines in exercise amount over time were associated with exponentially declining session initiation probability rather than decreasing amounts of exercise once a session was initiated. These findings confirm that an optimized challenge level and regular initiation of exercise sessions predict achievement of a greater amount of overall rehabilitation exercise in a group of users of commercial home rehabilitation technology and suggest how home rehabilitation programs and exercise technologies can be optimized to promote perseverance.
The Association Between Plant-Based Diet Indices and Obesity and Metabolic Diseases in Chinese Adults: Longitudinal Analyses From the China Health and Nutrition Survey
Authors: Chen Bo , Zeng Jingjing , Qin Minghui , Xu Wenlei , Zhang Zhaoxia , Li Xiaying , Xu Shaoyong
Published: June 2022

Background

A wide range of health benefits are associated with consuming a diet high in plant-based foods. Diet quality can be accurately assessed using plant-based diet indices, however there is inadequate evidence that plant-based diet indices are linked to obesity, hypertension, and type 2 diabetes (T2D), especially in Chinese cultures who have traditionally consumed plant-rich foods.

Methods

The data came from the China Nutrition and Health Survey. Overall, 11,580 adult participants were enrolled between 2004 and 2006 and followed up until 2009 or 2015 (follow-up rate: 73.4%). Dietary intake was assessed across three 24-h recalls, and two plant-based dietary indices [overall plant-based diet indice (PDI) and healthy plant-based diet indice (hPDI)] were calculated using China Food Composition Code and categorized into quintiles. The study's endpoints were overweight/obesity, hypertension, and T2D. The Hazard ratio (HR) and dose-response relationship were assessed using the Cox proportional risk model and restricted cubic splines. The areas under the curve of the receiver operating characteristic curve analyses were used to evaluate the predictive performance of the PDI and hPDI.

Results

During the median follow-up period of more than 10 years, 1,270 (33.4%), 1,509 (31.6%), and 720 (11.5%) participants developed overweight / obesity, hypertension, and T2D, respectively. The higher PDI score was linked with a reduced risk of overweight/obesity [HR: 0.71 (95% CI: 0.55–0.93), P-trend <0.001], hypertension [HR: 0.63 (95% CI: 0.51–0.79), P-trend <0.001], and T2D [HR: 0.79 (95% CI: 0.72–0.87), P-trend <0.001]. The hPDI score was inversely associated with overweight/obesity [HR: 0.79 (95% CI: 0.62–0.98), P-trend = 0.02] and T2D [HR: 0.84 (95% CI: 0.75–0.93), P-trend = 0.001]. In the aged <55-year-old group, subgroup analysis indicated a significant negative association between PDI/hPDI and overweight/obesity, hypertension, and T2D. There was no significant difference in the areas under the curve of the fully adjusted obesity, hypertension, and diabetes prediction models between PDI and hPDI.

Conclusion

The PDI and hPDI scores were very similar in application in Chinese populations, and our findings highlight that adherence to overall plant-based diet index helps to reduce the risk of T2D, obesity, and hypertension in Chinese adults who habitually consume plant-based foods, especially for those aged <55 year. Further understanding of how plant-based diet quality is associated with chronic disease will be needed in the future, which will help develop dietary strategies to prevent diabetes, hypertension, and related chronic diseases.
Effects of Gut Microbiota and Metabolites on Heart Failure and Its Risk Factors: A Two-Sample Mendelian Randomization Study
Authors: Luo Qiang , Hu Yilan , Chen Xin , Luo Yong , Chen Jie , Wang Han
Published: June 2022

Introduction

Previous observational studies have indicated that gut microbiota and metabolites may contribute to heart failure and its risk factors. However, with the limitation of reverse causality and confounder in observational studies, such relationship remains unclear. This study aims to reveal the causal effect of gut microbiota and metabolites on heart failure and its risk factors.

Methods

This study collected summary statistics regarding gut microbiota and metabolites, heart failure, diabetes, hypertension, chronic kidney disease, myocardial infarction, atrial fibrillation, hypertrophic cardiomyopathy, dilated cardiomyopathy, coronary heart disease, valvular heart disease, and myocarditis. Two-sample Mendelian randomization analysis was performed using MR-Egger, inverse variance weighted (IVW), MR-PRESSO, maximum likelihood, and weighted median.

Results

Results from gene prediction showed that among all gut microbiota, candida, shigella, and campylobacter were not associated with higher incidence of heart failure. However, genetic prediction suggested that for every 1 unit increase in shigella concentration, the relative risk increased by 38.1% for myocarditis and 13.3% for hypertrophic cardiomyopathy. Besides, for every 1 unit increased in candida concentration, the relative risk of chronic kidney disease increased by 7.1%. As for intestinal metabolites, genetic prediction results suggested that for every 1 unit increase in betaine, the relative risk of heart failure and myocardial infarction increased by 1.4% and 1.7%, separately.

Conclusions

This study suggested new evidence of the relationship between gut microbiota and heart failure and its risk factors, which may shed light on designing microbiome- and microbiome-dependent metabolite interventions on heart failure and its risk factors in clinical trials in the future.
A Nutraceutical Product Based on a Mixture of Algae and Extra Virgin Olive Oils and Olive Leaf Extract Attenuates Sepsis-Induced Cardiovascular and Muscle Alterations in Rats
Authors: González-Hedström Daniel , Moreno-Rupérez Álvaro , de la Fuente-Fernández María , de la Fuente-Muñoz Mario , Román-Carmena Marta , Amor Sara , García-Villalón Ángel Luís , López-Calderón Asunción , Isabel Martín Ana , Priego Teresa , Granado Miriam
Published: June 2022

Nutraceuticals are products of natural origin widely used for the treatment and/or prevention of some chronic diseases that are highly prevalent in Western countries, such as obesity or type II diabetes, among others. However, its possible use in the prevention of acute diseases that can put life at risk has been poorly studied. Sepsis is an acute condition that causes cardiovascular and skeletal muscle damage due to a systemic inflammatory state. The aim of this work was to evaluate the possible beneficial effect of a new nutraceutical based on a mixture of algae oil (AO) and extra virgin olive oil (EVOO) supplemented with an olive leaf extract (OLE) in the prevention of cardiovascular alterations and skeletal muscle disorders induced by sepsis in rats. For this purpose, male Wistar rats were treated with the nutraceutical or with water p.o. for 3 weeks and after the treatment they were injected with 1mg/kg LPS twice (12 and 4 h before sacrifice). Pretreatment with the nutraceutical prevented the LPS-induced decrease in cardiac contractility before and after the hearts were subjected to ischemia-reperfusion. At the vascular level, supplementation with the nutraceutical did not prevent hypotension in septic animals, but it attenuated endothelial dysfunction and the increased response of aortic rings to the vasoconstrictors norepinephrine and angiotensin-II induced by LPS. The beneficial effects on cardiovascular function were associated with an increased expression of the antioxidant enzymes SOD-1 and GSR in cardiac tissue and SOD-1 and Alox-5 in arterial tissue. In skeletal muscle, nutraceutical pretreatment prevented LPS-induced muscle proteolysis and autophagy and significantly increased protein synthesis as demonstrated by decreased expression of MURF-1, atrogin-1, LC3b and increased MCH-I and MCH -IIa in gastrocnemius muscle. These effects were associated with a decrease in the expression of TNFα, HDAC4 and myogenin. In conclusion, treatment with a new nutraceutical based on a mixture of AO and EVOO supplemented with OLE is useful to prevent cardiovascular and muscular changes induced by sepsis in rats. Thus, supplementation with this nutraceutical may constitute an interesting strategy to reduce the severity and mortality risk in septic patients.
Complete Response to Immunotherapy Combined With Chemotherapy in a Patient With Gynecological Mixed Cancer Mainly Composed of Small Cell Neuroendocrine Carcinoma With High Tumor Mutational Burden: A Case Report
Authors: Su Xingyun , Zhou Xinhui , Xiao Cheng , Peng Wei , Wang Qiangfeng , Zheng Yulong
Published: June 2022

Small cell neuroendocrine carcinoma (SCNEC) is rare in the gynecologic tract, which has high invasive and metastatic ability. Due to the aggressive behavior and lack of treatment, patients have an extremely poor prognosis. Here we report a 66-year-old female diagnosed with SCNEC in the gynecologic tract, mixed with endometrioid adenocarcinoma, squamous cell, and adenosquamous carcinoma. A tumor mutational burden of 13.14 Muts/Mb was detected by next-generation sequencing. The patient underwent a palliative operation of total hysterectomy with bilateral adnexectomy but suffered from disease progression in a short time after the operation. Chemotherapy (paclitaxel + carboplatin) combined with immunotherapy (toripalimab) was conducted every 3 weeks, achieving a partial response after 2 cycles of treatment. After 5 cycles of combined treatment, the patient consolidated with monotherapy of toripalimab for about half a year and achieved a complete response. Until December 2021, the patient has achieved 27 months of progression-free survival and maintains a continued complete response. This case is presented due to the rare combination of pathological types and durable response to treatment especially immunotherapy, suggesting the potential value of immunotherapy in SCNEC of the gynecologic tract.
Blocking ATM Attenuates SKOV3 Cell Proliferation and Migration by Disturbing OGT/OGA Expression via hsa-miR-542-5p
Authors: Wang Ning , Yu Miaomiao , Fu Yan , Ma Zhanchuan
Published: June 2022

Blocking ataxia telangiectasia mutated (ATM), a crucial player in DNA repair responses, has been proposed as a promising strategy in anti-cancer therapy. Most previous studies have focused on DNA damage response-related pathways after administration of ATM inhibitors. However, ATM inhibition could potentially influence a wide range of changes in gene expression, which remain poorly defined. Here, we report that administration of the ATM inhibitor KU60019 led to impaired migration and enhanced apoptosis in the ovarian cancer cell line SKOV3, accompanied by abnormally elevated O-GlcNAc transferase and O-GlcNAcase expression levels. In addition, KU60019 treatment significantly suppressed expression of hsa-miR-542-5p in SKOV3 cells. Up-regulation of hsa-miR-542-5p expression inhibited increases in OGT and OGA level, and reversed the effects of ATM inhibition on apoptosis and migration in SKOV3 cells. Finally, we found aberrant expression of OGT and OGA to be associated with ovarian cancer patient survival. Taken together, our results suggest that ATM inhibition may promote SKOV3 cell apoptosis via suppressing hsa-miR-542-5p and elevating OGT and OGA expression, providing new insights into the application of ATM inhibitors in cancer immunotherapy.
Clinical Diagnostic and Prognostic Potential of NDRG1 and NDRG2 in Hepatocellular Carcinoma Patients
Authors: Xu Shaohua , Gao Ruihuan , Zhou Yidan , Yang Ying , Zhang Yi , Li Qianyuan , Luo Chunhua , Liu Song-Mei
Published: June 2022

Background

Primary liver cancer is still the most common lethal malignancy. The N-myc downstream-regulated gene family (NDRG1–4) is a group of multifunctional proteins associated with carcinogenesis. However, systematic evaluation of the diagnostic and prognostic values of NDRG1 or NDRG2 expression in liver cancer is poorly investigated.

Method

The gene expression matrix of liver hepatocellular carcinoma (LIHC) was comprehensively analyzed by the “limma” and “Dseq2” R packages. The Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were used to identify the biological functional differences. A single-sample GSEA (ssGSEA) was conducted to quantify the extent of immune cell infiltration. Finally, the clinical and prognostic information of LIHC patients was systematically investigated using Kaplan–Meier analysis and logistic and Cox regression analysis.

Results

Compared with normal tissues, NDRG1 expression was higher, whereas NDRG2 expression was lower in tumor tissues (P <0.001). The area under the receiver operator characteristic curve (AUROC) of NDRG1 and NDRG2 for LIHC was 0.715 and 0.799, respectively. Kaplan–Meier analysis revealed that NDRG1 and NDRG2 were independent clinical prognostic biomarkers for the overall survival (OS, P = 0.001 and 2.9e−06), progression-free interval (PFI, P = 0.028 and 0.005) and disease-specific survival (DSS, P = 0.027 and P <0.001). The C-indexes and calibration plots of the nomogram suggest that NDRG1 and NDRG2 have an effective predictive performance for OS (C-index: 0.676), DSS (C-index: 0.741) and PFI (C-index: 0.630) of liver cancer patients. The mutation rate of NDRG1 in liver cancer reached up to 14%, and DNA methylation levels of NDRG1 and NDRG2 promoters correlated significantly with clinical prognosis.

Conclusions

The mRNA expression and DNA methylation of NDRG superfamily members have the potential for LIHC diagnosis and prognosis via integrative analysis from multiple cohorts.
Inhibiting PI3K–AKT–mTOR Signaling in Multiple Myeloma-Associated Mesenchymal Stem Cells Impedes the Proliferation of Multiple Myeloma Cells
Authors: Heinemann Luca , Möllers Klara Maria , Ahmed Helal Mohammed Mohammed , Wei Lanying , Sun Kaiyan , Nimmagadda Subbaiah Chary , Frank Daria , Baumann Anja , Poos Alexandra M. , Dugas Martin , Varghese Julian , Raab Marc-Steffen , Khandanpour Cyrus
Published: June 2022

The microenvironment of cancer cells is receiving increasing attention as an important factor influencing the progression and prognosis of tumor diseases. In multiple myeloma (MM), a hematological cancer of plasma cells, mesenchymal stem cells (MSCs) represent an integral part of the bone marrow niche and tumor microenvironment. It has been described that MM cells alter MSCs in a way that MM-associated MSCs promote the proliferation and survival of MM cells. Yet, our understanding of the molecular mechanisms governing the interaction between MM cells and MSCs and whether this can be targeted for therapeutic interventions is limited. To identify potential molecular targets, we examined MSCs by RNA sequencing and Western blot analysis. We report that MSCs from MM patients with active disease (MM-Act-MSCs) show a distinct gene expression profile as compared with MSCs from patients with other (non-) malignant diseases (CTR-MSCs). Of note, we detected a significant enrichment of the PI3K–AKT–mTOR hallmark gene set in MM-Act-MSCs and further confirmed the increased levels of related proteins in these MSCs. Pictilisib, a pan-PI3K inhibitor, selectively reduced the proliferation of MM-Act-MSCs as compared with CTR-MSCs. Furthermore, pictilisib treatment impaired the MM-promoting function of MM-Act-MSCs. Our data thus provide a deeper insight into the molecular signature and function of MSCs associated with MM and show that targeting PI3K–AKT–mTOR signaling in MSCs may represent an additional therapeutic pathway in the treatment of MM patients.
CircASPH Promotes Hepatocellular Carcinoma Progression Through Methylation and Expression of HAO2
Authors: Zhuo Han , Xia Jinguo , Zhang Jin , Tang Junwei , Han Sheng , Zheng Qitong , Zhu Deming , Zhang Feihong , Xu Zhenggang , Sun Dongwei , Tan Zhongming , Wu Chen
Published: June 2022

CircRNAs have been reported to be related to hepatocellular carcinoma (HCC) development. Limited studies have revealed the expression profile of circRNAs in tumor and para-tumor normal samples in HCC patients. We found that circASPH was significantly increased in HCC tumor samples and that the level of circASPH was closely related to the overall survival of HCC patients. Mechanistically, circASPH could regulate the methylation of the promoter and expression of hydrocyanic oxidase 2 (HAO2) to promote HCC progression by acting as a sponge for miR-370-3p, and miR-370-3p could target DNMT3b and increase the 5mC level. In summary, our study determined that circASPH could regulate the methylation and expression of HAO2 and it could be considered an important epigenetic regulator in HCC progression.
Efficacy and Safety of Anlotinib in the Treatment of Small Cell Lung Cancer: A Real-World Observation Study
Authors: Yuan Jing , Cheng Feng , Xiao Guodong , Wang Xiaofeng , Fan Huijie
Published: June 2022

Aims

This study aimed to observe the efficacy and safety of anlotinib in the treatment of small cell lung cancer (SCLC) in the real world, as first-line maintenance therapy, second-line, and above.

Methods

Clinical data of 109 patients with SCLC treated with anlotinib and hospitalized at The First Affiliated Hospital of Zhengzhou University from June 2018 to June 2020 were retrospectively analyzed. Analysis of short-term efficacy and survival was performed, with p<0.05 being considered statistically significant.

Results

The median progression-free survival (mPFS) of anlotinib monotherapy used as first-line maintenance treatment of SCLC was 6.3 months (11.7 months in the limited phase and 5.8 months in the extensive phase) and median overall survival (mOS) was 16.7 months (not reached in limited phase, 12.6 months in extensive phase). In second-line treatment, anlotinib with chemotherapy prolonged PFS and OS as compared to anlotinib monotherapy (p<0.05). In third-line and above treatment, there was no improvement in mPFS with the chemotherapy combination regimen compared to anlotinib monotherapy (3.6 months vs. 3.8 months, p=0.398), with a trend toward impaired mOS (8.5 months vs. not achieved, p=0.060). Univariate analyses and multivariate analyses revealed that Eastern Cooperative Oncology Group performance status and liver metastases were independent prognostic factors affecting PFS and OS. No new anlotinib-related adverse reactions were identified.

Conclusion

Anlotinib was effective for first-line maintenance and second-line treatment, and the chemotherapy combination regimen was superior to monotherapy when applied as second-line treatment. However, this trend was not observed in third-line and above therapy.
The BET Inhibitor JQ1 Potentiates the Anticlonogenic Effect of Radiation in Pancreatic Cancer Cells
Authors: Garcia Patrick L. , Miller Aubrey L. , Zeng Ling , van Waardenburg Robert C. A. M. , Yang Eddy S. , Yoon Karina J.
Published: June 2022

We reported previously that the BET inhibitor (BETi) JQ1 decreases levels of the DNA repair protein RAD51 and that this decrease is concomitant with increased levels of DNA damage. Based on these findings, we hypothesized that a BETi would augment DNA damage produced by radiation and function as a radiosensitizer. We used clonogenic assays to evaluate the effect of JQ1 ± ionizing radiation (IR) on three pancreatic cancer cell lines in vitro. We performed immunofluorescence assays to assess the impact of JQ1 ± IR on DNA damage as reflected by levels of the DNA damage marker γH2AX, and immunoblots to assess levels of the DNA repair protein RAD51. We also compared the effect of these agents on the clonogenic potential of transfectants that expressed contrasting levels of the principle molecular targets of JQ1 (BRD2, BRD4) to determine whether levels of these BET proteins affected sensitivity to JQ1 ± IR. The data show that JQ1 + IR decreased the clonogenic potential of pancreatic cancer cells more than either modality alone. This anticlonogenic effect was associated with increased DNA damage and decreased levels of RAD51. Further, lower levels of BRD2 or BRD4 increased sensitivity to JQ1 and JQ1 + IR, suggesting that pre-treatment levels of BRD2 or BRD4 may predict sensitivity to a BETi or to a BETi + IR. We suggest that a BETi + IR merits evaluation as therapy prior to surgery for pancreatic cancer patients with borderline resectable disease.
Development and Validation of Nomogram for Predicting Survival of Primary Liver Cancers Using Machine Learning
Authors: Chen Rui , Hou Beining , Qiu Shaotian , Shao Shuai , Yu Zhenjun , Zhou Feng , Guo Beichen , Li Yuhan , Zhang Yingwei , Han Tao
Published: June 2022

Background and Aims

Primary liver cancer (PLC) is a common malignancy with poor survival and requires long-term follow-up. Hence, nomograms need to be established to predict overall survival (OS) and cancer-specific survival (CSS) from different databases for patients with PLC.

Methods

Data of PLC patients were downloaded from Surveillance, Epidemiology, and End Results (SEER) and the Cancer Genome Atlas (TCGA) databases. The Kaplan Meier method and log-rank test were used to compare differences in OS and CSS. Independent prognostic factors for patients with PLC were determined by univariate and multivariate Cox regression analyses. Two nomograms were developed based on the result of the multivariable analysis and evaluated by calibration curves and receiver operating characteristic curves.

Results

OS and CSS nomograms were based on age, race, TNM stage, primary diagnosis, and pathologic stage. The area under the curve (AUC) was 0.777, 0.769, and 0.772 for 1-, 3- and 5-year OS. The AUC was 0.739, 0.729 and 0.780 for 1-, 3- and 5-year CSS. The performance of the two new models was then evaluated using calibration curves.

Conclusions

We systematically reviewed the prognosis of PLC and developed two nomograms. Both nomograms facilitate clinical application and may benefit clinical decision-making.
Multi-Omics Integration Analysis Identifies Lipid Disorder of a Non-Alcoholic Fatty Liver Disease (NAFLD) Mouse Model Improved by Zexie–Baizhu Decoction
Authors: Cao Yuhan , Shi Jingying , Song Luyao , Xu Junjiu , Lu Henglei , Sun Jianhua , Hou Jinjun , Chen Jing , Wu Wanying , Gong Likun
Published: June 2022

Non-alcoholic fatty liver disease (NAFLD) is an increasingly epidemic metabolic disease with complex pathogenesis. Multi-target therapy may be an effective strategy for NAFLD treatment, and traditional Chinese medicine (TCM) characterized by multi-ingredients and multi-targets has unique advantages in long-term clinical practice. Zexie–Baizhu (ZXBZ) decoction is a Chinese classical formula to treat body fluid disorders initially. Although many bioactive monomers from Zexie and Baizhu had been discovered to improve lipid disorders, limited research studies were focused on the aqueous decoction of ZXBZ, the original clinical formulation. In the current study, we identified 94% chemical composition of ZXBZ decoction and first discovered its hepaprotective effect in a gubra-amylin NASH (GAN) diet-induced NAFLD mouse model. Based on metabolomics and transcriptomics analyses, we speculated that lipid and glucose metabolisms might be regulated by ZXBZ decoction, which was further confirmed by improved dyslipidemia and hepatic steatosis in ZXBZ groups. Consistently with cross-omics analysis, we discovered ZXBZ decoction could influence two energy sensors, Sirt1 and AMPK, and subsequently affect related proteins involved in lipid biosynthesis, catabolism, and transport. In conclusion, ZXBZ decoction regulated energy sensors, consequently impeded lipogenesis, and promoted fatty acid oxidation (FAO) to alleviate lipid disorders and protect the liver in NAFLD models, which suggested ZXBZ decoction might be a promising treatment for NAFLD.
CPDR: An R Package of Recommending Personalized Drugs for Cancer Patients by Reversing the Individual’s Disease-Related Signature
Authors: Chen Ruzhen , Wang Xun , Deng Xinru , Chen Lanhui , Liu Zhongyang , Li Dong
Published: June 2022

Due to cancer heterogeneity, only some patients can benefit from drug therapy. The personalized drug usage is important for improving the treatment response rate of cancer patients. The value of the transcriptome of patients has been recently demonstrated in guiding personalized drug use, and the Connectivity Map (CMAP) is a reliable computational approach for drug recommendation. However, there is still no personalized drug recommendation tool based on transcriptomic profiles of patients and CMAP. To fill this gap, here, we proposed such a feasible workflow and a user-friendly R package—Cancer-Personalized Drug Recommendation (CPDR). CPDR has three features. 1) It identifies the individual disease signature by using the patient subgroup with transcriptomic profiles similar to those of the input patient. 2) Transcriptomic profile purification is supported for the subgroup with high infiltration of non-cancerous cells. 3) It supports in silico drug efficacy assessment using drug sensitivity data on cancer cell lines. We demonstrated the workflow of CPDR with the aid of a colorectal cancer dataset from GEO and performed the in silico validation of drug efficacy. We further assessed the performance of CPDR by a pancreatic cancer dataset with clinical response to gemcitabine. The results showed that CPDR can recommend promising therapeutic agents for the individual patient. The CPDR R package is available at https://github.com/AllenSpike/CPDR.
Anti-Inflammatory Effects of Natural Products on Cerebral Ischemia
Authors: Shang Yuanhong , Zhang Zhe , Tian Jinfeng , Li Xiaokai
Published: June 2022

Cerebral ischemia with high mortality and morbidity still requires the effectiveness of medical treatments. A growing number of investigations have shown strong links between inflammation and cerebral ischemia. Natural medicine’s treatment methods of cerebral ischemic illness have amassed a wealth of treatment experience and theoretical knowledge. This review summarized recent progress on the disease inflammatory pathways as well as 26 representative natural products that have been routinely utilized to treat cerebral ischemic injury. These natural products have exerted anti-inflammatory effects in cerebral ischemia based on their inflammatory mechanisms, including their inflammatory gene expression patterns and their related different cell types, and the roles of inflammatory mediators in ischemic injury. Overall, the combination of the potential therapeutic interventions of natural products with the inflammatory mechanisms will make them be applicable for cerebral ischemic patients in the future.
Amyloid-Like Aggregation in Native Protein and its Suppression in the Bio-Conjugated Counterpart
Authors: Mukhopadhyay Anasua , Stoev Iliya D. , King David. A. , Sharma Kamendra P. , Eiser Erika
Published: June 2022

Prevention of protein aggregation and thus stabilization of proteins has large biological and biotechnological implications. Here we introduce Dynamic Light Scattering (DLS) and DLS-based microrheology to show how native bovine serum albumin (nBSA) forms amyloid fibrils in weakly denaturing conditions as function of time, and how stoichiometric conjugation of BSA with polymer-surfactants (PSpBSA) protects the protein form such aggregation. Employing a combination of Thioflavin-T fluorescence, Fourier transform infrared spectroscopy and other methods, we show that nBSA forms filamentous aggregates with amyloid-like structure, while PSpBSA proteins remain fully dispersed with only minor changes in their folding state, even when continuously heated for up to 5 days in denaturation conditions at 65 °C. Time-resolved DLS-based microrheology studies demonstrate that suspensions of the filamentous nBSA aggregates become viscoelastic for concentrations ≥200 μM. Our results indicate that after 6 days in aggregation conditions, the elastic modulus G′(ω) of nBSA solutions went from zero initially to values of up to 3.6 Pa, indicating that the filaments become long enough to form an entangled, viscoelastic network. Interestingly, heating 200 μM native BSA solutions at 65 °C for 2 days in Eppendorf tubes resulted in self-standing films rather than dispersed filaments. These films exhibited strong ThT-fluorescence intensities and a predominant β-sheet secondary structure in FTIR studies, suggesting that the self-standing microstructure of the film resulted from hierarchical self-assembly of the amyloid fibrils.
Smooth Muscle Cell—Macrophage Interactions Leading to Foam Cell Formation in Atherosclerosis: Location, Location, Location
Authors: Xiang Pinhao , Blanchard Valentin , Francis Gordon A.
Published: June 2022

Cholesterol-overloaded cells or “foam cells” in the artery wall are the biochemical hallmark of atherosclerosis, and are responsible for much of the growth, inflammation and susceptibility to rupture of atherosclerotic lesions. While it has previously been thought that macrophages are the main contributor to the foam cell population, recent evidence indicates arterial smooth muscle cells (SMCs) are the source of the majority of foam cells in both human and murine atherosclerosis. This review outlines the timeline, site of appearance and proximity of SMCs and macrophages with lipids in human and mouse atherosclerosis, and likely interactions between SMCs and macrophages that promote foam cell formation and removal by both cell types. An understanding of these SMC-macrophage interactions in foam cell formation and regression is expected to provide new therapeutic targets to reduce the burden of atherosclerosis for the prevention of coronary heart disease, stroke and peripheral vascular disease.
Aerosol Transport Modeling: The Key Link Between Lung Infections of Individuals and Populations
Authors: Darquenne Chantal , Borojeni Azadeh A.T. , Colebank Mitchel J. , Forest M. Gregory , Madas Balázs G. , Tawhai Merryn , Jiang Yi
Published: June 2022

The recent COVID-19 pandemic has propelled the field of aerosol science to the forefront, particularly the central role of virus-laden respiratory droplets and aerosols. The pandemic has also highlighted the critical need, and value for, an information bridge between epidemiological models (that inform policymakers to develop public health responses) and within-host models (that inform the public and health care providers how individuals develop respiratory infections). Here, we review existing data and models of generation of respiratory droplets and aerosols, their exhalation and inhalation, and the fate of infectious droplet transport and deposition throughout the respiratory tract. We then articulate how aerosol transport modeling can serve as a bridge between and guide calibration of within-host and epidemiological models, forming a comprehensive tool to formulate and test hypotheses about respiratory tract exposure and infection within and between individuals.
Aerosol Impacts on Water Relations of Camphor (Cinnamomum camphora)
Authors: Chi Chia-Ju Ellen , Zinsmeister Daniel , Lai I-Ling , Chang Shih-Chieh , Kuo Yau-Lun , Burkhardt Jürgen
Published: June 2022

Major parts of anthropogenic and natural aerosols are hygroscopic and deliquesce at high humidity, particularly when depositing to leaf surfaces close to transpiring stomata. Deliquescence and subsequent salt creep may establish thin, extraordinary pathways into the stomata, which foster stomatal uptake of nutrients and water but may also cause stomatal liquid water loss by wicking. Such additional water loss is not accompanied by a wider stomatal aperture with a larger CO2 influx and hypothetically reduces water use efficiency (WUE). Here, the possible direct impacts of aerosols on physical and physiological parameters of camphor (Cinnamomum camphora) were studied (i) in a greenhouse experiment using aerosol exclusion and (ii) in a field study in Taiwan, comparing trees at two sites with different aerosol regimes. Scanning electron microscopy (SEM) images showed that leaves grown under aerosol exclusion in filtered air (FA) were lacking the amorphous, flat areas that were abundant on leaves grown in ambient air (AA), suggesting salt crusts formed from deliquescent aerosols. Increasing vapor pressure deficit (VPD) resulted in half the Ball-Berry slope and double WUE for AA compared to FA leaves. This apparent contradiction to the wicking hypothesis may be due to the independent, overcompensating effect of stomatal closure in response to VPD, which affects AA more than FA stomata. Compared to leaves in a more polluted region in the Taiwanese Southwest, NaCl aerosols dominated the leaf surface conditions on mature camphor trees in Eastern Taiwan, while the considerably lower contact angles and the 2.5 times higher minimum epidermal conductances might have come from organic surfactants. Interpretations of SEM images from leaf surface microstructures should consider amorphous areas as possible indicators of aerosol deposition and other hygroscopic material. The amount and type of the material determine the resulting impacts on plant water relations, together with the surrounding atmosphere and ecophysiological traits.
R2R3-MYBs in Durum Wheat: Genome-Wide Identification, Poaceae-Specific Clusters, Expression, and Regulatory Dynamics Under Abiotic Stresses
Authors: Blanco Emanuela , Curci Pasquale Luca , Manconi Andrea , Sarli Adele , Zuluaga Diana Lucia , Sonnante Gabriella
Published: June 2022

MYB transcription factors (TFs) represent one of the biggest TF families in plants, being involved in various specific plant processes, such as responses to biotic and abiotic stresses. The implication of MYB TFs in the tolerance mechanisms to abiotic stress is particularly interesting for crop breeding, since environmental conditions can negatively affect growth and productivity. Wheat is a worldwide-cultivated cereal, and is a major source of plant-based proteins in human food. In particular, durum wheat plays an important role in global food security improvement, since its adaptation to hot and dry conditions constitutes the base for the success of wheat breeding programs in future. In the present study, a genome-wide identification of R2R3-MYB TFs in durum wheat was performed. MYB profile search and phylogenetic analyses based on homology with Arabidopsis and rice MYB TFs led to the identification of 233 R2R3-TdMYB (Triticum durum MYB). Three Poaceae-specific MYB clusters were detected, one of which had never been described before. The expression of eight selected genes under different abiotic stress conditions, revealed that most of them responded especially to salt and drought stress. Finally, gene regulatory network analyses led to the identification of 41 gene targets for three TdR2R3-MYBs that represent novel candidates for functional analyses. This study provides a detailed description of durum wheat R2R3-MYB genes and contributes to a deeper understanding of the molecular response of durum wheat to unfavorable climate conditions.
Intelligent Monitoring System of Migratory Pests Based on Searchlight Trap and Machine Vision
Authors: Sun Guojia , Liu Shuhua , Luo Haolun , Feng Zelin , Yang Baojun , Luo Ju , Tang Jian , Yao Qing , Xu Jiajun
Published: June 2022

Three species of rice migratory pests (Cnaphalocrocis medinalis, Sogatella furcifera, and Nilaparvata lugens) cause severe yield and economic losses to rice food every year. It is important that these pests are timely and accurately monitored for controlling them and ensuring food security. Insect radar is effective monitoring equipment for migratory pests flying at high altitude. But insect radar is costly and has not been widely used in fields. Searchlight trap is an economical device, which uses light to trap migratory pests at high altitude. But the trapped pests need to be manually identified and counted from a large number of non-target insects, which is inefficient and labor-intensive. In order to replace manual identification of migratory pests, we develop an intelligent monitoring system of migratory pests based on searchlight trap and machine vision. This system includes a searchlight trap based on machine vision, an automatic identification model of migratory pests, a Web client, and a cloud server. The searchlight trap attracts the high-altitude migratory insects through lights at night and kills them with the infrared heater. All trapped insects are dispersed through a multiple layers of insect conveyor belts and a revolving brush. The machine vision module collects the dispersed insect images and sends them to the cloud server through 4G network. The improved model YOLO-MPNet based on YOLOv4 and SENet channel attention mechanism is proposed to detect three species of migratory pests in the images. The results show that the model effectively improves the detection effect of three migratory pests. The precision is 94.14% for C. medinalis, 85.82% for S. furcifera, and 88.79% for N. lugens. The recall is 91.99% for C. medinalis, 82.47% for S. furcifera, and 85.00% for N. lugens. Compared with some state-of-the-art models (Faster R-CNN, YOLOv3, and YOLOv5), our model shows a low false detection and missing detection rates. The intelligent monitoring system can real-timely and automatically monitor three migratory pests instead of manually pest identification and count, which can reduce the technician workload. The trapped pest images and historical data can be visualized and traced, which provides reliable evidence for forecasting and controlling migratory pests.
Covering the Combinatorial Design Space of Multiplex CRISPR/Cas Experiments in Plants
Authors: Van Huffel Kirsten , Stock Michiel , Ruttink Tom , De Baets Bernard
Published: June 2022

Over the past years, CRISPR/Cas-mediated genome editing has revolutionized plant genetic studies and crop breeding. Specifically, due to its ability to simultaneously target multiple genes, the multiplex CRISPR/Cas system has emerged as a powerful technology for functional analysis of genetic pathways. As such, it holds great potential for application in plant systems to discover genetic interactions and to improve polygenic agronomic traits in crop breeding. However, optimal experimental design regarding coverage of the combinatorial design space in multiplex CRISPR/Cas screens remains largely unexplored. To contribute to well-informed experimental design of such screens in plants, we first establish a representation of the design space at different stages of a multiplex CRISPR/Cas experiment. We provide two independent computational approaches yielding insights into the plant library size guaranteeing full coverage of all relevant multiplex combinations of gene knockouts in a specific multiplex CRISPR/Cas screen. These frameworks take into account several design parameters (e.g., the number of target genes, the number of gRNAs designed per gene, and the number of elements in the combinatorial array) and efficiencies at subsequent stages of a multiplex CRISPR/Cas experiment (e.g., the distribution of gRNA/Cas delivery, gRNA-specific mutation efficiency, and knockout efficiency). With this work, we intend to raise awareness about the limitations regarding the number of target genes and order of genetic interaction that can be realistically analyzed in multiplex CRISPR/Cas experiments with a given number of plants. Finally, we establish guidelines for designing multiplex CRISPR/Cas experiments with an optimal coverage of the combinatorial design space at minimal plant library size.
Development of a High Oleic Cardoon Cell Culture Platform by SAD Overexpression and RNAi-Mediated FAD2.2 Silencing
Authors: Cappetta Elisa , De Palma Monica , D’Alessandro Rosa , Aiello Alessandra , Romano Raffaele , Graziani Giulia , Ritieni Alberto , Paolo Dario , Locatelli Franca , Sparvoli Francesca , Docimo Teresa , Tucci Marina
Published: June 2022

The development of effective tools for the sustainable supply of phyto-ingredients and natural substances with reduced environmental footprints can help mitigate the dramatic scenario of climate change. Plant cell cultures-based biorefineries can be a technological advancement to face this challenge and offer a potentially unlimited availability of natural substances, in a standardized composition and devoid of the seasonal variability of cultivated plants. Monounsaturated (MUFA) fatty acids are attracting considerable attention as supplements for biodegradable plastics, bio-additives for the cosmetic industry, and bio-lubricants. Cardoon (Cynara cardunculus L. var. altilis) callus cultures accumulate fatty acids and polyphenols and are therefore suitable for large-scale production of biochemicals and valuable compounds, as well as biofuel precursors. With the aim of boosting their potential uses, we designed a biotechnological approach to increase oleic acid content through Agrobacterium tumefaciens-mediated metabolic engineering. Bioinformatic data mining in the C. cardunculus transcriptome allowed the selection and molecular characterization of SAD (stearic acid desaturase) and FAD2.2 (fatty acid desaturase) genes, coding for key enzymes in oleic and linoleic acid formation, as targets for metabolic engineering. A total of 22 and 27 fast-growing independent CcSAD overexpressing (OE) and CcFAD2.2 RNAi knocked out (KO) transgenic lines were obtained. Further characterization of five independent transgenic lines for each construct demonstrated that, successfully, SAD overexpression increased linoleic acid content, e.g., to 42.5%, of the relative fatty acid content, in the CcSADOE6 line compared with 30.4% in the wild type (WT), whereas FAD2.2 silencing reduced linoleic acid in favor of the accumulation of its precursor, oleic acid, e.g., to almost 57% of the relative fatty acid content in the CcFAD2.2KO2 line with respect to 17.7% in the WT. Moreover, CcSADOE6 and CcFAD2.2KO2 were also characterized by a significant increase in total polyphenolic content up to about 4.7 and 4.1 mg/g DW as compared with 2.7 mg/g DW in the WT, mainly due to the accumulation of dicaffeoyl quinic and feruloyl quinic acids. These results pose the basis for the effective creation of an engineered cardoon cells-based biorefinery accumulating high levels of valuable compounds from primary and specialized metabolism to meet the industrial demand for renewable and sustainable sources of innovative bioproducts.
Metabolomics Analysis Provides New Insights Into the Molecular Mechanisms of Parasitic Plant Dodder Elongation in vitro
Authors: Zhang Yuexia , Zhang Yushi , Jiang Linjian , Li Zhaohu , Zhang Mingcai
Published: June 2022

Dodder (Cuscuta spp.) species are obligate parasitic flowering plants that totally depend on host plants for growth and reproduction and severely suppress hosts’ growth. As a rootless and leafless plant, excised dodder shoots exhibit rapid growth and elongation for several days to hunt for new host stems, and parasitization could be reestablished. This is one unique ability of the dodder to facilitate its success in nature. Clearly, excised dodder stems have to recycle stored nutrients to elongate as much as possible. However, the mechanism of stored nutrient recycling in the in vitro dodder shoots is still poorly understood. Here, we found that dodder is a carbohydrate-rich holoparasitic plant. During the in vitro dodder shoot development, starch was dramatically and thoroughly degraded in the dodder shoots. Sucrose derived from starch degradation in the basal stems was transported to the shoot tips, in which EMP and TCA pathways were activated to compensate for carbon demand for the following elongation according to the variations of sugar content related to the crucial gene expression, and the metabolomics analysis. Additionally, antioxidants were significantly accumulated in the shoot tips in contrast to those in the basal stems. The variations of phytohormones (jasmonic acid, indole-3-acetic acid, and abscisic acid) indicated that they played essential roles in this process. All these data suggested that starch and sucrose degradation, EMP and TCA activation, antioxidants, and phytohormones were crucial and associated with the in vitro dodder shoot elongation.
Linking Leader’s Behavioral Integrity With Workplace Ostracism: A Mediated-Moderated Model
Authors: Chaman Seemab , Shaheen Sadia , Hussain Asrar
Published: June 2022

Drawing on the social exchange theory (SET) and research on leadership influences, we developed and inspected a multilevel model to test the conditions and mechanisms through which a leader’s behavioral integrity (LBI) deters workplace ostracism (WO). We used trust as a mediator and the narcissistic personality of a leader as a boundary condition in the connection between a LBI and WO. Data were collected from 249 employees working in different five- and four-star hotels in Pakistan over three time lags. The statistical results revealed that a LBI reduces WO. Additionally, a LBI has an indirect effect on WO through interpersonal trust. We did not find statistical support for the moderating role of the narcissistic personality of a leader in the relationship between a LBI and WO. Implications, along with limitations and future research directions, are also discussed.