bluuebunny/crossref_metadata_2025 huggingface dataset:
Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule
Authors: Lawal Bashir , Wu Alexander T. H. , Huang Hsu-Shan
Published: May 2022

Lung cancer poses a serious threat to human health and has recently been tagged the most common malignant disease with the highest incidence and mortality rate. Although epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, patients often develop resistance to these drugs. There is therefore a need to identify new drug candidates with multitarget potential for treating NSCLC. We hereby provide preclinical evidence of the therapeutic efficacy of NLOC-015A a multitarget small-molecule inhibitor of EGFR/mitogen-activated protein (MAP) kinase kinase 1 (MAP2K1)/mammalian target of rapamycin (mTOR)/yes-associated protein 1 (YAP1) for the treatment NSCLC. Our multi-omics analysis of clinical data from cohorts of NSCLC revealed that dysregulation of EGFR/MAP2K1/mTOR/YAP1 signaling pathways was associated with the progression, therapeutic resistance, immune-invasive phenotypes, and worse prognoses of NSCLC patients. Analysis of single-cell RNA sequencing datasets revealed that MAP2K1, mTOR, YAP1 and EGFR were predominantly located on monocytes/macrophages, Treg and exhaustive CD8 T cell, and are involved in M2 polarization within the TME of patients with primary and metastatic NSCLC which further implied gene’s role in remodeling the tumor immune microenvironment. A molecular-docking analysis revealed that NLOC-015A bound to YAP1, EGFR, MAP kinase/extracellular signal-related kinase kinase 1 (MEK1), and mTOR with strong binding efficacies ranging –8.4 to –9.50 kcal/mol. Interestingly, compared to osimertinib, NLOC-015 bound with higher efficacy to the tyrosine kinase (TK) domains of both T790M and T790M/C797S mutant-bearing EGFR. Our in vitro studies and sequencing analysis revealed that NLOC-015A inhibited the proliferation and oncogenic phenotypes of NSCLC cell lines with concomitant downregulation of expression levels of mTOR, EGFR, YAP1, and MEK1 signaling network. We, therefore, suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR, mTOR/NF-κB, YAP1, MEK1 in NSCLC.
Bracovirus Sneaks Into Apoptotic Bodies Transmitting Immunosuppressive Signaling Driven by Integration-Mediated eIF5A Hypusination
Authors: Zhou Gui-Fang , Chen Chang-Xu , Cai Qiu-Chen , Yan Xiang , Peng Nan-Nan , Li Xing-Cheng , Cui Ji-Hui , Han Yun-Feng , Zhang Qi , Meng Jiang-Hui , Tang Hong-Mei , Cai Chen-hui , Long Jin , Luo Kai-Jun
Published: May 2022

A typical characteristics of polydnavirus (PDV) infection is a persistent immunosuppression, governed by the viral integration and expression of virulence genes. Recently, activation of caspase-3 by Microplitis bicoloratus bracovirus (MbBV) to cleave Innexins, gap junction proteins, has been highlighted, further promoting apoptotic cell disassembly and apoptotic body (AB) formation. However, whether ABs play a role in immune suppression remains to be determined. Herein, we show that ABs transmitted immunosuppressive signaling, causing recipient cells to undergo apoptosis and dismigration. Furthermore, the insertion of viral–host integrated motif sites damaged the host genome, stimulating eIF5A nucleocytoplasmic transport and activating the eIF5A-hypusination translation pathway. This pathway specifically translates apoptosis-related host proteins, such as P53, CypA, CypD, and CypJ, to drive cellular apoptosis owing to broken dsDNA. Furthermore, translated viral proteins, such Vank86, 92, and 101, known to complex with transcription factor Dip3, positively regulated DHYS and DOHH transcription maintaining the activation of the eIF5A-hypusination. Mechanistically, MbBV-mediated extracellular vesicles contained inserted viral fragments that re-integrated into recipients, potentially via the homologous recombinant repair system. Meanwhile, this stimulation regulated activated caspase-3 levels via PI3K/AKT 308 and 473 dephosphorylation to promote apoptosis of granulocyte-like recipients Sf9 cell; maintaining PI3K/AKT 473 phosphorylation and 308 dephosphorylation inhibited caspase-3 activation leading to dismigration of plasmatocyte-like recipient High Five cells. Together, our results suggest that integration-mediated eIF5A hypusination drives extracellular vesicles for continuous immunosuppression.
Weak Hypoxia Enhanced Denitrification in a Dissimilatory Nitrate Reduction to Ammonium (DNRA)-Dominated Shallow and Eutrophic Coastal Waterbody, Jinhae Bay, South Korea
Authors: Huang Yan , An Soonmo
Published: May 2022

The effects of seasonal hypoxia on sediment-water interface nitrogen (N) transformations in Jinhae Bay were examined from 2015 to 2019. The rates of benthic denitrification, anaerobic ammonium oxidation (anammox), dissimilatory nitrate reduction to ammonium (DNRA), nutrient exchange, and sediment oxygen consumption were measured seasonally. The oxygen (O2) and hydrogen sulfide (H2S) depth profiles were measured using microelectrodes. Neither penetration nor consumption of oxygen decreased during hypoxia. Denitrification, anammox, and DNRA ranged from 0 to 0.73, 0.13, and 1.09 mmol N m-2 day-1, respectively. Denitrification, the dominant N removal pathway, increased by 75% while anammox ceased, which led to an overall increase of 55% in the total N2 gas production during hypoxia relative to that during normoxia. Enhanced denitrification is the result of increased coupled nitrification–denitrification due to the intermittent supply of oxygen during bottom water hypoxia (“weak hypoxia”). In the hypoxic period, DNRA decreased by 62%, and the relative contribution of DNRA to the total nitrogen reduction process decreased from 81 to 58%, but it still outperformed denitrification as the main nitrate reduction pathway. Sediments were strong sources of ammonium for the water column, both under normoxia and hypoxia, whereas they were a sink of nitrate from the water column during hypoxia. Bioturbation may be important for maintaining oxygen penetration and consumption in sediments. The dominance of DNRA was mainly due to the relatively high content of sulfide and organic-rich sediments. The repressed macrofaunal activity and increased coupling of nitrification and denitrification during hypoxia may have contributed to enhanced denitrification. Taken together, the overall dominance of DNRA might contribute to the development and maintenance of eutrophication and seasonal hypoxia in this system. However, in contrast to the previous results, denitrification was enhanced during “weak hypoxia,” which might be helpful in alleviating eutrophication.
A Novel Bacterium, Butyricimonas virosa, Preventing HFD-Induced Diabetes and Metabolic Disorders in Mice via GLP-1 Receptor
Authors: Lee Heetae , An Jinho , Kim Jiyeon , Choi Dohyun , Song Youngcheon , Lee Chong-Kil , Kong Hyunseok , Kim Sang Bum , Kim Kyungjae
Published: May 2022

Knowledge of the impact of the gut microbiota on human health has increased, and modulation of the bacterial community is now considered a therapeutic target for various diseases. Certain novel bacterial species have probiotic properties associated with improvement in obesity and related metabolic disorders. The relative abundance of Butyricimonas spp. is correlated with metabolic parameters; however, the physiological role of Butyricimonas in metabolic improvement is unclear. In this study, live and heat-killed Butyricimonas virosa were administered to mice with high-fat diet (HFD)-induced obesity. Both live and heat-killed B. virosa ameliorated HFD-impaired body weight, serum glucose level, insulin resistance, and liver steatosis. Moreover, activation of the glucagon-like peptide-1 receptor (GLP-1R) and peroxisome proliferator-activated receptor α (PPARα) was observed in the liver, and the expression levels of insulin receptor substrate (IRS)-1, IRS-2, Toll-like receptor 5 (TLR5), and zonula occludens-1 (ZO-1) were upregulated in the ileum. Finally, we demonstrated that the effect of B. virosa treatment on glucose regulation may be linked to the upregulation of GLP-1R in the liver and is not a result of colonization of the gut by B. virosa or B. virosa-produced butyrate. Our results provide a rationale for the development of Butyricimonas spp.-based therapeutics and prophylactics for hyperglycemia.
Profile of the Nasopharyngeal Microbiota Affecting the Clinical Course in COVID-19 Patients
Authors: Tchoupou Saha Ornella la fortune , Dubourg Grégory , Yacouba Abdourahamane , Bossi Vincent , Raoult Didier , Lagier Jean-Christophe
Published: May 2022

While populations at risk for severe SARS-CoV-2 infections have been clearly identified, susceptibility to the infection and its clinical course remain unpredictable. As the nasopharyngeal microbiota may promote the acquisition of several respiratory infections and have an impact on the evolution of their outcome, we studied the nasopharyngeal microbiota of COVID-19 patients in association with baseline disease-related clinical features compared to that of patients tested negative. We retrospectively analyzed 120 nasopharyngeal pseudonymized samples, obtained for diagnosis, divided into groups (infected patients with a favorable outcome, asymptomatic, and deceased patients) and patients tested negative for SARS-CoV-2, by using Illumina-16S ribosomal ribonucleic acid (rRNA) sequencing and specific polymerase chain reaction (PCR) targeting pathogens. We first found a depletion of anaerobes among COVID-19 patients, irrespective of the clinical presentation of the infection (p < 0.029). We detected 9 taxa discriminating patients tested positive for SARS-CoV-2 from those that were negative including Corynebacterium propinquum/pseudodiphtericum (p ≤ 0.05), Moraxella catarrhalis (p ≤ 0.05), Bacillus massiliamazoniensis (p ≤ 0.01), Anaerobacillus alkalidiazotrophicus (p ≤ 0.05), Staphylococcus capitis subsp. capitis (p ≤ 0.001), and Afipia birgiae (p ≤ 0.001) with 16S rRNA sequencing, and Streptococcus pneumoniae (p ≤ 0.01), Klebsiella pneumoniae (p ≤ 0.01), and Enterococcus faecalis (p ≤ 0.05) using real-time PCR. By designing a specific real-time PCR, we also demonstrated that C. propinquum is decreased in asymptomatic individuals compared to other SARS-CoV 2 positive patients. These findings indicate that the nasopharyngeal microbiota as in any respiratory infection plays a role in the clinical course of the disease. Further studies are needed to elucidate the potential role in the clinical course of the disease of M. catarrhalis, Corynebacterium accolens, and more specifically Corynebacterium propinquum/diphteriticum in order to include them as predictors of the severity of COVID-19.
Intergenerational Transfer of Persistent Bacterial Communities in Female Nile Tilapia
Authors: Abdelhafiz Yousri , Fernandes Jorge M. O. , Donati Claudio , Pindo Massimo , Kiron Viswanath
Published: May 2022

Resident microbial communities that can support various host functions play a key role in their development and health. In fishes, microbial symbionts are vertically transferred from the parents to their progeny. Such transfer of microbes in mouthbrooder fish species has not been reported yet. Here, we employed Nile tilapia (Oreochromis niloticus) to investigate the vertical transmission of microbes across generations using a 16S rRNA amplicon sequencing approach, based on the presence of bacteria in different generations. Our analysis revealed that the core microbiome in the buccal cavity and posterior intestine of parents shapes the gut microbiome of the progeny across generations. We speculate that the route of this transmission is via the buccal cavity. The identified core microbiome bacteria, namely Nocardioides, Propionibacterium, and Sphingomonas have been reported to play an essential role in the health and development of offspring. These core microbiome members could have specific functions in fish, similar to mammals.
Comparative Transcriptomics Suggests Early Modifications by Vintec® in Grapevine Trunk of Hormonal Signaling and Secondary Metabolism Biosynthesis in Response to Phaeomoniella chlamydospora and Phaeoacremonium minimum
Authors: Romeo-Oliván Ana , Chervin Justine , Breton Coralie , Lagravère Thierry , Daydé Jean , Dumas Bernard , Jacques Alban
Published: May 2022

Given their well-known antifungal abilities, species of the genusTrichodermaare of significant interest in modern agriculture. Recent studies have shown thatTrichodermaspecies can induce plant resistance against different phytopathogens. To further extend this line of investigation, we investigate herein the transcriptomic response of grapevine trunk to Vintec®, which is aTrichoderma atrovirideSC1-based commercial formulation for biological control of grapevine trunk diseases and which reduces wood colonization. The aim of the study is to understand whether the biocontrol agent Vintec®modifies the trunk response toPhaeoacremonium minimumandPhaeomoniella chlamydospora, which are two esca-associated fungal pathogens. An analysis of transcriptional regulation identifies clusters of co-regulated genes whose transcriptomic reprogramming in response to infection depends on the absence or presence of Vintec®. On one hand, the results show that Vintec®differentially modulates the expression of putative genes involved in hormonal signaling, especially those involved in auxin signaling. On the other hand, most significant gene expression modifications occur among secondary-metabolism-related genes, especially regarding phenylpropanoid metabolism and stilbene biosynthesis. Taken together, these results suggest that the biocontrol agent Vintec®induces wood responses that counteract disease development.
Methamphetamine Exposure in Adolescent Impairs Memory of Mice in Adulthood Accompanied by Changes in Neuroplasticity in the Dorsal Hippocampus
Authors: Liang Min , Zhu Li , Wang Rui , Su Hang , Ma Dongliang , Wang Hongyan , Chen Teng
Published: May 2022

Methamphetamine (METH) has been shown to alter learning and memory by affecting the neuroplasticity of the dorsal hippocampus, a key structure that undergoes extensive remodeling during adolescence. In this study, we investigated whether mid-to-late adolescent exposure to METH leads to long-lasting memory impairment. To do this, adolescents (35–48 postnatal days) were exposed to different doses of METH for 14 days and then evaluated by the Morris water maze (MWM), new object recognition test (NORT), and the Y-maze, to investigate the learning and memory abilities of mice in their adolescence and adulthood, respectively. We also detected the mRNA levels of genes associated with neuroplasticity in the dorsal hippocampus. The synaptic ultrastructure and the number of neurons and astrocytes in the dorsal hippocampus were also determined by transmission electron microscopy (TEM) and immunofluorescence (IF). Exposure to METH in mid-to-late adolescence impaired spatial memory retrieval ability and the long-term recognition memory of mice in their adulthood, but not in their adolescence. Of note, the impairment of memory capacity in adulthood was accompanied by molecular and structural changes in synapses in the dorsal hippocampus. Our results indicate that mice exposed to METH in mid-to-late adolescence have impaired memory ability in their adulthood; this may be the result of abnormal changes in the structural plasticity of the dorsal hippocampus; the causal relationship between changes in synaptic structural plasticity and memory impairment needs to be further confirmed. In summary, our study provides evidence for the detrimental consequences of adolescent addiction and the prevention of adolescent drug abuse.
Sex-Specific Neural Networks of Cued Threat Conditioning: A Pilot Study
Authors: du Plessis Kamryn C. , Basu Sreetama , Rumbell Timothy H. , Lucas Elizabeth K.
Published: May 2022

Cued threat conditioning is the most common preclinical model for emotional memory, which is dysregulated in anxiety disorders and post-traumatic stress disorder. Though women are twice as likely as men to develop these disorders, current knowledge of threat conditioning networks was established by studies that excluded female subjects. For unbiased investigation of sex differences in these networks, we quantified the neural activity marker c-fos across 112 brain regions in adult male and female mice after cued threat conditioning compared to naïve controls. We found that trained females engaged prelimbic cortex, lateral amygdala, cortical amygdala, dorsal peduncular cortex, and subparafasicular nucleus more than, and subparaventricular zone less than, trained males. To explore how these sex differences in regional activity impact the global network, we generated interregional cross-correlations of c-fos expression to identify regions that were co-active during conditioning and performed hub analyses to identify regional control centers within each neural network. These exploratory graph theory-derived analyses revealed sex differences in the functional coordination of the threat conditioning network as well as distinct hub regions between trained males and females. Hub identification across multiple networks constructed by sequentially pruning the least reliable connections revealed globus pallidus and ventral lateral septum as the most robust hubs for trained males and females, respectively. While low sample size and lack of non-associative controls are major limitations, these findings provide preliminary evidence of sex differences in the individual circuit components and broader global networks of threat conditioning that may confer female vulnerability to fear-based psychiatric disease.
Comparison of the Fungal Community, Chemical Composition, Antioxidant Activity, and Taste Characteristics of Fu Brick Tea in Different Regions of China
Authors: Chen Yulian , Chen Jiaxu , Chen Ruyang , Xiao Leike , Wu Xing , Hu Lin , Li Zongjun , Wang Yuanliang , Zhu Mingzhi , Liu Zhonghua , Xiao Yu
Published: May 2022

In this study, the fungal community structure, metabolites, antioxidant ability, and taste characteristics of five Fu brick tea (FBT) from different regions of China were determined and compared. A total of 69 operational taxonomic units (OTUs) were identified and assigned into 5 phyla and 27 genera, with Eurotium as the predominant genus in all samples. Hunan (HN) sample had the strongest fungal diversity and richness, followed by Guangxi (GX) sample, and Zhejiang (ZJ) sample had the lowest. GX sample had higher amounts of gallic acid (GA), total catechins, gallocatechin (GC), and epicatechin gallate (ECG) as well as antioxidant activity than the other samples. The levels of total phenolics, total flavonoids, epigallocatechin (EGC), catechin, epicatechin (EC), thearubigins (TRs), and theaflavins (TFs) were the highest in the ZJ sample. Guizhou (GZ) and Shaanxi (SX) samples contained the highest contents of epigallocatechin gallate (EGCG) and gallocatechin gallate (GCG), respectively. Total phenolics, GA, EC, CG, and TFs were positively associated with most of fungal genera. Total phenolic content (TPC), total flavonoid content (TFC), and most of catechins contributed to the antioxidant activities of FBT. HN sample had the strongest sourness and sweetness, ZJ sample had the strongest saltiness, SX sample had the strongest umami, and GZ sample had the strongest astringency, which was ascribed to the varied metabolites. This work reveals that FBT in different regions vary greatly in fungal community, metabolites, antioxidant activity, and taste characteristics, and provides new insight into the quality characteristics formation of FBT in different regions.
Early and Late Transcriptional Changes in Blood, Neural, and Colon Tissues in Rat Models of Stress-Induced and Comorbid Pain Hypersensitivity Reveal Regulatory Roles in Neurological Disease
Authors: Mocci Evelina , Goto Taichi , Chen Jie , Ament Seth , Traub Richard J. , Dorsey Susan G.
Published: May 2022

Background

Irritable bowel syndrome (IBS) and temporomandibular disorder (TMD) are two chronic pain conditions that frequently overlap in the same individual, more commonly in women. Stress is a significant risk factor, exacerbating or triggering one or both conditions. However, the mechanisms underlying IBS–TMD co-morbidity are mostly unknown.

Aim

To detect both specific and common stress-induced visceral hypersensitivity (SIH) and comorbid TMD–IBS pain hypersensitivity (CPH) genetic signatures over time.

Method

Twenty-four female rats were randomly assigned to one of three experimental groups: naïve, SIH, and CPH (orofacial pain plus stress). RNA was extracted from blood, colon, spinal cord, and dorsal root ganglion 1 or 7 weeks after the stress paradigm. We combined differential gene expression and co-expression network analyses to define both SIH and CPH expression profiles across tissues and time.

Results

The transcriptomic profile in blood and colon showed increased expression of genes enriched in inflammatory and neurological biological processes in CPH compared to SIH rats, both at 1 and 7 weeks after stress. In lumbosacral spinal tissue, both SIH and CPH rats compared to naïve revealed decreased expression of genes related to synaptic activity and increased expression of genes enriched in “angiogenesis,” “Neurotrophin,” and “PI3K-Akt” pathways. Compared to SIH, CPH rats showed increased expression of angiogenesis-related genes 1 week after exposure to stress, while 7 weeks post-stress the expression of these genes was higher in SIH rats. In dorsal root ganglia (DRG), CPH rats showed decreased expression of immune response genes at week 1 and inhibition of nerve myelination genes at 7 weeks compared to naïve. For all tissues, we observed higher expression of genes involved in ATP production in SIH compared to CPH at 1 week and this was reversed 7 weeks after the induction of stress.

Conclusion

Our study highlights an increased inflammatory response in CPH compared to SIH rats in the blood and colon. DRG and spinal transcriptomic profiles of both CPH and SIH rats showed inhibition of synaptic activity along with activation of angiogenesis. Targeting these biological processes may lead to a more profound understanding of the mechanisms underlying IBS–TMD comorbidities and new diagnostic and therapeutic strategies.
Assessing the Diets of Young Children and Adolescents in India: Challenges and Opportunities
Authors: Locks Lindsey M. , Shah Miloni , Bhaise Shilpa , Hibberd Patricia L. , Patel Archana
Published: May 2022

Sustainably addressing the crisis of undernutrition for children and adolescents in underserved and resource-limited communities will require, among other investments, interventions aimed at optimizing the diets of these vulnerable populations. However, to date, there are substantial global gaps in the collection of dietary data in children and adolescents. This review article summarizes the challenges and opportunities in assessing diet among children and adolescents in India. National surveys in India identify the scale of the triple burden of malnutrition (undernutrition, micronutrient deficiencies and overnutrition) in children and adolescents and assess key nutrition and food security indicators for making informed policy decisions. However, national surveys do not collect data on diet, instead relying on anthropometry, biomarkers of micronutrient deficiencies, and summary measures of diet, such as the WHO infant and young child feeding summary indicators. Sub-national surveys and the scientific literature thus fill important gaps in describing the nutrient intakes of children and adolescents in India; however large gaps remain. Future research can be improved by investments in infrastructure to streamline the assessment of diet in India. The current challenges confronting the collection and analysis of high-quality dietary data occur in both the data collection and data analysis phases. Common methods for assessing diets in low-resource settings—such as 24 h recalls and food frequency questionnaires are particularly challenging to implement well in young children and adolescents due to motivation and memory issues in young respondents. Additionally, there are challenges with parental recall including children having multiple caretakers and meals outside the home. Furthermore, analysis of dietary data is hindered by the lack of affordable, accessible software for dietary data analysis relevant to the diversity in Indian diets. New technologies can address some of the challenges in dietary data collection and analysis, but to date, there are no platforms designed for population-level dietary assessment in India. Public and private sector investment in dietary assessment, as well as collaboration of researchers and the creation of open-source platforms for the sharing of data inputs (local food lists, recipe databases, etc.) will be essential to build infrastructure to better understand the diets of children and adolescents in India and improve dietary interventions in these target groups.
A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay
Authors: Hexner-Erlichman Zufit , Fichtman Boris , Zehavi Yoav , Khayat Morad , Jabaly-Habib Haneen , Izhaki-Tavor Lee S. , Dessau Moshe , Elpeleg Orly , Spiegel Ronen
Published: May 2022

Cleft lip and/or cleft palate are a common group of birth defects that further classify into syndromic and non-syndromic forms. The syndromic forms are usually accompanied by additional physical or cognitive abnormalities. Isolated cleft palate syndromes are less common; however, they are associated with a variety of congenital malformations and generally have an underlying genetic etiology. A single report in 2019 described a novel syndrome in three individuals, characterized by cleft palate, developmental delay and proliferative retinopathy due to a homozygous non-sense mutation in the LRRC32 gene encoding glycoprotein A repetitions predominant (GARP), a cell surface polypeptide crucial for the processing and maturation of transforming growth factor β (TGF-β). We describe a patient who presented with cleft palate, prenatal and postnatal severe growth retardation, global developmental delay, dysmorphic facial features and progressive vitreoretinopathy. Whole exome sequencing (WES) revealed a very rare homozygous missense variant in the LRRC32 gene, which resulted in substitution of a highly conserved isoleucine to threonine. Protein modeling suggested this variant may negatively affect GARP function on latent TGF-β activation. In summary, our report further expands the clinical features of cleft palate, proliferative retinopathy and developmental delay syndrome and emphasizes the association of LRRC32 pathogenic variants with this new syndrome.
The Etiology of Chest Pain in Children Admitted to Cardiology Clinics and the Use Echocardiography to Screen for Cardiac Chest Pain in Children
Authors: Chen Li , Duan Hongzhou , Li Gang , Li Xiaoyan
Published: May 2022

Aims

Chest pain is a common disease in children. Most cardiac specialists use echocardiography to evaluate the etiology of and screen for children’s cardiac chest pain. We analyzed the etiology and echocardiography results of children with chest pain in pediatric cardiology clinics, clarified the disease spectrum and evaluated the diagnostic value of echocardiography in screening cardiac chest pain in children.

Methods and Results

The clinical data of children with chest pain aged younger than 18 years who admitted to the pediatric cardiology clinic of Beijing Anzhen Hospital between 2005 and 2019 were analyzed. The patients were divided into three groups, including the preschool group, the school-age group and the adolescent group. Total 3,477 children were enrolled in this study. 232 (6.7%) patients were caused by cardiac diseases and chest pain was of non-cardiac origin in 3,245 patients (93.3%). The incidence of non-cardiac chest pain in the adolescent group was significantly lower than the other two groups, respectively (91.4 vs. 94.9 vs. 94.3%,P< 0.05). In the preschool group, most of the patients were girls (51.4%), while in the school-age group and the adolescent group, most of the patients were boys (P< 0.05). Among the children (n= 3,205) who underwent echocardiography, 108 children had positive results, and 3,097 children had negative results. Among the 108 positive results, 10 cases of cardiac diseases were related to chest pain. The sensitivity, specificity of echocardiography in the diagnosis of cardiac chest pain were 6.7, and 96.9%, while the positive predictive value and negative predictive value was 12.96 and 93.67%, respectively.

Conclusion

In children with chest pain who are admitted to pediatric cardiology clinics, chest pain is mostly benign and rarely due to cardiac diseases. The use of echocardiography in evaluating cardiac chest pain in children is of little diagnostic value and leads to excess costs for patients and the health care system.
Association of Mineralocorticoid Receptor Antagonists With the Mortality and Cardiovascular Effects in Dialysis Patients: A Meta-analysis
Authors: Gou Wen-Jun , Zhou Fa-Wei , Providencia Rui , Wang Bo , Zhang Heng , Hu Shou-Liang , Gao Xiao-Li , Tuo Yan-hong , Zhang Yong , Li Tian
Published: May 2022

Whether Mineralocorticoid receptor antagonists (MRA) reduce mortality and cardiovascular effects of dialysis patients remains unclear. A meta-analysis was designed to investigate whether MRA reduce mortality and cardiovascular effects of dialysis patients, with a registration in INPLASY (INPLASY2020120143). The meta-analysis revealed that MRA significantly reduced all-cause mortality (ACM) and cardiovascular mortality (CVM). Patients receiving MRA presented improved left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF), decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP). There was no significant difference in the serum potassium level between the MRA group and the placebo group. MRA vs. control exerts definite survival and cardiovascular benefits in dialysis patients, including reducing all-cause mortality and cardiovascular mortality, LVMI, and arterial blood pressure, and improving LVEF. In terms of safety, MRA did not increase serum potassium levels for dialysis patients with safety.

Systematic Review Registration: (https://inplasy.com/inplasy-protocol-1239-2/), identifier (INPLASY2020120143).
Aloe-Emodin Induces Mitochondrial Dysfunction and Pyroptosis by Activation of the Caspase-9/3/Gasdermin E Axis in HeLa Cells
Authors: Li Tonghui , Shi Liuliu , Liu Wenqiang , Hu Xuhao , Hui Yuanjian , Di Maojun , Xue Shen , Zheng Yan , Yao Mengjuan , Li Chen , Meng Kun
Published: May 2022

Aloe-emodin (1,8-dihydroxy-3-hydroxymethyl-anthraquinone), derived from some Chinese edible medicinal herbs, exerts a potential anticancer activity on various cancer cells, making it a drug candidate for cancer therapy. Yet, the role of aloe-emodin in pyroptosis, a new type of cell death, is uncharacterized. In this study, we explored the molecular mechanisms of aloe-emodin-triggered pyroptosis. Aloe-emodin inhibited proliferation and migration and triggered caspase-dependent cell death of HeLa cells in a dose-dependent manner. Aloe-emodin caused mitochondrial dysfunction and induced pyroptosis by activating the caspase-9/3/GSDME axis. Transcriptional analysis showed extensive changes in gene expressions in cellular pathways, including MAPK, p53, and PI3K-Akt pathways when treated with aloe-emodin. This study not only identified a novel role of aloe-emodin in pyroptotic cell death, but also performed a systematical genome-wide analysis of cellular pathways responding to aloe-emodin, providing a theoretical basis for applying anthraquinone derivatives in the treatment of GSDME-expressing cancers.
Assessment of Adverse Drug Events, Their Risk Factors, and Management Among Patients Treated for Multidrug-Resistant TB: A Prospective Cohort Study From Pakistan
Authors: Khan Farman Ullah , Khan Amjad , Khan Faiz Ullah , Hayat Khezar , Rehman Asim ur. , Chang Jie , Khalid Waseem , Noor Sidra , Khan Asad , Fang Yu
Published: May 2022

Background: Multidrug-resistant tuberculosis (MDR-TB) is a growing public health problem. Treatment regimens used against MDR-TB are costly, prolonged, and associated with more side effects as compared with the drug-susceptible tuberculosis. This study was framed to determine the incidence of adverse drug events, risk factors, and their management in MDR-TB patients.

Methods: This prospective follow-up cohort study was conducted at the site of programmatic management of drug-resistant TB located at the Pakistan Institute of Medical Sciences, Islamabad. All patients, irrespective of their age, gender, and ethnicity, were included in the study. Adverse drug events were observed in patients at different time points during the study. Patients enrolled for the treatment from January 2018 were prospectively followed till December 2020 up to their end treatment outcomes.

Results: Out of 126 MDR-TB patients enrolled for treatment, 116 met the inclusion criteria and were included in the final analysis. Most patients (50.9%) were between 18 and 45 years of age. A minimum of one adverse event was experienced by (50.9%) patients. Of all the adverse events, gastrointestinal disorders were more frequent (47.4%), followed by arthralgia (28.4%) and psychiatric disturbance (20.6%). Furthermore, multivariate analysis showed a significant association with the incidence of adverse events in patients with age group above 60 years (odds ratio (OR) 4.50; 95% CI 1.05-19.2), active smokers (OR 4.20; 95% CI 1.31-13.4), delayed reporting to the TB center (OR 4.03; 95% CI 1.34-12.1), and treatment without bedaquiline regime (OR 3.54; 95% CI 1.23-10.1). Most of the patients (94.6%), counseled by the pharmacist, were found to be satisfied with the information provided and looked for more pharmacist counseling opportunities in the management of MDR-TB.

Conclusion: Current findings recommend that ADEs might be well managed by timely identification and reporting. Bedaquiline coupled with other active medications lowered the chance of ADEs in MDR-TB patients. Elderly patients, active smoking behavior, and those who have a delay in the treatment initiation are more prone to ADEs. Clinical pharmacist’s contribution to TB control programs may help caregivers and patients concerning the rational use of medication, early detection, and management of ADEs.
Plasma Rivaroxaban Level in Patients With Early Stages of Chronic Kidney Disease—Relationships With Renal Function and Clinical Events
Authors: Sin Chun-Fung , Wong Ka-Ping , Wong Hoi-Man , Siu Chung-Wah , Yap Desmond Y. H.
Published: May 2022

Introduction Drug accumulation of rivaroxaban is a concern in patients with chronic kidney disease (CKD). Data regarding the plasma rivaroxaban levels in early CKD patients and its relationship with clinical events is lacking. Methods Early CKD patients (Stage 1–3) with atrial fibrillation who received rivaroxaban (15 or 20 mg daily) were recruited. Plasma rivaroxaban levels were measured at 2 hours (peak) and 24 hours (trough) after drug administration, and correlated with eGFR and clinically significant events during the follow-up period (1 January 2018 to 31 October 2021). Results Ninety-two patients were included (CKD stage 1 n=10, stage 2 n=53, stage 3 n=29). Plasma trough levels in patients with stage 3 CKD were significantly higher than those with stage 2 and 1 CKD (66.0±34.9 ng/ml vs. 35.7 ± 24.7 ng/ml vs. 34.7 ± 26.2 ng/ml, respectively, p=0.005), and showed inverse relationship with eGFR (r=0.391, p=0.001) in patients receiving 20 mg daily. The plasma trough rivaroxaban level correlated with PT and APTT (r = 0.650 and 0.44, respectively, p<0.001 for both). Plasma trough rivaroxaban level in those with bleeding were higher than those who did not (59.9 ± 35.6 ng/ml vs. 41.1 ± 29.2 ng/ml, p=0.011), and multivariate analysis suggested that plasma trough rivaroxaban level was associated with the rate of bleeding complications (OR: 1.020, 95% CI 1.002-1.038, p=0.028). Conclusion Plasma trough rivaroxaban levels correlated with renal function in early CKD patients, and its measurement may help dosage optimization in patients with renal impairment. Moreover, our data suggests that there may be an association between plasma trough rivaroxaban level and the rate of bleeding complication
Alternative Therapy of Psychosis: Potential Phytochemicals and Drug Targets in the Management of Schizophrenia
Authors: Saleem Ammara , Qurat-ul-Ain  , Akhtar Muhammad Furqan
Published: May 2022

Schizophrenia is a chronic mental and behavioral disorder characterized by clusters of symptoms including hallucinations, delusions, disorganized thoughts and social withdrawal. It is mainly contributed by defects in dopamine, glutamate, cholinergic and serotonergic pathways, genetic and environmental factors, prenatal infections, oxidative stress, immune system activation and inflammation. Management of schizophrenia is usually carried out with typical and atypical antipsychotics, but it yields modest benefits with a diversity of side effects. Therefore, the current study was designed to determine the phytochemicals as new drug candidates for treatment and management of schizophrenia. These phytochemicals alter and affect neurotransmission, cell signaling pathways, endocannabinoid receptors, neuro-inflammation, activation of immune system and status of oxidative stress. Phytochemicals exhibiting anti-schizophrenic activity are mostly flavonoids, polyphenols, alkaloids, terpenoids, terpenes, polypropanoids, lactones and glycosides. However, well-designed clinical trials are consequently required to investigate potential protective effect and therapeutic benefits of these phytochemicals against schizophrenia.
Momordica charantia L.—Diabetes-Related Bioactivities, Quality Control, and Safety Considerations
Authors: Çiçek Serhat S.
Published: May 2022

Momordica charantia L. (Cucurbitaceae), commonly known as bitter gourd or bitter melon, is widely cultivated in many tropical and subtropical regions of the world, where its unripe fruits are eaten as a vegetable. Apart from its culinary use, M. charantia has a long history in traditional medicine, serving as stomachic, laxative or anthelmintic, and, most notably, for the treatment of diabetes and its complications. Its antidiabetic properties and its beneficial effects on blood glucose and lipid concentrations have been reported in numerous in vitro and in vivo studies, but the compounds responsible for the observed effects have not yet been adequately described. Early reports were made for charantin, a mixture of two sterol glucosides, and the polypeptide p-insulin, but their low concentrations in the fruits or their limited bioavailability cannot explain the observed therapeutic effects. Still, for many decades the search for more reasonable active principles was omitted. However, in the last years, research more and more focused on the particular cucurbitane-type triterpenoids abundant in the fruits and other parts of the plant. This mini review deals with compounds isolated from the bitter gourd and discusses their bioactivities in conjunction with eventual antidiabetic or adverse effects. Furthermore, methods for the quality control of bitter gourd fruits and preparations will be evaluated for their meaningfulness and their potential use in the standardization of commercial preparations.
Cecal Metabolomic Fingerprint of Unscathed Rats: Does It Reflect the Good Response to a Provocative Decompression?
Authors: Desruelle Anne-Virginie , Maistre Sébastien de , Gaillard Sandrine , Richard Simone , Tardivel Catherine , Martin Jean-Charles , Blatteau Jean-Eric , Boussuges Alain , Rives Sarah , Risso Jean-Jacques , Vallee Nicolas
Published: May 2022

On one side, decompression sickness (DCS) with neurological disorders lead to a reshuffle of the cecal metabolome of rats. On the other side, there is also a specific and different metabolomic signature in the cecum of a strain of DCS-resistant rats, that are not exposed to hyperbaric protocol. We decide to study a conventional strain of rats that resist to an accident-provoking hyperbaric exposure, and we hypothesize that the metabolomic signature put forward may correspond to a physiological response adapted to the stress induced by diving. The aim is to verify and characterize whether the cecal compounds of rats resistant to the provocative dive have a cecal metabolomic signature different from those who do not dive. 35 asymptomatic diver rats are selected to be compared to 21 rats non-exposed to the hyperbaric protocol. Because our aim is essentially to study the differences in the cecal metabolome associated with the hyperbaric exposure, about half of the rats are fed soy and the other half of maize in order to better rule out the effect of the diet itself. Lower levels of IL-1β and glutathione peroxidase (GPX) activity are registered in blood of diving rats. No blood cell mobilization is noted. Conventional and ChemRICH approaches help the metabolomic interpretation of the 185 chemical compounds analyzed in the cecal content. Statistical analysis show a panel of 102 compounds diet related. 19 are in common with the hyperbaric protocol effect. Expression of 25 compounds has changed in the cecal metabolome of rats resistant to the provocative dive suggesting an alteration of biliary acids metabolism, most likely through actions on gut microbiota. There seem to be also weak changes in allocations dedicated to various energy pathways, including hormonal reshuffle. Some of the metabolites may also have a role in regulating inflammation, while some may be consumed for the benefit of oxidative stress management.
Standard Thermodynamic Properties, Biosynthesis Rates, and the Driving Force of Growth of Five Agricultural Plants
Authors: Popovic Marko , Minceva Mirjana
Published: May 2022

Graphical Abstract

Intercepted photosynthetic energy q is partly converted into usable photosynthetic energy, ΔpsG, with an efficiency μ. A part of ΔpsG is used for biosynthesis ΔbsG, which is represented by the growth reaction in the bottom, where “Bio” denotes newly formed live matter. The remaining energy is the driving force of growth, ΔDFG, used to make growth at a desired rate. The background for the figure was taken from Pixabay (https://www.pixabay.com/), image ID number: 4779065, under Pixabay license.
High-Quality Genome Assembly of Olea europaea subsp. cuspidata Provides Insights Into Its Resistance to Fungal Diseases in the Summer Rain Belt in East Asia
Authors: Wang Li , Zhang Jianguo , Peng Dan , Tian Yang , Zhao Dandan , Ni Wanning , Long Jinhua , Li Jinhua , Zeng Yanfei , Wu Zhiqiang , Tang Yiyun , Wang Zhaoshan
Published: May 2022

The olive tree (Olea europaea L.) is the most iconic fruit crop of the Mediterranean Basin. Since the plant was introduced to China in the 1960s, the summer rain climate makes it susceptible to pathogens, leading to some olive diseases. Olea europaea L. subsp. cuspidata is natively distributed in the Yunnan province of China. It has a smaller fruit size, lower oil content, and higher resistance compared to subsp. europaea, which makes subsp. cuspidata a critical germplasm resource to be investigated. Here, a high-quality genome of subsp. cuspidata with 1.38 Gb in size was assembled and anchored onto 23 pseudochromosomes with a mounting rate of 85.57%. It represents 96.6% completeness [benchmarking universal single-copy orthologs (BUSCO)] with a contig N50 of 14.72 Mb and a scaffold N50 of 52.68 Mb, which shows a significant improvement compared with other olive genomes assembled. The evaluation of the genome assembly showed that 92.31% of resequencing reads and an average of 96.52% of assembled transcripts could be aligned to the assembled genome. We found that a positively selected gene, evm.model.Chr16.1133, was shared with the results of transcriptome analysis. This gene belongs to the susceptible gene and negatively regulates the disease resistance process. Furthermore, we identified the Cercospora genus which causes the leaf spot disease in the infected leaves. The high-quality chromosome-level genomic information presented here may facilitate the conservation and utilization of germplasm resources of this subspecies and provide an essential genetic basis for further research into the differences in oil content and resistance between subsp. cuspidata and europaea.
The Experiences of Parents and Infants Using a Home-Based Art Intervention Aimed at Improving Wellbeing and Connectedness in Their Relationship
Authors: Armstrong Victoria Gray , Ross Josephine
Published: May 2022

During the period of COVID-19 restrictions, we offered vulnerable families with 0 to 3 year old children boxes of art resources and guided creative activities to do together at home. This paper explores families’ experiences of this intervention, highlighting their perceptions of change in wellbeing and attachment. There is a developing case for the social benefits of art, including the impact of arts on mental health and on the wellbeing of children. However, we know that social factors impact upon arts participation, and existing inequalities and mental health difficulties have been exacerbated in the context of the pandemic. This project aimed to adapt to restrictions, to provide a meaningful remote intervention, supporting parent-infant dyads to have positive interactions through art making. We sought to explore the benefits of this intervention for infants and parents with a view to understanding more about the psychological benefits of art participation and about ways to engage families into art making, as well as thinking about how best we can evidence these kinds of arts in health interventions. Preliminary findings showed promising outcomes from the art boxes and this paper brings together the full results, primarily based on interviews with sixteen parents and four referrers alongside collected feedback. We highlight potential mechanisms for change within the intervention and detail the perceived impact of the art boxes in supporting attachment. Parents felt that the art-boxes facilitated changes in their own wellbeing that would make them more available to connection, and recognised changes for babies that reflected their increased capacity to mentalise about their child. Importantly, there were also concrete changes for the dyad that represented improved connection, such as more playful time together and increased shared attention and eye contact. Our observations suggest that the quality of the parent-infant relationship benefited from home-based art intervention, and we speculate about the potential efficacy of this approach beyond the pandemic.
Emotion Regulation Strategies and Sense of Life Meaning: The Chain-Mediating Role of Gratitude and Subjective Wellbeing
Authors: Lin Zhengzheng
Published: May 2022

This study aimed to explore the mechanism of college students’ meaning of life. The Emotion Regulation Questionnaire, the Gratitude Questionnaire Six-Item Form, the General Wellbeing Schedule, the Meaning in Life Questionnaire were used as measurement instruments. In total, 1,312 valid responses were obtained. The results showed that the cognitive reappraisal and expression suppression strategies were significantly positively and negatively correlated with gratitude, subjective wellbeing, and the sense of life meaning, respectively. Further, Emotion regulation strategies can affect college students’ sense of life meaning through three paths: the mediating effect of gratitude; the mediating effect of subjective wellbeing; the chain mediating effect of gratitude and subjective wellbeing. This study illuminated the roles of gratitude, and subjective wellbeing in influencing the sense of life meaning among the Chinese college students. Limitations and future research directions are discussed.