bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone morphogenetic protein inhibitors and mitochondria targeting agents synergistically induce apoptosis-inducing factor (AIF) caspase-independent cell death in lung cancer cells
Authors: Mondal Arindam , Roberge Jacques , Gilleran John , Peng Youyi , Jia Dongxuan , Akel Moumen , Patel Yash , Zoltowski Harrison , Doraiswamy Anupama , Langenfeld John 
Published: June 2022

Abstract
Background
Bone morphogenetic proteins (BMP) are evolutionarily conserved morphogens that are reactivated in lung carcinomas. In lung cancer cells, BMP signaling suppresses AMP activated kinase (AMPK) by inhibiting LKB1. AMPK is activated by mitochondrial stress that inhibits ATP production, which is enhanced 100-fold when phosphorylated by LKB1. Activated AMPK can promote survival of cancer cells but its “hyperactivation” induces cell death. The studies here reveal novel cell death mechanisms induced by BMP inhibitors, together with agents targeting the mitochondria, which involves the “hyperactivation” of AMPK.

Methods
This study examines the synergistic effects of two BMP inhibitors together with mitochondrial targeting agents phenformin and Ym155, on cell death of lung cancer cells expressing LKB1 (H1299), LKB1 null (A549), and A549 cells transfected with LKB1 (A549-LKB1). Cell death mechanisms evaluated were the activation of caspases and the nuclear localization of apoptosis inducing factor (AIF). A769662 was used to allosterically activate AMPK. Knockdown of BMPR2 and LKB1 using siRNA was used to examine their effects on nuclear localization of AMPK. Validation studies were performed on five passage zero primary NSCLC.

Results
Both BMP inhibitors synergistically suppressed growth when combined with Ym155 or phenformin in cells expressing LKB1. The combination of BMP inhibitors with mitochondrial targeting agents enhanced the activation of AMPK in lung cancer cells expressing LKB1. Allosteric activation of AMPK with A769662 induced cell death in both H1299 and A549 cells. Cell death induced by the combination of BMP inhibitors and mitochondrial-targeting agents did not activate caspases. The combination of drugs induced nuclear localization of AIF in cells expressing LKB1, which was attenuated by knockdown of LKB1. Knockdown of BMPR2 together with Ym155 increased nuclear localization of AIF. Combination therapy also enhanced cell death and AIF nuclear localization in primary NSCLC.

Conclusions
These studies demonstrate that inhibition of BMP signaling together with mitochondrial targeting agents induce AIF caspase-independent cell death, which involves the “hyperactivation” of AMPK. AIF caspase-independent cell death is an evolutionarily conserved cell death pathway that is infrequently studied in cancer. These studies provide novel insight into mechanisms inducing AIF caspase-independent cell death in cancer cells using BMP inhibitors.
Adolescents’ exposure to and evaluation of food promotions on social media: a multi-method approach
Authors: van der Bend D. L. M. , Jakstas T , van Kleef E , Shrewsbury V. A. , Bucher T 
Published: June 2022

AbstractBackgroundTraditional food marketing, mostly involving advertisement of nutrient poor and energy dense foods, has the effect of enhancing attitudes, preferences, and increasing intake of marketed foods in adolescents, with detrimental consequences for health. While the use of social media applications in adolescents has proliferated, little is known about the content of food promotions within these applications. The aim of this study was to investigate adolescents’ exposure to and evaluation of social media food promotions (SMFPs).MethodsAustralian adolescents aged 13–16 years joined one-on-one Zoom meetings with the researcher on the device they normally used for social media. Participants shared their screen and visited up to three of their favourite social media platforms for 10 min each, during which the researcher pointed out examples of SMFPs to participants. Next, participants answered questions about their awareness and appreciation of SMFPs. Screenshots of SMFPs were de-identified and analysed.ResultsThe study included 35 adolescents aged 14.4 (± 1.2) years (boys:n = 18; girls:n = 17). Instagram, Snapchat and YouTube were the most favoured social media platforms. During a total of 1000 min of viewing time, 1801 unbranded (n = 1221) and branded (n = 580) SMFPs were identified. Participants viewed a median rate (IQR) of 12.0 (6.3–20) SMFPs per 10 min, with a median rate of 6.0 (3–11) non-core SMFPs per 10 min. A majority of SMFPs (62%) were embedded into celebrity influencer or entertaining content (e.g., vlogs, cooking videos, streamed TV content). In total, 60% of the participants said they had sometimes, rarely or never noticed the SMFPs pointed out by the researcher themselves. Participants largely remembered non-core foods or brands (77%). Almost half (49%) of participants liked SMFPs, while only 6% disliked them.ConclusionsThis study contributes to a relatively unexplored research area. The outcomes show adolescents’ SMFP exposure mostly concerns unhealthy foods, shown in advertisements and other food-related posts, which are integrated into a wide variety of entertainment that is appreciated by adolescents. The results emphasise the need for more research on SMFPs, with particular focus on the impact on adolescent dietary behaviours, and clearer definitions and stricter regulations regarding adolescent-targeted social media food marketing.
Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis
Authors: Xu Hao-ming , Xu Jing , Yang Mei-feng , Liang Yu-jie , Peng Quan-zhou , Zhang Yuan , Tian Cheng-mei , Nie Yu-qiang , Wang Li-sheng , Yao Jun , Li De-feng 
Published: June 2022

Abstract
Background and aims
Ulcerative colitis (UC) is a heterogeneous disorder with complex pathogenesis. Therefore, in the present study, we aimed to assess genome-wide DNA methylation changes associated explicitly with the pathogenesis of UC.

Methods
DNA methylation changes were identified by comparing UC tissues with healthy controls (HCs) from the GEO databases. The candidate genes were obtained and verified in clinical samples. Moreover, the underlying molecular mechanism related to Zbtb7b in the pathogenesis of UC was explored using the dextran sodium sulfate (DSS)-induced colitis model.

Results
Bioinformatic analysis from GEO databases confirmed that Zbtb7b, known as Th-inducing POZ-Kruppel factor (ThPOK), was demethylated in UC tissues. Then, we demonstrated that Zbtb7b was in a hypo-methylation pattern through the DSS-induced colitis model (P = 0.0357), whereas the expression of Zbtb7b at the mRNA and protein levels was significantly up-regulated in the inflamed colonic tissues of UC patients (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0079, P < 0.0001) and DSS-induced colitis model (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0045, P = 0.0004). Moreover, the expression of Zbtb7b was positively associated with the degree of UC activity. Mechanically, over-expression of Zbtb7b might activate the maturation of CD4+T cells (FCM, IF: P = 0.0240, P = 0.0003) and repress the differentiation of double-positive CD4+CD8+T (DP CD4+CD8+T) cells (FCM, IF: P = 0.0247, P = 0.0118), contributing to the production of inflammatory cytokines, such as TNF-α (P = 0.0005, P = 0.0005), IL-17 (P = 0.0014, P = 0.0381), and IFN-γ (P = 0.0016, P = 0.0042), in the serum and colonic tissue of DSS-induced colitis model.

Conclusions
Epigenetic DNA hypo-methylation of Zbtb7b activated the maturation of CD4+T cells and repressed the differentiation of DP CD4+CD8+ T cells, resulting in the production of inflammatory cytokines and colonic inflammation in UC. Therefore, Zbtb7b might be a diagnostic and therapeutic biomarker for UC, and hypo-methylation might affect the biological function of Zbtb7b.
Astrocyte reactivation in medial prefrontal cortex contributes to obesity-promoted depressive-like behaviors
Authors: Yu Gang , Cao Feng , Hou Tingting , Cheng Yunsheng , Jia Benli , Yu Liang , Chen Wanjing , Xu Yanyan , Chen Mingming , Wang Yong 
Published: June 2022

Abstract
Background
Little is known about how the obesogenic environment influences emotional states associated with glial responses and neuronal function. Here, we investigated glial reactivation and neuronal electrophysiological properties in emotion-related brain regions of high-fat diet (HFD) and ob/ob mice under chronic stress.

Methods
The glial reactivation and neuronal activities in emotion-related brain regions were analyzed among normal diet mice (ND), HFD mice, wild-type mice, and ob/ob mice. To further activate or inhibit astrocytes in medial prefrontal cortex (mPFC), we injected astrocytes specific Gq-AAV or Gi-AAV into mPFC and ongoing treated mice with CNO.

Results
The results showed that obesogenic factors per se had no significant effect on neuronal activities in emotion-related brain regions, or on behavioral performance. However, exposure to a chronic stressor profoundly reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs) in the mPFC; depressive-like behaviors were seen, accompanied by significant upregulation of astrocyte reactivation. We identified resilient and susceptible mice among chronic social defeat stress-exposed HFD mice. As expected, astrocyte reactivity was upregulated, while neuronal activity was depressed, in the mPFC of susceptible compared to resilient mice. Furthermore, activating astrocytes resulted in similar levels of neuronal activity and depressive-like behaviors between resilient and susceptible mice. Additionally, inhibiting astrocyte reactivation in the mPFC of HFD mice upregulated neuronal activities and inhibited depressive-like behaviors.

Conclusions
These observations indicate that obesogenic factors increase the risk of depression, and improve our understanding of the pathological relationship between obesity and depression.

Graphical Abstract
Comprehensive evaluation of caloric restriction-induced changes in the metabolome profile of mice
Authors: Xie Dadi , Huang Jinxi , Zhang Qiang , Zhao Shiyuan , Xue Hongjia , Yu Qing-Qing , Sun Zhuohao , Li Jing , Yang Xiumei , Shao Minglei , Pang Deshui , Jiang Pei 
Published: June 2022

Abstract
Objects
Caloric restriction (CR) is known to extend lifespan and exert a protective effect on organs, and is thus a low-cost and easily implemented approach to the health maintenance. However, there have been no studies that have systematically evaluated the metabolic changes that occur in the main tissues affected by CR. This study aimed to explore the target tissues metabolomic profile in CR mice.

Methods
Male C57BL/6J mice were randomly allocated to the CR group (n = 7) and control group (n = 7). A non-targeted gas chromatography–mass spectrometry approach and multivariate analysis were used to identify metabolites in the main tissues (serum, heart, liver, kidney, cortex, hippocampus, lung, muscle, and white adipose) in model of CR.

Results
We identified 10 metabolites in the heart that showed differential abundance between the 2 groups, along with 9 in kidney, 6 in liver, 6 in lung, 6 in white adipose, 4 in hippocampus, 4 in serum, 3 in cortex, and 2 in muscle. The most significantly altered metabolites were amino acids (AAs) (glycine, aspartic acid, l-isoleucine, l-proline, l-aspartic acid, l-serine, l-hydroxyproline, l-alanine, l-valine, l-threonine, l-glutamic acid, and l-phenylalanine) and fatty acids (FAs) (palmitic acid, 1-monopalmitin, glycerol monostearate, docosahexaenoic acid, 16-octadecenoic acid, oleic acid, stearic acid, and hexanoic acid). These metabolites were associated with 7 different functional pathways related to the metabolism of AAs, lipids, and energy.

Conclusion
Our results provide insight into the specific metabolic changes that are induced by CR and can serve as a reference for physiologic studies on how CR improves health and extends lifespan.
scDART: integrating unmatched scRNA-seq and scATAC-seq data and learning cross-modality relationship simultaneously
Authors: Zhang Ziqi , Yang Chengkai , Zhang Xiuwei 
Published: June 2022

AbstractIt is a challenging task to integrate scRNA-seq and scATAC-seq data obtained from different batches. Existing methods tend to use a pre-defined gene activity matrix to convert the scATAC-seq data into scRNA-seq data. The pre-defined gene activity matrix is often of low quality and does not reflect the dataset-specific relationship between the two data modalities. We propose scDART, a deep learning framework that integrates scRNA-seq and scATAC-seq data and learns cross-modalities relationships simultaneously. Specifically, the design of scDART allows it to preserve cell trajectories in continuous cell populations and can be applied to trajectory inference on integrated data.
Improved skeletal muscle fatigue resistance in experimental autoimmune myositis mice following high-intensity interval training
Authors: Yamada Takashi , Ashida Yuki , Tamai Katsuyuki , Kimura Iori , Yamauchi Nao , Naito Azuma , Tokuda Nao , Westerblad Håkan , Andersson Daniel C. , Himori Koichi 
Published: June 2022

AbstractBackgroundMuscle weakness and decreased fatigue resistance are key manifestations of systemic autoimmune myopathies (SAMs). We here examined whether high-intensity interval training (HIIT) improves fatigue resistance in the skeletal muscle of experimental autoimmune myositis (EAM) mice, a widely used animal model for SAM.MethodsFemale BALB/c mice were randomly assigned to control (CNT) or EAM groups (n= 28 in each group). EAM was induced by immunization with three injections of myosin emulsified in complete Freund’s adjuvant. The plantar flexor (PF) muscles of mice with EAM were exposed to either an acute bout or 4 weeks of HIIT (a total of 14 sessions).ResultsThe fatigue resistance of PF muscles was lower in the EAM than in the CNT group (P< 0.05). These changes were associated with decreased activities of citrate synthase and cytochrome c oxidase and increased expression levels of the endoplasmic reticulum stress proteins (glucose-regulated protein 78 and 94, and PKR-like ER kinase) (P< 0.05). HIIT restored all these alterations and increased the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and the mitochondrial electron transport chain complexes (I, III, and IV) in the muscles of EAM mice (P< 0.05).ConclusionsHIIT improves fatigue resistance in a SAM mouse model, and this can be explained by the restoration of mitochondria oxidative capacity via inhibition of the ER stress pathway and PGC-1α-mediated mitochondrial biogenesis.
dsSynthetic: synthetic data generation for the DataSHIELD federated analysis system
Authors: Banerjee Soumya , Bishop Tom R. P. 
Published: June 2022

Abstract

Objective

Platforms such as DataSHIELD allow users to analyse sensitive data remotely, without having full access to the detailed data items (federated analysis). While this feature helps to overcome difficulties with data sharing, it can make it challenging to write code without full visibility of the data. One solution is to generate realistic, non-disclosive synthetic data that can be transferred to the analyst so they can perfect their code without the access limitation. When this process is complete, they can run the code on the real data.

Results

We have created a package in DataSHIELD (dsSynthetic) which allows generation of realistic synthetic data, building on existing packages. In our paper and accompanying tutorial we demonstrate how the use of synthetic data generated with our package can help DataSHIELD users with tasks such as writing analysis scripts and harmonising data to common scales and measures.
Symphytum ibericum Steven: LC–HRMS/MS-based phytochemical profile, in vitro antioxidant and enzyme inhibitory potential
Authors: Trifan Adriana , Zengin Gokhan , Sinan Kouadio Ibrahime , Skalicka-Woźniak Krystyna , Minceva Mirjana , Luca Simon Vlad 
Published: June 2022

Abstract
Background
Symphytum L. (comfrey, Boraginaceae) has a longstanding use as a remedy to alleviate the clinical symptomatology in arthritis, strains, contusions or sprains. In the recent years, considerable research efforts were put into assessing the chemico-biological profile of unexploited Symphytum species, with the aim to extend the medicinal valences of the genus to new pharmacological applications. However, to date there are no previous comprehensive phytochemical characterization and multi-biological evaluation of S. ibericum Steven, a perennial Boraginaceae plant distributed in the Northeastern Turkey and Caucasus region.

Results
Total phenolic and flavonoid content of extracts obtained from the leaves and roots of S. ibericum varied between 10.53 ± 0.20 to 84.95 ± 0.60 mg gallic acid equivalents/g and between 0.81 ± 0.06 to 20.88 ± 0.29 mg rutin equivalents/g. The liquid chromatography hyphenated with tandem high-resolution mass spectrometry (LC–HRMS/MS)-based phytochemical profiling revealed a number of 29 distinct compounds, such as phenolic acids (e.g., caffeic acid, rosmarinic acid, globoidnan B, rabdosiin, globoidnan A), flavonoids (e.g., quercetin derivatives, luteolin, apigenin), pyrrolizidine alkaloids (e.g., intermedine–N-oxide, lycopsamine-N-oxide, symphytine-N-oxide), organic and oxygenated unsaturated fatty acids. The evaluation of the antioxidant activity showed potent scavenging activity against synthetic radicals, cupric ion reducing (37.60 ± 0.15–436.26 ± 7.12 mg Trolox equivalents/g), ferric ion reducing (21.01 ± 0.74–229.99 ± 3.86 mg Trolox equivalents/g) and chelating capacity; in general, the leaf extracts displayed superior antioxidant effects than the corresponding root extracts. With respect to the inhibitory activity tested on various pharmacologically relevant enzymes, interesting anti-acetylcholinesterase (0.32 ± 0.03–3.32 ± 0.12 mg galanthamine equivalents/g), anti-butyrylcholinesterase (0.88 ± 0.06–5.85 ± 0.16 mg galanthamine equivalents/g) and anti-tyrosinase (21.84 ± 0.21–61.94 ± 2.86 mg kojic acid equivalents/g) properties were noticed. Exploratory multivariate analysis revealed four clusters with respect to phytochemical profile, of which one rich in danshensu, quercetin hexoside, dehydrorabdosiin, dihydrogloboidnan B and quercetin acetylhexoside.

Conclusions
As evidenced through the phytochemical characterization and multi-biological evaluation, S. ibericum can be regarded as a prospective source of pharmaceutical or cosmeceutical ingredients with putative uses in the management of chronic conditions linked to oxidative stress, such as Alzheimer’s disease or skin pigmentation disorders.

Graphical Abstract
Alpha-lipoic acid-role in improving both reserpine toxicity and paroxetine treatment in the cerebral cortex of albino rats; histological, ultrastructural, immunohistohemical and biochemical studies
Authors: Arisha Samah M. 
Published: June 2022

Abstract
Background
Reserpine is a monoamine depletory drug cause oxidative damage and used to induce depression-like features in rodent model. Paroxetine is an antidepressant drug that exerts its effects by inhibiting dopaminergic neurons although it may exert much pathological damage. Alpha-lipoic acid (ALA) is an endogenous antioxidant co-factor of important enzymatic complexes. The present study was aimed to elucidate the possible protective effect of ALA in the improvement of the deleterious cerebral cortex injury after reserpine and paroxetine treatment. Forty adult male albino rats were equally divided into 5 groups. Group I served as control group orally treated with saline solution all the experiment period. Group II animals orally treated with ALA (200 mg/kg/day) for six weeks. The induction of depression-like features occurred when the rest of animals were intraperitoneally treated with 25 mg/kg of reserpine once daily for consecutive 14 day. Then these animals were divided into; Group III (reserpine group) animals in this group were sacrificed on 15th day. Group IV; reserpine-treated animals were treated with paroxetine (20 mg/kg) daily for 6 weeks. Group V, animals in this group were received paroxetine and ALA daily for 6 weeks.

Results
Reserpine-treated rats showed disorganized layers of cerebral cortex with degenerative, apoptotic and necrotic changes. Ultrastructure changes include both pyramidal and granule cells with severe degenerative, necrotic and apoptotic features. The nuclei appeared pyknotic; irregular with chromatin condensation as well as the cytoplasm of these cells contained many degenerated organelles. In addition, a significant increase in total oxidative stress and decrease in total antioxidant capacity, norepinephrine, dopamine and serotonin levels were recorded. The same treatment showed significant decrease in proliferating cell nuclear antigen (PCNA) expression and significant increase in caspase-3 expression in the granule and pyramidal cells. After paroxetine-treatment these parameters were more or less similar to those observed in reserpine-treated ones. While an obvious improvement was appeared when animal treated with both paroxetine and ALA and; all parameters restored its normal features.

Conclusions
This study concluded that; ALA treatment attenuated the cerebral injury induced by reserpine and improved the effects of paroxetine in rats due to its anti-inflammatory, anti-apoptotic and antioxidant activities.
Maternal Testosterone and Offspring Birth Weight: A Mendelian Randomization Study
Authors: Zheng Bing-Kun , Sun Xue-Yi , Xian Jie , Niu Peng-Peng 
Published: June 2022

Abstract

Context
Evidence has shown maternal androgen levels in both the general population and populations with hyperandrogenic disorders are inversely associated with offspring birth weight.

Context
We aimed to investigate the causal effect of maternal testosterone levels in the general population on offspring birth weight and preterm delivery risk using a two-sample Mendelian randomization (MR) method.

Methods
We obtained independent genetic instruments from a sex-specific genome-wide association study with up to 230 454 females of European descent from the UK Biobank. Genetic instruments with consistent testosterone effects but no aggregate effect on sex hormone–binding globulin were used to perform the main analysis. Summary-level data of offspring birth weight adjusted for genotype were obtained from a study with 210 406 females of European descent. Summary-level data of preterm delivery were obtained from the FinnGen study (6736 cases and 116 219 controls).

Results
MR analysis showed that each SD (0.62 nmol/L) increase in testosterone levels could reduce the offspring birth weight by 37.26 g (95% CI, 19.59-54.94 g; P = 3.62 × 10-5). Each SD increase in testosterone levels was also associated with an increased risk of preterm delivery (odds ratio = 1.329; 95% CI, 1.161-1.520; P = 3.57 × 10-5). Similar results were found using different MR methods and multivariable MR analyses.

Conclusion
This two-sample MR study showed genetically determined higher circulating testosterone levels in females from the general population were associated with low birth weight of offspring and increased risk of preterm delivery.
A Systematic Review of Maintenance Measurement in Early Childhood Autism Spectrum Disorder Research
Authors: Pokorski Elizabeth A. , LeJeune Lauren M. 
Published: June 2022

Abstract
Single case research designs (SCRDs) are integral to identifying evidence-based practices (EBPs) for young children with autism spectrum disorder (ASD); however, the field lacks guidance on measuring response maintenance within SCRDs. We identified 103 studies in which researchers used SCRD to investigate the maintenance of behavioral intervention outcomes for children with ASD ages 0–5. Findings include: (a) maintenance conditions across most EBP categories, (b) limited within-case replication of maintenance assessment, (c) inconsistent use of maintenance terminology, (d) varying frequencies of maintenance assessment, and (e) wide range in latency to first and last maintenance probe. Results indicate a pressing need for the regular inclusion of maintenance conditions in behavioral research to increase our understanding of programming for and assessing maintenance.