bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of LASSO Regression and Tree-Based Models for Delayed Cerebral Ischemia in Elderly Patients With Subarachnoid Hemorrhage
Authors: Hu Ping , Liu Yangfan , Li Yuntao , Guo Geng , Su Zhongzhou , Gao Xu , Chen Junhui , Qi Yangzhi , Xu Yang , Yan Tengfeng , Ye Liguo , Sun Qian , Deng Gang , Zhang Hongbo , Chen Qianxue
Published: March 2022

Backgrounds

As a most widely used machine learning method, tree-based algorithms have not been applied to predict delayed cerebral ischemia (DCI) in elderly patients with aneurysmal subarachnoid hemorrhage (aSAH). Hence, this study aims to develop the conventional regression and tree-based models and determine which model has better prediction performance for DCI development in hospitalized elderly patients after aSAH.

Methods

This was a multicenter, retrospective, observational cohort study analyzing elderly patients with aSAH aged 60 years and older. We randomly divided the multicentral data into model training and validation cohort in a ratio of 70–30%. One conventional regression and tree-based model, such as least absolute shrinkage and selection operator (LASSO), decision tree (DT), random forest (RF), and eXtreme Gradient Boosting (XGBoost), was developed. Accuracy, sensitivity, specificity, area under the precision-recall curve (AUC-PR), and area under the receiver operating characteristic curve (AUC-ROC) with 95% CI were employed to evaluate the model prediction performance. A DeLong test was conducted to calculate the statistical differences among models. Finally, we figured the importance weight of each feature to visualize the contribution on DCI.

Results

There were 111 and 42 patients in the model training and validation cohorts, and 53 cases developed DCI. According to AUC-ROC value in the model internal validation, DT of 0.836 (95% CI: 0.747–0.926, p = 0.15), RF of 1 (95% CI: 1–1, p < 0.05), and XGBoost of 0.931 (95% CI: 0.885–0.978, p = 0.01) outperformed LASSO of 0.793 (95% CI: 0.692–0.893). However, the LASSO scored a highest AUC-ROC value of 0.894 (95% CI: 0.8–0.989) than DT of 0.764 (95% CI: 0.6–0.928, p = 0.05), RF of 0.821 (95% CI: 0.683–0.959, p = 0.27), and XGBoost of 0.865 (95% CI: 0.751–0.979, p = 0.69) in independent external validation. Moreover, the LASSO had a highest AUC-PR value of 0.681 than DT of 0.615, RF of 0.667, and XGBoost of 0.622 in external validation. In addition, we found that CT values of subarachnoid clots, aneurysm therapy, and white blood cell counts were the most important features for DCI in elderly patients with aSAH.

Conclusions

The LASSO had a superior prediction power than tree-based models in external validation. As a result, we recommend the conventional LASSO regression model to predict DCI in elderly patients with aSAH.
Integrating Philosophy of Understanding With the Cognitive Sciences
Authors: Khalifa Kareem , Islam Farhan , Gamboa J. P. , Wilkenfeld Daniel A. , Kostić Daniel
Published: March 2022

We provide two programmatic frameworks for integrating philosophical research on understanding with complementary work in computer science, psychology, and neuroscience. First, philosophical theories of understanding have consequences about how agents should reason if they are to understand that can then be evaluated empirically by their concordance with findings in scientific studies of reasoning. Second, these studies use a multitude of explanations, and a philosophical theory of understanding is well suited to integrating these explanations in illuminating ways.
Dietary Phospholipid-Bound Conjugated Linoleic Acid and Docosahexaenoic Acid Incorporation Into Fetal Liver and Brain Modulates Fatty Acid and N-Acylethanolamine Profiles
Authors: Murru Elisabetta , Carta Gianfranca , Manca Claudia , Saebo Asgeir , Santoni Michele , Mostallino Rafaela , Pistis Marco , Banni Sebastiano
Published: March 2022

We evaluated whether maternal intake of conjugated linoleic acid (CLA) and docosahexaenoic acid (DHA) in the phospholipid (PL) form (CLA-DHA PL) affects maternal and fetal brain and liver fatty acids (FAs) profile and the biosynthesis of FA-derived bioactive lipid mediators N-acylethanolamines (NAEs) involved in several neurophysiological functions. We fed rat dams during the first 2/3 of their pregnancy a CLA-DHA PL diet containing PL-bound 0.5% CLA and 0.2% DHA. FA and NAE profiles were analyzed in maternal and fetal liver and brain by Liquid Chromatography diode array detector (LC-DAD) and MS/MS in line. We found that CLA and DHA crossed the placenta and were readily incorporated into the fetal liver and brain. CLA metabolites were also found abundantly in fetal tissues. Changes in the FA profile induced by the CLA-DHA PL diet influenced the biosynthesis of NAE derived from arachidonic acid (ARA; N-arachidonoylethanolamine, AEA) and from DHA (N-docosahexaenoylethanolamine, DHEA). The latter has been previously shown to promote synaptogenesis and neuritogenesis. The reduced tissue n6/n3 ratio was associated to a significant decrease of AEA levels in the fetal and maternal liver and an increase of DHEA in the fetal and maternal liver and in the fetal brain. Maternal dietary CLA-DHA PL by promptly modifying fetal brain FA metabolism, and thereby, increasing DHEA, might represent an effective nutritional strategy to promote neurite growth and synaptogenesis and protect the offspring from neurological and psychiatric disorders with neuroinflammatory and neurodegenerative basis during the critical prenatal period.
Insoluble Dietary Fibers From By-Products of Edible Fungi Industry: Basic Structure, Physicochemical Properties, and Their Effects on Energy Intake
Authors: Tian Baoming , Pan Yizhu , Wang Jian , Cai Ming , Ye Bangwei , Yang Kai , Sun Peilong
Published: March 2022

With the rapid development of the edible fungi industry in the world, especially in China, the resource utilization of edible fungi by-products has become an urgent problem for the industry's sustainable development. The waste residue of edible fungi after polysaccharide extraction by water accounts for a large proportion, which contains a large amount of water-insoluble dietary fiber (IDF). At present, the extracted residue is generally treated as fertilizer or solid waste, which not only pollutes the environment, but wastes resources too. In order to develop these by-products, expand their potential utilization in the food industry, the structure characterization, physicochemical properties, and the influence of IDF on dietary energy intake were studied. The IDF from the residues of polysaccharides extracted from four edible fungi was extracted using the Association of Official Analytical Chemists (AOAC) method. The results showed that IDF in the four kinds of edible fungi residues was similar in composition but different in texture. Cellulose and hemicellulose are the main IDF extracted from four kinds of edible fungi. Among them, Hericium erinaceus is the softest without obvious granular texture, following Lentinus edodes, while Ganoderma lucidum and Grifola frondosa have a relatively hard texture. The yield of four kinds of IDF from high to low came from Ganoderma lucidum, Hericium erinaceus, Lentinus edodes, and Grifola frondosa. Fourier transform IR (FTIR) and X-ray diffraction (XRD) spectra showed that the four IDFs had similar functional groups and all of them contained a large amount of cellulose. Physical and chemical analysis showed that all the four IDFs had certain water holding capacity, water binding capacity, and oil holding capacity. In-vitro digestion experiments showed that the four IDFs could inhibit the digestion of starch and fat to a certain extent. By-products of edible fungi are an ideal material for the recovery of IDFs, which have the potential to be processed into functional food materials due to their physicochemical properties and physiological functions.
Fbw7 Inhibits the Progression of Activated B-Cell Like Diffuse Large B-Cell Lymphoma by Targeting the Positive Feedback Loop of the LDHA/lactate/miR-223 Axis
Authors: Yao Su , Guo Tairan , Zhang Fen , Chen Yu , Xu Fangping , Luo Donglan , Luo Xinlan , Lin Danyi , Chen Wendan , Li Zhi , Liu Yanhui
Published: March 2022

Background

F-box and WD repeat domain-containing 7 (Fbw7) is well known as a tumor suppressor and ubiquitin ligase which targets a variety of oncogenic proteins for proteolysis. We previously reported that Fbw7 promotes apoptosis in diffuse large B-cell lymphoma (DLBCL) through Fbw7-mediated ubiquitination of Stat3. This study aimed to identify the mechanism of Fbw7-mediated aerobic glycolysis reprogramming in DLBCL.

Methods

Expression levels of Fbw7 and Lactate Dehydrogenase A (LDHA) in human DLBCL samples were evaluated by immunohistochemistry. Crosstalk between Fbw7 and LDHA signaling was analyzed by co-immunoprecipitation, ubiquitination assay, western blotting and mRNA quanlitative analyses. In vitro and in vivo experiments were used to assess the effect of the Fbw7-mediated LDHA/lactate/miR-223 axis on DLBCL cells growth.

Results

Fbw7 could interact with LDHA to trigger its ubiquitination and degradation. Inversely, lactate negatively regulated Fbw7 via trigging the expression of miR-223, which targeted Fbw7 3’-UTR to inhibit its expression. In vivo and in vitro experiments revealed that miR-223 promoted tumor growth and that the effects of miR-223 on tumor growth were primarily related to the inhibition of Fbw7-mediated LDHA’s ubiquitination.

Conclusions

We demonstrated that the ubiquitin-ligase Fbw7 played a key role in LDHA-related aerobic glycolysis reprogramming in DLBCL. Our study uncovers a negative functional loop consisting of a Fbw7-mediated LDHA/lactate/miR-223 axis, which may support the future ABC-DLBCL therapy by targeting LDHA-related inhibition.
The AlkB Family: Potential Prognostic Biomarkers and Therapeutic Targets in Glioblastoma
Authors: Feng Songshan , Xu Zhijie , Peng Jinwu , Zhang Mingyu
Published: March 2022

The AlkB family of Fe (II) and α-ketoglutarate-dependent dioxygenases works by removing alkyl substituents from alkylation-damaged nucleic acid bases through oxidative dealkylation, subsequently affecting tumor progression and patient prognosis. However, the specific roles of the AlkB family in Glioblastoma remain to be elucidated. By taking advantage of the abundant bioinformatics databases, such as GEPIA2, cBioPortal and TIMER, we performed a comprehensive analysis of the AlkB family in GBM, and managed to identify the significant prognostic hallmarks and therapeutic targets within this family. We found that the expression levels of ALKBH2 and ALKBH8 were significantly up-regulated in GBM compared with normal tissues. Meanwhile, the patients with high levels of ALKBH2 and ALKBH8 possessed significant poor overall survival (OS). In addition, the results suggested that the biological function of the AlkB family was closely related to DNA damage repair, cell metabolism, cell proliferation and tumor immune infiltration in GBM. Furthermore, the high expression of ALKBH8 in GBM was verified by immunohistochemistry. Taken together, this study could provide meaningful information about the aberrant AlkB family associated with GBM initiation and progression, and help clinicians precisely predict patient survival and select alternative therapeutic drugs.
Cytokines in the Pathogenesis of Large Granular Lymphocytic Leukemia
Authors: Isabelle Colleen , Boles Amy , Chakravarti Nitin , Porcu Pierluigi , Brammer Jonathan , Mishra Anjali
Published: March 2022

Large granular lymphocytic leukemia (LGLL) is a lymphoproliferative disorder of older adults characterized by the clonal expansion of cytotoxic T/natural killer cells due to constitutive pro-survival signaling. In recent years, it has become clear that cytokines and their receptors are aberrantly expressed in LGLL cells. The exact initiation process of LGLL is unknown, although several cytokine-driven mechanisms have emerged. Elevated levels of several cytokines, including interleukin-15 (IL-15) and platelet-derived growth factor (PDGF), have been described in LGLL patients. Evidence from humans and animal models has shown that cytokines may also contribute to the co-occurrence of a wide range of autoimmune diseases seen in patients with LGLL. The goal of this review is to provide a comprehensive analysis of the link between cytokines and pro-survival signaling in LGLL and to discuss the various strategies and research approaches that are being utilized to study this link. This review will also highlight the importance of cytokine-targeted therapeutics in the treatment of LGLL.
BAP31 Regulates Wnt Signaling to Modulate Cell Migration in Lung Cancer
Authors: Li Tianye , Hao Zhenzhen , Tang Zihan , Li Chunting , Cheng Linglin , Wang Tao , Zhu Xiaojin , He Yunhao , Huang Yongye , Wang Bing
Published: March 2022

B-cell receptor-associated protein 31 (BAP31) has been shown to overexpress in a wide range type of cancers. The present study aims to investigate the role of BAP31 on migration in lung cancer. Results showed that the migration of BAP31 knockdown cells was weaken than the control cells. Applying TGFβ to treat BAP31 knockdown cells could reduce cell migration. The enhancement on proliferation by TGFβ treatment was downregulated after BAP31 knockdown. The cell death and G0/G1 phase arrest was increased in the cells with TGFβ and BAP31 siRNA treatment when compared with TGFβ treatment alone. Gene expression analysis showed that Bax/Bcl2, MLKL and LC3 was upregulated in the cells with combinatorial treatment of TGFβ and BAP31 siRNA. In addition, BAP31 was shown to regulate multiple signaling pathways, especially for Wnt signaling. It found that BAP31 knockdown cells treated with TGFβ decreased β-catenin cytosolic expression and nuclear localization. Wnt signaling activator BIO could restore the downregulation of proliferation by BAP31 knockdown. This finding suggested that BAP31 regulated cancer cell migration is possibly involved with cell death mechanisms and Wnt signaling.
Poincaré Plot Is Useful for Distinguishing Vasovagal Syncope From Postural Tachycardia Syndrome in Children
Authors: Yuan Piaoliu , Lian Zhouhui , Wang Yuanyuan , Wang Yaru , Zhang Chunyu , Du Junbao , Huang Yaqian , Liao Ying
Published: March 2022

Objectives

To explore the role of the Poincaré plot derived from a 24-hour Holter recording in distinguishing vasovagal syncope (VVS) from postural tachycardia syndrome (POTS) in pediatric patients.

Materials and Methods

Pediatric patients with VVS or POTS, hospitalized in Peking University First Hospital between January 2012 and December 2018, were included in a derivation study. The transverse axis (T), longitudinal axis (L), T/L ratio, product T × L, distance between the origin and the proximal end of the longitudinal axis (pro-D), and distance between the origin and distal end of the longitudinal axis (dis-D) of the Poincaré plot were compared between the VVS and POTS groups, and the differential diagnostic performance of the above-mentioned graphic parameters was evaluated using receiver operating characteristic curve analysis. A validation study was conducted in pediatric patients hospitalized between January 2019 and December 2020.

Results

In school-aged children, the T, L, T/L, T × L, and dis-D values of patients with VVS were greater than those of patients with POTS; in adolescents, the T, T/L, T × L, and pro-D values of patients with VVS were greater than those of patients with POTS. Using a T/L cut-off value of 0.3 to distinguish between the two diseases, the sensitivity and specificity were 91.0 and 90.5%, respectively, for the total participants; 91.6 and 88.9%, respectively, for the school-aged children; and 82.1 and 95.7%, respectively, for the adolescents. In the validation study, a T/L cut-off value of 0.3 yielded an accuracy, sensitivity, and specificity of 81.8, 87.2, and 77.6%, respectively, in the total participants; 76.5, 82.6, and 71.4%, respectively, in the school-aged children; and 89.2, 93.8, and 85.7%, respectively, in the adolescents, in distinguishing VVS from POTS validated by clinical diagnosis.

Conclusions

The graphic parameters of the Poincaré plot are significantly different between VVS and POTS in pediatric patients, and the T/L of the Poincaré plot may be a useful measure to help differentiate VVS from POTS in children and adolescents.
Electromagnetic Waves Can Help Improve the Rate of Increase of Milk Feeds Per Day in Premature Infants With Necrotizing Enterocolitis: A Pilot Trial
Authors: Liu Xuexiu , Zhang Xianhong , Li Luquan , Wang Jianhui , Wu Liping
Published: March 2022

Objective

To evaluate the effects of electromagnetic waves generated by a commercial medical electromagnetic instrument (trade name, TDP, the Chinese phonetic abbreviation of “Te-ding Dian-ci-bo Pu”) as an adjuvant to improve the rate of increase of milk feeds per day by premature infants with necrotizing enterocolitis (NEC).

Methods

This study was a prospective randomized clinical trial. A total of 103 premature infants were diagnosed with NEC II, but there was no need for surgery. The infants were randomly divided into the TDP intervention group and the control group by a randomized method using SPSS 24.0. The patients in the TDP intervention group were treated with TDP irradiation and routine interventions; those in the control group were treated with routine interventions. The rate of increase of milk feeds per day, the time to achieve total gastrointestinal nutrition, the velocity of weight gain, and the complication incidence rate were recorded and compared.

Results

The rate of increase of milk feeds per day in the TDP intervention group was significantly greater than that in the control group [14.51 (11.58~22.11) ml/kg/d vs. 10.15 (6.15~15.87) ml/kg/d, P = 0.002]. Compared to the control group, the time to achieve total gastrointestinal nutrition (21.45 ± 1.87 d vs. 36.43 ± 2.585 d, P = 0.000) and the velocity of weight gain (19.65 ± 15.27% vs. 13.68 ± 7.15%, P = 0.013) in the TDP intervention group were substantially better than those in the control group. The complication incidence rate was not significantly different between the two groups (P > 0.05).

Conclusion

Treatment with TDP-generated electromagnetic waves improved the volume of milk consumed per day in premature infants with NEC II and were conducive to improving their clinical outcomes.
Transition From Parenteral to Enteral Nutrition and Postnatal Growth in Very Preterm Infants During Their First 28 Days of Life
Authors: Wang Na , Zhang Jia , Wang Bo , Yu Zhangbin , Han Shuping , Wang Huaiyan , Chen Rongrong , Gu Li , Gao Yan , Hou Weiwei , Lu Xingxing
Published: March 2022

Background

Nutrition practices for preterm infants during the first few weeks of life can be divided into three phases: the parenteral nutrition (PN), enteral nutrition (EN), and transition (TN) phases; the TN phase includes both PN and EN. Our purpose was to analyze nutrition practices for very preterm infants during the TN phase and their association with the infants' growth during the first 28 days of life.

Methods

Data from 268 very preterm infants <32 weeks old from six neonatal intensive care units were analyzed retrospectively. The TN phase was defined as enteral feedings of 30-120 ml/kg/d. Postnatal growth failure (PGF) was defined as a 28-day growth velocity <15 g/kg/d. Differences in protein and energy intake between the PGF and non-PGF groups during the TN phase were calculated, and risk factors for PGF were identified using multivariate regression analysis.

Results

The total protein (parenteral + enteral) intake during the TN was 3.16 (2.89, 3.47) g/kg/d, which gradually decreased as the enteral feeding volume increased in the TN phase. The total energy (parenteral + enteral) intake during the TN phase was 115.72 (106.98, 122.60) kcal/kg/d. The PGF group had a lower total protein intake (parenteral + enteral) than the non-PGF group had [3.09 (2.85, 3.38) g/kg/d vs. 3.27 (3.06, 3.57) g/kg/d, P = 0.007, respectively]. No significant difference was found in energy intake during the TN phase. The variables associated with PGF included a lower total protein (parenteral + enteral) intake, a smaller day of age at the end of the TN phase, and a higher birth weight z-score.

Conclusion

Increasing the total protein intake (parenteral + enteral) during the TN could reduce the incidence of PGF.
Predictors of Low Cardiac Output Syndrome in Infants After Open-Heart Surgery
Authors: Zou Liang , Yu Di , Wang Ruonan , Cun Yueshuang , Li Yaping , Wang Qingfeng , Shu Yaqin , Mo Xuming
Published: March 2022

Objective

To evaluate the predictors of low cardiac output syndrome (LCOS) in infants with congenital heart disease (CHD) after cardiopulmonary bypass (CPB).

Study design

A total of 217 infants were enrolled and classified according to whether they developed LCOS after cardiac surgery. Each infant's preoperative and intraoperative clinical variables were collected.

Results

The incidence of LCOS was 28.11% in our study. The univariate analysis showed that the LCOS group was younger than the non-LCOS group (25.69 ± 25.01 days vs. 44.45 ± 26.97 days, P < 0.001), with a higher proportion of neonates (60.7 vs. 27.6%, P < 0.001) and a higher proportion of patients with a RACHS-1 score ≥4 (50.8 vs. 17.9%, P < 0.001). A lower weight (3.70 ± 0.74 vs. 4.23 ± 1.10 kg, P = 0.001), longer ACC time (61.96 ± 21.44 min vs. 41.06 ± 18.37 min, P < 0.001) and longer CPB time (131.54 ± 67.21 min vs. 95.78 ± 62.67 min, P < 0.001) were found in the LCOS group. The levels of free triiodothyronine (FT3) (4.55 ± 1.29 pmol/L vs. 5.18 ± 1.42 pmol/L, P = 0.003) and total triiodothyronine (TT3) (1.80 ± 0.56 nmol/L vs. 1.98 ± 0.54 nmol/L, P = 0.026) were also lower in the LCOS group. The multivariate binary logistic regression analysis and receiver operating characteristic (ROC) indicated that the ACC time, FT3 level and body weight were independent predictors of LCOS.

Conclusions

In our patient population, we first propose that preoperative FT3 can predict the occurrence of postoperative LCOS. ACC time, FT3 level and body weight are independent predictors of LCOS and maybe helpful in reducing the incidence of postoperative LCOS in the future.
A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma–LuDO-N
Authors: Sundquist Fredrik , Georgantzi Kleopatra , Jarvis Kirsten Brunsvig , Brok Jesper , Koskenvuo Minna , Rascon Jelena , van Noesel Max , Grybäck Per , Nilsson Joachim , Braat Arthur , Sundin Mikael , Wessman Sandra , Herold Nikolas , Hjorth Lars , Kogner Per , Granberg Dan , Gaze Mark , Stenman Jakob
Published: March 2022

Background

Half the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent 177Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. “A phase II trial of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N” (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule.

Methods

The LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022.

Results

The pediatric use of the Investigational Medicinal Product (IMP) 177Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (68Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3–5 years.

Discussion

In this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.
Metabonomics Study in Mice With Learning and Memory Impairment on the Intervention of Essential Oil Extracted From Cinnamomum camphora Chvar. Borneol
Authors: Tang Yin , Lv Xiaofan , Liu Yumin , Cui Donghong , Wu Yani
Published: March 2022

Our objective was to explore the mechanism of essential oil that was extracted from Cinnamomum camphora chvar. Borneol (Borneol essential oil) for improving learning and memory impairment in mice. Brain tissue and plasma samples of a normal group, a model group, a Borneol essential oil group and a reference group were detected using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) in order to find differential metabolites and analyze metabolic pathways. Results showed that there were 11 different metabolites --including glycine and azelaic acid --in plasma samples, and that there were 26 different metabolites--including adenine and aspartic acid --in brain tissue samples. These metabolites are involved in phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, beta-alanine metabolism, glyoxylate acid and dicarboxylate metabolism, and aminoacyl-tRNA biosynthesis. Thus, Borneol essential oil may improve learning and memory impairment by regulating amino acid metabolism and/or neurotransmitter changes.
Regression of Liver Steatosis Following Phosphatidylcholine Administration: A Review of Molecular and Metabolic Pathways Involved
Authors: Osipova D. , Kokoreva K. , Lazebnik L. , Golovanova E. , Pavlov Ch. , Dukhanin A. , Orlova S. , Starostin K.
Published: March 2022

Liver steatosis is a key pathology in non-alcoholic or metabolic associated fatty liver disease. Though largely ignored for decades it is currently becoming the focus of research in hepatology. It is important to consider its origin and current opportunities in terms of pharmacotherapy. Essential phospholipids (EPLs) rich in phosphatidylcholine (PCH) is a widely used treatment option for fatty liver disease, and there is a solid amount of consistent clinical evidence for the regression of steatosis after treatment with EPLs. As knowledge of PCH (a key component of EPLs) pharmacodynamics and mode of action driving this widely observed clinical effect is currently insufficient, we aimed to explore the potential molecular and metabolic pathways involved in the positive effects of PCH on steatosis regression.
Celastrol Alleviates Autoimmune Hepatitis Through the PI3K/AKT Signaling Pathway Based on Network Pharmacology and Experiments
Authors: Wang Shuhui , Huang Zheng , Lei Yu , Han Xu , Tian Dean , Gong Jin , Liu Mei
Published: March 2022

Objective: This work aims to explore the potential targets and underlying therapeutic mechanisms of celastrol in autoimmune hepatitis (AIH) through network pharmacology and experiments on Laboratory Animals.

Methods: A drug-target interaction network was constructed to predict the possible targets of celastrol and their potential relationship with the drug; docking studies were also performed for validation. This study used both acute and chronic rodent models of autoimmune hepatitis. Gross appearance of liver and spleen were obtained from murine models, hematoxylin-eosin staining and Sirius red staining were performed to examine hepatic inflammation and fibrosis respectively. By combining molecular docking and enrichment analysis results, the most prominent signaling pathway was selected and further confirmed by Western blot in AIH models administered with celastrol.

Results: In total, 82 common targets of celastrol and AIH were obtained from databases, identified by network pharmacology, and adequately enriched. Among them, PIK3R1, SRC, MAPK1, AKT1, and HRAS were selected as the top 5 closely related targets to celastrol. They all performed effectively in molecular docking, with AKT1 and PIK3R1 exhibiting more-prominent binding energy. Subsequently, celastrol administration significantly ameliorated hepatitis and liver fibrosis by reducing AKT1 and PI3K phosphorylation in both acute liver injury and chronic models of autoimmune hepatitis.

Conclusion: In summary, celastrol significantly attenuates autoimmune hepatitis by suppressing the PI3K/AKT signaling pathway, confirmed by validated animal models. These findings may help identify the mechanism involved in the anti-inflammatory action of celastrol in autoimmune hepatitis and provide ideas for future comprehensive studies.
From Data to Knowledge: Systematic Review of Tools for Automatic Analysis of Molecular Dynamics Output
Authors: Baltrukevich Hanna , Podlewska Sabina
Published: March 2022

An increasing number of crystal structures available on one side, and the boost of computational power available for computer-aided drug design tasks on the other, have caused that the structure-based drug design tools are intensively used in the drug development pipelines. Docking and molecular dynamics simulations, key representatives of the structure-based approaches, provide detailed information about the potential interaction of a ligand with a target receptor. However, at the same time, they require a three-dimensional structure of a protein and a relatively high amount of computational resources. Nowadays, as both docking and molecular dynamics are much more extensively used, the amount of data output from these procedures is also growing. Therefore, there are also more and more approaches that facilitate the analysis and interpretation of the results of structure-based tools. In this review, we will comprehensively summarize approaches for handling molecular dynamics simulations output. It will cover both statistical and machine-learning-based tools, as well as various forms of depiction of molecular dynamics output.
Towards Ultrafast Laser Micromachining of X-Ray Gratings and Creation of Sub-Micron Hole Patterns, Comparison of Results With Bessel and Gaussian Beams
Authors: Carreto Romain , Lüscher Beat , Holtz Ronald , Resan Bojan
Published: March 2022

We compare micromachining results with Gaussian and Bessel beams using an UV picosecond laser system and demonstrate feasibility to produce tungsten gratings for x-ray interferometry medical imaging, and sub-micrometer size hole patterns. The advantages of Bessel beams compared to Gaussian beams, are demonstrated for micromachining of rectangular shallow profile gratings with sharp edges. The high-aspect ratio grating (10 microns wide and 200 microns deep) from tungsten foil could only be obtained with the Gaussian beam and focusing with an F-Theta type lens. Bessel beams contain significant amount of energy in the side lobes in comparison with the central peak. The limited amount of the pulse energy in the central, 2-micron peak of the beam and destruction of the Bessel beam structure due to the narrow slit clipping the side lobes, prevented the Bessel beam deeper penetration. On the other hand, the axicon lens and the Bessel beam shape enable creation of shallow sub-micron size structures.
Background Pressure Induced Structural and Chemical Change in NiV/B4C Multilayers Prepared by Magnetron Sputtering
Authors: Wei Zhenbo , Zhang Zhe , Jiang Li , Yang Yang , Chang Chenyuan , Feng Yufei , Qi Runze , Huang Qiushi , Yan Wensheng , Xie Chun , Wang Zhanshan
Published: March 2022

NiV/B4C multilayers with a small d-spacing are suitable for multilayer monochromator working at a photon energy region from 5 to 8 keV, or photon energy region from 10 to 100 keV. To investigate the influence of background pressure during fabrication, NiV/B4C multilayers with a d-spacing of 3.0 nm were fabricated by magnetron sputtering with different background pressures. The grazing incidence x-ray reflectivity (GIXR) and transmission electron microscopy (TEM) measurement illustrated the structural change that happened in NiV/B4C multilayers when background pressure is high. The electron dispersive x-ray spectroscopy (EDX) of NiV/B4C multilayer deposited with a high background pressure suggests a gradient distribution of oxygen, which corresponds to the gradient thickness change. The detailed x-ray absorption near edge spectroscopy (XANES) comparison of NiV/B4C multilayers, NiV coating, and B4C coating showed the chemical state change induced by background pressure. We concluded that during the deposition, vanadium oxide promoted the oxidation of boron. In order to fabricate a good performance of NiV/B4C multilayers, the background pressure needs lower than 1 × 10−4 Pa.
User-Accessible Machine Learning Approaches for Cell Segmentation and Analysis in Tissue
Authors: Winfree Seth
Published: March 2022

Advanced image analysis with machine and deep learning has improved cell segmentation and classification for novel insights into biological mechanisms. These approaches have been used for the analysis of cells in situ, within tissue, and confirmed existing and uncovered new models of cellular microenvironments in human disease. This has been achieved by the development of both imaging modality specific and multimodal solutions for cellular segmentation, thus addressing the fundamental requirement for high quality and reproducible cell segmentation in images from immunofluorescence, immunohistochemistry and histological stains. The expansive landscape of cell types-from a variety of species, organs and cellular states-has required a concerted effort to build libraries of annotated cells for training data and novel solutions for leveraging annotations across imaging modalities and in some cases led to questioning the requirement for single cell demarcation all together. Unfortunately, bleeding-edge approaches are often confined to a few experts with the necessary domain knowledge. However, freely available, and open-source tools and libraries of trained machine learning models have been made accessible to researchers in the biomedical sciences as software pipelines, plugins for open-source and free desktop and web-based software solutions. The future holds exciting possibilities with expanding machine learning models for segmentation via the brute-force addition of new training data or the implementation of novel network architectures, the use of machine and deep learning in cell and neighborhood classification for uncovering cellular microenvironments, and the development of new strategies for the use of machine and deep learning in biomedical research.
Sleeve Gastrectomy-Induced AMPK Activation Attenuates Diabetic Cardiomyopathy by Maintaining Mitochondrial Homeostasis via NR4A1 Suppression in Rats
Authors: Li Songhan , Dong Shuohui , Xu Qian , Shi Bowen , Li Linchuan , Zhang Wenjie , Zhu Jiankang , Cheng Yugang , Zhang Guangyong , Zhong Mingwei
Published: March 2022

Diabetic cardiomyopathy (DCM) is characterized by impaired diastolic and systolic myocardial performance and is a major cause of morbidity and mortality in patients with diabetes. Surgical bariatric procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes (T2DM) and have benefits with myocardial function. Maintaining cardiac mitochondrial homeostasis is a promising therapeutic strategy for DCM. However, whether SG surgery affects mitochondrial function and its underlying mechanism remains unclear. This study aimed to investigate the effect of SG surgery on mitochondrial homeostasis and intracellular oxidative stress in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose and high fat-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a remarkably metabolic benefit of SG, including a reduced body weight, food intake, blood glucose levels, and restored glucose tolerance and insulin sensitivity post-operatively. Also, SG ameliorated the pathological cardiac hypertrophy, myocardial fibrosis and the dysfunction of myocardial contraction and diastole, consequently delayed the progression of DCM. Also, SG restored the mitochondrial dysfunction and fragmentation through the AMPK signaling activation mediated nuclear receptor subfamily 4 group A member 1 (NR4A1)/DRP1 suppression in vivo. H9c2 cardiomyocytes showed that activation of AMPK could reverse the mitochondrial dysfunction somehow. Collectively, our study provided evidence that SG surgery could alleviate mitochondrial dysfunction in DCM. Moreover, AMPK-activated NR4A1/DRP1 repression might act as a significant reason for maintaining mitochondrial homeostasis in the myocardium, thus contributing to morphological and functional alleviation of DCM.
The Importance of Stem Photosynthesis for Two Desert Shrubs Across Different Groundwater Depths
Authors: Liu Ran , Feng Xiaolong , Li Congjuan , Ma Jie , Wang Yugang , Li Yan
Published: March 2022

Water availability could alter multiple ecophysiological processes such as water use strategy, photosynthesis, and respiration, thereby modifying plant water use and carbon gain. However, a lack of field observations hinders our understanding of how water availability affects stem photosynthesis at both organ and plant levels of desert shrubs. In this study, we measured gas exchange and oxygen stable isotopes to quantify water sources, stem recycling photosynthesis, and whole-plant carbon balance in two coexisting Haloxylon species (Haloxylon ammodendron and Haloxylon persicum) at different groundwater depths in the Gurbantonggut Desert. The overall aim of the study was to analyze and quantify the important role of stem recycling photosynthesis for desert shrubs (Haloxylon species) under different groundwater depths. The results showed that (1) regardless of changes in groundwater depth, H. ammodendron consistently used groundwater and H. persicum used deep soil water as their main water source, with greater than 75% of xylem water being derived from groundwater and deep soil water for the two species, respectively; (2) stem recycling photosynthesis refixed 72–81% of the stem dark respiration, and its contribution to whole-plant carbon assimilation was 10–21% for the two species; and (3) deepened groundwater increased stem water use efficiency and its contribution to whole-plant carbon assimilation in H. persicum but not in H. ammodendron. Our study provided observational evidence that deepened groundwater depth induced H. persicum to increase stem recycling photosynthetic capacity and a greater contribution to whole-plant carbon assimilation, but this did not occur on H. ammodendron. Our study indicates that stem recycling photosynthesis may play an important role in the survival of desert shrubs in drought conditions.
Enhancing Wheat Disease Diagnosis in a Greenhouse Using Image Deep Features and Parallel Feature Fusion
Authors: Zhang Zhao , Flores Paulo , Friskop Andrew , Liu Zhaohui , Igathinathane C. , Han X. , Kim H. J. , Jahan N. , Mathew J. , Shreya S.
Published: March 2022

Since the assessment of wheat diseases (e.g., leaf rust and tan spot) via visual observation is subjective and inefficient, this study focused on developing an automatic, objective, and efficient diagnosis approach. For each plant, color, and color-infrared (CIR) images were collected in a paired mode. An automatic approach based on the image processing technique was developed to crop the paired images to have the same region, after which a developed semiautomatic webtool was used to expedite the dataset creation. The webtool generated the dataset from either image and automatically built the corresponding dataset from the other image. Each image was manually categorized into one of the three groups: control (disease-free), disease light, and disease severity. After the image segmentation, handcrafted features (HFs) were extracted from each format of images, and disease diagnosis results demonstrated that the parallel feature fusion had higher accuracy over features from either type of image. Performance of deep features (DFs) extracted through different deep learning (DL) models (e.g., AlexNet, VGG16, ResNet101, GoogLeNet, and Xception) on wheat disease detection was compared, and those extracted by ResNet101 resulted in the highest accuracy, perhaps because deep layers extracted finer features. In addition, parallel deep feature fusion generated a higher accuracy over DFs from a single-source image. DFs outperformed HFs in wheat disease detection, and the DFs coupled with parallel feature fusion resulted in diagnosis accuracies of 75, 84, and 71% for leaf rust, tan spot, and leaf rust + tan spot, respectively. The methodology developed directly for greenhouse applications, to be used by plant pathologists, breeders, and other users, can be extended to field applications with future tests on field data and model fine-tuning.
Sulfur Stable Isotope Discrimination in Rice: A Sulfur Isotope Mass Balance Study
Authors: Cavallaro Viviana , Maghrebi Moez , Caschetto Mariachiara , Sacchi Gian Attilio , Nocito Fabio Francesco
Published: March 2022

The use of sulfur (S) stable isotopes to study S metabolism in plants is still limited by the relatively small number of studies. It is generally accepted that less S stable isotope discrimination occurs during sulfate (SO42–) uptake. However, S metabolism and allocation are expected to produce separations of S stable isotopes among the different plant S pools and organs. In this study, we measured the S isotope composition of the main S pools of rice plants grown under different SO42– availabilities in appropriate closed and open hydroponic-plant systems. The main results indicate that fractionation against 34S occurred during SO42– uptake. Fractionation was dependent on the amount of residual SO42– in the solution, showing a biphasic behavior related to the relative expression of two SO42– transporter genes (OsSULTR1;1 and OsSULTR1;2) in the roots. S isotope separations among S pools and organs were also observed as the result of substantial S isotope fractionations and mixing effects occurring during SO42– assimilation and plant S partitioning. Since the S stable isotope separations conserve the memory of the physiological and metabolic activities that determined them, we here underline the potential of the 32S/34S analysis for the detailed characterization of the metabolic and molecular processes involved in plant S nutrition and homeostasis.
Haplotype Analysis of Chloroplast Genomes for Jujube Breeding
Authors: Hu Guanglong , Wu Yang , Guo Chaojun , Lu Dongye , Dong Ningguang , Chen Bo , Qiao Yanjie , Zhang Yuping , Pan Qinghua
Published: March 2022

Jujube (family Rhamnaceae) is an important economic fruit tree in China. In this study, we reported 26 chloroplast (cp) sequences of jujube using Illumina paired-end sequencing. The sequence length of cp genome was 161, 367–161, 849 bp, which was composed of a large single-copy region (89053–89437 bp) and a small single-copy region (19356–19362 bp) separated by a pair of reverse repeat regions (26478–26533 bp). Each cp genome encodes the same 130 genes, including 112 unique genes, being quite conserved in genome structure and gene sequence. A total of 118 single base substitutions (SNPs) and 130 InDels were detected in 65 jujube accessions. Phylogenetic and haplotype network construction methods were used to analyze the origin and evolution of jujube and its sour-tasting relatives. We detected 32 effective haplotypes, consisting of 20 unique jujube haplotypes and 9 unique sour–jujube haplotypes. Compared with sour–jujube, jujube showed greater haplotype diversity at the chloroplast DNA level. To cultivate crisp and sweet fruit varieties featuring strong resistance, by combining the characteristics of sour-jujube and cultivated jujube, three hybrid combinations were suggested for reciprocal crosses: “Dongzao” × “Jingzao39,” “Dongzao” × “Jingzao60,” “Dongzao” × “Jingzao28.” This study provides the basis for jujube species’ identification and breeding, and lays the foundation for future research.
Cytidine Triphosphate Synthase Four From Arabidopsis thaliana Attenuates Drought Stress Effects
Authors: Krämer Moritz , Dörfer Eva , Hickl Daniel , Bellin Leo , Scherer Vanessa , Möhlmann Torsten
Published: March 2022

Cytidine triphosphate synthase (CTPS) catalyzes the final step in pyrimidine de novo synthesis. In Arabidopsis, this protein family consists of five members (CTPS1–5), and all of them localize to the cytosol. Specifically, CTPS4 showed a massive upregulation of transcript levels during abiotic stress, in line with increased staining of CTPS4 promoter:GUS lines in hypocotyl, root and to lesser extend leaf tissues. In a setup to study progressive drought stress, CTPS4 knockout mutants accumulated less fresh and dry weight at days 5–7 and showed impaired ability to recover from this stress after 3 days of rewatering. Surprisingly, a thorough physiological characterization of corresponding plants only revealed alterations in assimilation and accumulation of soluble sugars including those related to drought stress in the mutant. Bimolecular fluorescence complementation (BiFC) studies indicated the interaction of CTPS4 with other isoforms, possibly affecting cytoophidia (filaments formed by CTPS formation. Although the function of these structures has not been thoroughly investigated in plants, altered enzyme activity and effects on cell structure are reported in other organisms. CTPS activity is required for cell cycle progression and growth. Furthermore, drought can lead to the accumulation of reactive oxygen species (ROS) and by this, to DNA damage. We hypothesize that effects on the cell cycle or DNA repair might be relevant for the observed impaired reduced drought stress tolerance of CTPS4 mutants.
Molecular Dissection Unveiling Dwarfing Effects of Plant Growth Retardants on Pomegranate
Authors: Qian Jingjing , Wang Ning , Ren Wenxu , Zhang Rufan , Hong Xiyao , Chen Lingyue , Zhang Kaijing , Shu Yingjie , Hu Nengbing , Yang Yuchen
Published: March 2022

Dwarfed stature is a desired trait for modern orchard production systems. One effective strategy for dwarfing cultivation is exogenously applying plant growth retardants (PGRs) to plants. However, for many economic fruit trees, the current knowledge on the regulatory mechanisms underlying the dwarfing effect of PGRs is limited, which largely restricts the agricultural application of PGRs. In this study, we exogenously applied three kinds of PGRs [paclobutrazol, daminozide (B9), and mannitol] to the seedlings of pomegranate (Punica granatum L.) and performed comparative transcriptome analysis to elucidate the molecular features of PGR-induced dwarfing in pomegranates. Our results showed that all the three PGRs could significantly suppress plant growth of pomegranate. The inhibition of auxin biosynthetic processes, as well as auxin-mediated shoot development, may be considered as the main reason for the dwarfing. Besides that, different PGRs were also found to induce dwarfing via specific mechanisms, for example, cellular response to strigolactone was particularly suppressed by the application of paclobutrazol, while the level of carbohydrate homeostasis and metabolism were downregulated in conditions of either B9 or mannitol treatments. Furthermore, exogenous PGR application was supposed to cause adverse impacts on the normal physiological process of pomegranate seedlings, which may bring extra burden to pomegranate plants. These novel findings unveiled the genetic basis underlying the dwarfing in pomegranates, which provides deeper insights into PGR-mediated dwarfing cultivation of pomegranates.