bluuebunny/crossref_metadata_2025 huggingface dataset:
Beneath the Bark: Assessing Woody Stem Water and Carbon Fluxes and Its Prevalence Across Climates and the Woody Plant Phylogeny
Authors: Berry Z. Carter , Ávila-Lovera Eleinis , De Guzman Mark E. , O’Keefe Kimberly , Emery Nathan C.
Published: July 2021

While woody stems are known to influence carbon and water dynamics, direct exchange with the atmosphere is seldom quantified, limiting our understanding of how these processes influence the exchange of mass and energy. The presence of woody stem chlorophyll in a diversity of climates and across a range of species suggests an evolutionary advantage to sustaining carbon assimilation and water relations through permeable stem tissue. However, no formal evaluation of this hypothesis has been performed. In this mini-review, we explore the interactions between woody stems and the atmosphere by examining woody stem photosynthesis and bark-atmosphere water exchange. Specifically, we address the following questions: (1) How do water and carbon move between the atmosphere and woody stems? (2) In what climate space is woody stem photosynthesis and bark water uptake advantageous? (3) How ubiquitous across plant families is woody stem photosynthesis and bark-atmosphere water exchange? In the literature, only seven species have been identified as exhibiting bark water uptake while over 300 species are thought to conduct woody stem photosynthesis. The carbon dioxide and water gained from these processes can offset respiration costs and improve plant water balance. These species span diverse biomes suggesting a broad prevalence of bark-atmosphere permeability. Finally, our results demonstrate that there may be an evolutionary component as demonstrated by a high Pagel’s lambda for the presence of stem photosynthesis. We end with recommendations for future research that explores how bark water and carbon interactions may impact plant function and mass flow in a changing climate.
MEF2C Common Genetic Variation Is Associated With Different Aspects of Cognition in Non-Hispanic White and Caribbean Hispanic Non-demented Older Adults
Authors: Sunderaraman Preeti , Cosentino Stephanie , Schupf Nicole , Manly Jennifer , Gu Yian , Barral Sandra
Published: July 2021

Objectives

Myocyte Enhancer Factor 2C (MEF2C) is identified as a candidate gene contributing to the risk of developing Alzheimer’s disease. However, little is known about whether MEF2C plays a role in specific aspects of cognition among older adults. The current study investigated the association of common variants in the MEF2C gene with four cognitive domains including memory, visuospatial functioning, processing speed and language among non-demented individuals.

Method

Participants from two ethnic groups, Non-Hispanic White (NHW; n = 537) and Caribbean Hispanic (CH; n = 1,197) from the Washington Heights-Inwood Community Aging Project (WHICAP) study, were included. Genetic association analyses using WHICAP imputed genome-wide data (GWAS) were conducted for the various cognition domains.

Results

Single nucleotide polymorphisms (SNP) variants in the MEF2C gene showed nominally significant associations in all cognitive domains but for different SNPs across both the ethnic groups. In NHW participants, the strongest associations were present for memory (rs302484), language (rs619584), processing speed (rs13159808), and visuospatial functioning (several SNPs). In CH, strongest associations were observed for memory (rs34822815), processing speed (rs304141), visuospatial functioning (rs10066711 and rs10038371), and language (rs304153).

Discussion

MEF2C variant-cognitive associations shed light on an apparent role for MEF2C in both memory and non-memory aspects of cognition in individuals from NHW and CH ancestries. However, the little overlap in the specific SNP-cognition associations in CH versus NHW highlights the differences in genetic architectural variations among those from different ancestries that should be considered while studying the MEF2C gene.
Hidden Patterns of Anti-HLA Class I Alloreactivity Revealed Through Machine Learning
Authors: Vittoraki Angeliki G. , Fylaktou Asimina , Tarassi Katerina , Tsinaris Zafeiris , Siorenta Alexandra , Petasis George Ch. , Gerogiannis Demetris , Lehmann Claudia , Carmagnat Maryvonnick , Doxiadis Ilias , Iniotaki Aliki G. , Theodorou Ioannis
Published: July 2021

Detection of alloreactive anti-HLA antibodies is a frequent and mandatory test before and after organ transplantation to determine the antigenic targets of the antibodies. Nowadays, this test involves the measurement of fluorescent signals generated through antibody–antigen reactions on multi-beads flow cytometers. In this study, in a cohort of 1,066 patients from one country, anti-HLA class I responses were analyzed on a panel of 98 different antigens. Knowing that the immune system responds typically to “shared” antigenic targets, we studied the clustering patterns of antibody responses against HLA class I antigens without any a priori hypothesis, applying two unsupervised machine learning approaches. At first, the principal component analysis (PCA) projections of intra-locus specific responses showed that anti-HLA-A and anti-HLA-C were the most distantly projected responses in the population with the anti-HLA-B responses to be projected between them. When PCA was applied on the responses against antigens belonging to a single locus, some already known groupings were confirmed while several new cross-reactive patterns of alloreactivity were detected. Anti-HLA-A responses projected through PCA suggested that three cross-reactive groups accounted for about 70% of the variance observed in the population, while anti-HLA-B responses were mainly characterized by a distinction between previously described Bw4 and Bw6 cross-reactive groups followed by several yet undocumented or poorly described ones. Furthermore, anti-HLA-C responses could be explained by two major cross-reactive groups completely overlapping with previously described C1 and C2 allelic groups. A second feature-based analysis of all antigenic specificities, projected as a dendrogram, generated a robust measure of allelic antigenic distances depicting bead-array defined cross reactive groups. Finally, amino acid combinations explaining major population specific cross-reactive groups were described. The interpretation of the results was based on the current knowledge of the antigenic targets of the antibodies as they have been characterized either experimentally or computationally and appear at the HLA epitope registry.
SARS-CoV-2 Poorly Replicates in Cells of the Human Blood-Brain Barrier Without Associated Deleterious Effects
Authors: Constant Orianne , Barthelemy Jonathan , Bolloré Karine , Tuaillon Edouard , Gosselet Fabien , Chable-Bessia Christine , Merida Peggy , Muriaux Delphine , Van de Perre Philippe , Salinas Sara , Simonin Yannick
Published: July 2021

Various neurological symptoms have been associated to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection including headache, fever, anosmia, ageusia, but also, encephalitis, Guillain-Barre syndrome and ischemic stroke. Responsible for the current coronavirus disease (COVID-19) pandemic, SARS-CoV-2 may access and affect the central nervous system (CNS) by several pathways such as axonal retrograde transport or through interaction with the blood-brain barrier (BBB) or blood-cerebrospinal fluid (CSF) barrier. Here, we explored the molecular and cellular effects of direct SARS-CoV-2 infection of human BBB cells. We observed low replication of SARS-CoV-2 that was accompanied by very moderate inflammatory response. Using a human in vitro BBB model, we also described low replication levels without strong inflammatory response or modulation of endothelium integrity. Finally, using serum samples from COVID-19 patients, we highlighted strong concentrations of pro-inflammatory factors that did not perturb BBB integrity after short term exposure. Altogether, our results show that the main mechanism of brain access following SARS-CoV-2 infection does not seem to be directed by brain infection through endothelial cells.
Active Inflammatory and Chronic Structural Damages of Sacroiliac Joint in Patients With Radiographic Axial Spondyloarthritis and Non-Radiographic Axial Spondyloarthritis
Authors: Tu Liudan , Lin Churong , Xie Ya , Wang Xiaohong , Wei Qiujing , Zhang Yanli , Gu Jieruo
Published: July 2021

Objective

Evaluate the MRI evidence of active inflammatory and chronic structural damages in radiographic axial spondyloarthritis (r-axSpA) and non-radiographic axial spondyloarthritis (nr-axSpA).

Methods

A retrospective review of 253 patients who underwent sacroiliac joint (SIJ) MRI between June 2014 and December 2019 was performed. MRI images including short tau inversion recovery scan and T1-weighted spin echo scans were assessed using the Spondyloarthritis Research Consortium of Canada (SPARCC) score and SPARCC MRI SIJ structural score by two independent readers.

Results

Higher mean score of inflammatory (SPARCC) was seen in r-axSpA patients when compared with nr-axSpA patients (8.08 vs 4.37, P<0.05). Frequencies of MRI structural lesions in r-axSpA patients and nr-axSpA patients were as follows: erosion (65.84 vs 88.23%, P=0.002), backfill (33.17 vs 13.73%, P<0.001), fat metaplasia (79.21 vs 60.78%, P=0.01), and ankylosis (37.13 vs 1.96%, P<0.001). Patients with r-axSpA had a higher mean score for fat metaplasia (8.93 vs 4.06, P=0.0003) and ankylosis (4.49 vs 0.04, P<0.001).

Conclusion

More active inflammatory and chronic structural damages except for erosion were seen in r-axSpA patients than nr-axSpA patients, while higher percentage of nr-axSpA patients presented with erosion in MRI.
Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation
Authors: Estfanous Shady , Daily Kylene P. , Eltobgy Mostafa , Deems Nicholas P. , Anne Midhun N. K. , Krause Kathrin , Badr Asmaa , Hamilton Kaitlin , Carafice Cierra , Hegazi Ahmad , Abu Khweek Arwa , Kelani Hesham , Nimjee Shahid , Awad Hamdy , Zhang Xiaoli , Cormet-Boyaka Estelle , Haffez Hesham , Soror Sameh , Mikhail Adel , Nuovo Gerard , Barrientos Ruth M. , Gavrilin Mikhail A. , Amer Amal O.
Published: July 2021

Autophagy is a proposed route of amyloid-β (Aβ) clearance by microglia that is halted in Alzheimer’s Disease (AD), though mechanisms underlying this dysfunction remain elusive. Here, primary microglia from adult AD (5xFAD) mice were utilized to demonstrate that 5xFAD microglia fail to degrade Aβ and express low levels of autophagy cargo receptor NBR1. In 5xFAD mouse brains, we show for the first time that AD microglia express elevated levels of microRNA cluster Mirc1/Mir17-92a, which is known to downregulate autophagy proteins. By in situ hybridization in post-mortem AD human tissue sections, we observed that the Mirc1/Mir17-92a cluster member miR-17 is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We show that NBR1 expression is negatively correlated with expression of miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation, autophagy, and NBR1 puncta formation in vitro and improves NBR1 expression in vivo. These findings offer a mechanism behind dysfunctional autophagy in AD microglia which may be useful for therapeutic interventions aiming to improve autophagy function in AD.
A Deep Learning Approach in Optical Inspection to Detect Hidden Hardware Trojans and Secure Cybersecurity in Electronics Manufacturing Supply Chains
Authors: Kulkarni Ameya , Xu Chengying
Published: July 2021

Deep learning methods have been extensively studied and have been proven to be very useful in multiple fields of technology. This paper presents a deep learning approach to optically detect hidden hardware trojans in the manufacturing and assembly phase of printed circuit boards to secure electronic supply chains. Trojans can serve as backdoors of accessing on chip data, can potentially alter functioning and in some cases may even deny intended service of the chip. Apart from consumer electronics, printed circuit boards are used in mission critical applications like military and space equipment. Security compromise or data theft can have severe impact and thus demand research attention. The advantage of the proposed method is that it can be implemented in a manufacturing environment with limited training data. It can also provide better coverage in detection of hardware trojans over traditional methods. Image recognition algorithms need to have deeper penetration inside the training layers for recognizing physical variations of image patches. However, traditional network architectures often face vanishing gradient problem when the network layers are added. This hampers the overall accuracy of the network. To solve this a Residual network with multiple layers is used in this article. The ResNet34 algorithm can identify manufacturing tolerances and can differentiate between a manufacturing defect and a hardware trojan. The ResNet operates on the fundamental principle of learning from the residual of the output of preceding layer. In the degradation issue, it is observed that, a shallower network performs better than deeper network. However, this is with the downside of lower accuracy. Thus, a skip connection is made to provide an alternative path for the gradient to skip forward the training of few layers and add in multiple repeating blocks to achieve higher accuracy and lower training times. Implementation of this method can bolster automated optical inspection setup used to detect manufacturing variances on a printed circuit board. The results show a 98.5% accuracy in optically detecting trojans by this method and can help cut down redundancy of physically testing each board. The research results also provide a new consideration of hardware trojan benchmarking and its effect on optical detection.
PPOS Protocol Effectively Improves the IVF Outcome Without Increasing the Recurrence Rate in Early Endometrioid Endometrial Cancer and Atypical Endometrial Hyperplasia Patients After Fertility Preserving Treatment
Authors: Chen Jiazhou , Cheng Yali , Fu Wei , Peng Xiandong , Sun Xiaoxi , Chen Hua , Chen Xiaojun , Yu Min
Published: July 2021

Objective: To investigate the effectiveness and recurrence risk of different ovulation stimulation protocols in early-stage endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) patients after successful fertility preserving treatment.

Design: A retrospective review of clinical files between June 2012 and July 2018.

Setting: University hospital.

Patients: Ninety seven women (74 AEH and 23 early-stage EEC patients) underwent in vitro fertilization (IVF) and frozen-thawed embryo transfer (FET) after successful fertility preserving treatment. All patients received megestrol acetate which was initiated immediately after AEH or EEC diagnosis by hysteroscopy. Fertility treatment was initiated after confirmation of complete response by two consecutive hysteroscopic evaluations and endometrium biopsy in a 3-month interval. Women with tubal factors underwent IVF treatment directly. Women who failed to conceive spontaneously within 12 months or after other infertility treatments like ovulation induction for 6 consecutive months or 2 consecutive artificial insemination failures were also offered IVF treatment.

Main Outcome Measure (s): The clinical and laboratory embryo data, clinical pregnancy outcomes and endometrial disease recurrence rates.

Results: Compared with the standard regimen group, the good-quality embryo rate was higher in progestin primed ovarian stimulation (PPOS) regimen group (P = 0.034). Univariate analysis showed significant differences in age (P = 0.033), treatment time of endometrial lesions (P < 0.001), and duration of Gn treatment (P = 0.018) between the recurrent and non-recurrent groups. In the adjusted model of multivariate logistic regression analysis, the age (P = 0.014) at ovulation induction and treatment time of endometrial lesions (P < 0.001) were significantly correlated with the recurrence of endometrial disease.

Conclusions: The PPOS protocol is a feasible and safe strategy to stimulate ovulation during IVF after fertility preservation therapy, and the age at ovulation induction and treatment time of endometrial lesions are two stable predictors of recurrence in endometrial diseases.
Revisiting the Radiobiology of Targeted Alpha Therapy
Authors: Pouget Jean-Pierre , Constanzo Julie
Published: July 2021

Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of 223RaCl2 for patients with metastatic castration-resistant prostate cancer and the development of several alpha emitter-based radiopharmaceuticals. It is acknowledged that alpha particles are highly cytotoxic because they produce complex DNA lesions. Hence, the nucleus is considered their critical target, and many studies did not report any effect in other subcellular compartments. Moreover, their physical features, including their range in tissues (<100 μm) and their linear energy transfer (50–230 keV/μm), are well-characterized. Theoretically, TAT is indicated for very small-volume, disseminated tumors (e.g., micrometastases, circulating tumor cells). Moreover, due to their high cytotoxicity, alpha particles should be preferred to beta particles and X-rays to overcome radiation resistance. However, clinical studies showed that TAT might be efficient also in quite large tumors, and biological effects have been observed also away from irradiated cells. These distant effects are called bystander effects when occurring at short distance (<1 mm), and systemic effects when occurring at much longer distance. Systemic effects implicate the immune system. These findings showed that cells can die without receiving any radiation dose, and that a more complex and integrated view of radiobiology is required. This includes the notion that the direct, bystander and systemic responses cannot be dissociated because DNA damage is intimately linked to bystander effects and immune response. Here, we provide a brief overview of the paradigms that need to be revisited.
Student Outcomes From a Large-Enrollment Introductory Course-Based Undergraduate Research Experience on Soil Microbiomes
Authors: Lo Stanley M. , Le Bryan D.
Published: July 2021

In recent years, national reports have called for undergraduate laboratory education that engages students in authentic research experiences. As a result, a number of course-based undergraduate research experiences (CUREs) have been developed in biological sciences and some specifically in microbiology. Students benefit from CUREs much like in traditional mentored research experiences, where students carry out independent projects in faculty laboratories. These benefits include increased self-efficacy in research skills, enhanced identification as scientists, and higher graduation rates in science, technology, engineering, and mathematics majors. Because mentored research experiences are not readily available to every student, CUREs represent a potential mechanism to democratize the research experience by providing such opportunities to all students. However, many of existing CUREs described in the literature are designed for advanced undergraduates or are limited to a small number of students. Here, we report student outcomes from a large-enrollment introductory CURE on soil microbiomes that engages students in a real-world context with microbiology. In pre- and post-course surveys, students reported significant gains in self-efficacy on a number of research skills. These results are triangulated with post-course survey data on project ownership, sense of community, and CURE design elements such as collaboration, iteration, discovery, and relevance.
Reducing the Risk of Transmission of Critical Antimicrobial Resistance Determinants From Contaminated Pork Products to Humans in South-East Asia
Authors: Sirichokchatchawan Wandee , Apiwatsiri Prasert , Pupa Pawiya , Saenkankam Imporn , Khine Nwai Oo , Lekagul Angkana , Lugsomya Kittitat , Hampson David J. , Prapasarakul Nuvee
Published: July 2021

Antimicrobial resistance (AMR) is a critical challenge worldwide as it impacts public health, especially via contamination in the food chain and in healthcare-associated infections. In relation to farming, the systems used, waste management on farms, and the production line process are all determinants reflecting the risk of AMR emergence and rate of contamination of foodstuffs. This review focuses on South East Asia (SEA), which contains diverse regions covering 11 countries, each having different levels of development, customs, laws, and regulations. Routinely, here as elsewhere antimicrobials are still used for three indications: therapy, prevention, and growth promotion, and these are the fundamental drivers of AMR development and persistence. The accuracy of detection of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARG) depends on the laboratory standards applicable in the various institutes and countries, and this affects the consistency of regional data.Enterobacteriaceaesuch asEscherichia coliandKlebsiella pneumoniaeare the standard proxy species used for indicating AMR-associated nosocomial infections and healthcare-associated infections. Pig feces and wastewater have been suspected as one of the hotspots for spread and circulation of ARB and ARG. As part of AMR surveillance in a One Health approach, clonal typing is used to identify bacterial clonal transmission from the production process to consumers and patients – although to date there have been few published definitive studies about this in SEA. Various alternatives to antibiotics are available to reduce antibiotic use on farms. Certain of these alternatives together with improved disease prevention methods are essential tools to reduce antimicrobial usage in swine farms and to support global policy. This review highlights evidence for potential transfer of resistant bacteria from food animals to humans, and awareness and understanding of AMR through a description of the occurrence of AMR in pig farm food chains under SEA management systems. The latter includes a description of standard pig farming practices, detection of AMR and clonal analysis of bacteria, and AMR in the food chain and associated environments. Finally, the possibility of using alternatives to antibiotics and improving policies for future strategies in combating AMR in a SEA context are outlined.
Molecular Characterization of Advanced Colorectal Cancer Using Serum Proteomics and Metabolomics
Authors: Rao Jun , Wan Xianghui , Tou Fangfang , He Qinsi , Xiong Aihua , Chen Xinyi , Cui Wenhao , Zheng Zhi
Published: July 2021

Colorectal cancer (CRC) is a growing public health concern due to its high mortality rate. Currently, there is a lack of valid diagnostic biomarkers and few therapeutic strategies are available for CRC treatment, especially for advanced CRC whose underlying pathogenic mechanisms remain poorly understood. In the present study, we investigated the serum samples from 20 patients with stage III or IV advanced CRC using data-independent acquisition (DIA)-based proteomics and ultra-performance liquid chromatography coupled to time-of-flight tandem mass spectrometry (UPLC-TOF-MS/MS) metabolomics techniques. Overall, 551 proteins and 719 metabolites were identified. Hierarchical clustering analysis revealed that the serum proteomes of advanced CRC are more diversified than the metabolomes. Ten biochemical pathways associated with cancer cell metabolism were enriched in the detected proteins and metabolites, including glycolysis/gluconeogenesis, biosynthesis of amino acids, glutathione metabolism, and arachidonic acid metabolism, etc. A protein-protein interaction network in advanced CRC serum was constructed with 80 proteins and 21 related metabolites. Correlation analysis revealed conserved roles of lipids and lipid-like molecules in a regulatory network of advanced CRC. Three metabolites (hydroquinone, leucenol and sphingomyelin) and two proteins (coagulation factor XIII A chain and plasma kallikrein) were selected to be potential biomarkers for advanced CRC, which are positively and significantly correlated with CEA and/or CA 19–9. Altogether, the results expanded our understanding of the physiopathology of advanced CRC and discovered novel potential biomarkers for further validation and application to improve the diagnosis and monitoring of advanced CRC.
Low-Resolution Neurocognitive Aging and Cognition: An Embodied Perspective
Authors: Mille Jordan , Brambati Simona M. , Izaute Marie , Vallet Guillaume T.
Published: July 2021

Consistent with embodied cognition, a growing evidence in young adults show that sensorimotor processing is at the core of cognition. Considering that this approach predicts direct interaction between sensorimotor processing and cognition, embodied cognition may thus be particularly relevant to study aging, since this population is characterized by concomitant changes in sensorimotor and cognitive processing. The present perspective aims at showing the value and interest to explore normal aging throughout embodiment by focusing on the neurophysiological and cognitive changes occurring in aging. To this end, we report some of the neurophysiological substrates underpinning the perceptual and memory interactions in older adults, from the low and high perceptual processing to the conjunction in the medial temporal lobe. We then explore how these changes could explain more broadly the cognitive changes associated with aging in terms of losses and gains.
Hemicellulose-Derived Oligosaccharides: Emerging Prebiotics in Disease Alleviation
Authors: Jana Uttam Kumar , Kango Naveen , Pletschke Brett
Published: July 2021

The gut microbiota in the human body is an important component that plays a pivotal role in the ability of the host to prevent diseases and recover from these diseases. If the human microbiome changes for any reason, it affects the overall functioning of the host. Healthy and vigorous gut microbiota require dietary fiber supplementation. Recently, oligosaccharides have been found to play a significant role in the modulation of microbiota. Several such oligosaccharides, i.e., xylooligosaccharides (XOS), mannooligosaccharides (MOS), and arabino-xylooligosaccharides (AXOS), are derived from hemicellulosic macromolecules such as xylan, mannan, and arabino-xylan, respectively. These oligosaccharides serve as substrates for the probiotic production of health-promoting substances (short-chain fatty acids, branched chain amino acids etc.), which confer a variety of health benefits, including the prevention of some dreaded diseases. Among hemicellulose-derived oligosaccharides (HDOs), XOS have been largely explored, whereas, studies on MOS and AXOS are currently underway. HDOs, upon ingestion, help reduce morbidities by lowering populations of harmful or pathogenic bacteria. The ATP-binding cassette (ABC) transporters are mainly utilized for the uptake of oligosaccharides in probiotics. Butyrate generated by the selective fermentation of oligosaccharides, along with other short-chain fatty acids, reduces gut inflammation. Overall, oligosaccharides derived from hemicelluloses show a similar potential as conventional prebiotics and can be supplemented as functional foods. This review summarizes the role of HDOs in the alleviation of autoimmune diseases (inflammatory bowel disease, Crohn's disease), diabetes, urinary tract infection, cardiovascular diseases, and antimicrobial resistance (AMR) through the modulation of the gut microbiota. The mechanism of oligosaccharide utilization and disease mitigation is also explained.
Low-Dose Lactulose as a Prebiotic for Improved Gut Health and Enhanced Mineral Absorption
Authors: Karakan Tarkan , Tuohy Kieran Michael , Janssen-van Solingen Gwendolyn
Published: July 2021

Although medium and high doses of lactulose are used routinely for the treatment of constipation and hepatic encephalopathy, respectively, a wealth of evidence demonstrates that, at low doses, lactulose can also be used as a prebiotic to stimulate the growth of health-promoting bacteria in the gastrointestinal tract. Indeed, multiple preclinical and clinical studies have shown that low doses of lactulose enhance the proliferation of health-promoting gut bacteria (e.g., Bifidobacterium and Lactobacillus spp.) and increase the production of beneficial metabolites [e.g., short-chain fatty acids (SCFAs)], while inhibiting the growth of potentially pathogenic bacteria (e.g., certain clostridia). SCFAs produced upon microbial fermentation of lactulose, the most abundant of which is acetate, are likely to contribute to immune regulation, which is important not only within the gut itself, but also systemically and for bone health. Low-dose lactulose has also been shown to enhance the absorption of minerals such as calcium and magnesium from the gut, an effect which may have important implications for bone health. This review provides an overview of the preclinical and clinical evidence published to date showing that low-dose lactulose stimulates the growth of health-promoting gut bacteria, inhibits the growth of pathogenic bacteria, increases the production of beneficial metabolites, improves mineral absorption, and has good overall tolerability. Implications of these data for the use of lactulose as a prebiotic are also discussed.
Case Report: Rare Case of Synchronous Neck Metastasis From Metachronous Bilateral Renal Cell Carcinoma
Authors: Dai Jun , Fang Chen , Yang Xiaoqun , Huang Xin , He Wei , Wang Chenghe , Zhao Juping , Sun Fukang
Published: July 2021

Renal cell carcinoma (RCC) is a malignant tumor that can metastasize easily. Hence, many patients have already developed metastasis when they are diagnosed. It is also one of the most common tumors that metastasize to the head and neck through extranodal disease. Herein, we reported a case of a 53-year-old man with cervical metastasis from bilateral RCC. Interestingly, whole exome sequencing (WES) and clonal evolution analysis revealed that bilateral renal tumor lesions and neck metastases (squamous cell carcinoma) share the same subclones and a large number of gene variants, while the pathological morphology is different (left nephrotic foci, a mixed pattern of mucinous tubular and spindle cell carcinoma (MTSCC) with papillary adenoma; right renal foci, papillary renal cell carcinoma (PRCC)). This was first reported in RCCs to the best of our knowledge. This case suggests that genotype analysis can be a powerful supplementary examination for clinical histopathological diagnosis. Gene detection has great significance for the accurate diagnosis and treatment of RCC metastasis or multiple lesions.
Downregulation of miR-142a Contributes to the Enhanced Anti-Apoptotic Ability of Murine Chronic Myelogenous Leukemia Cells
Authors: Chen Zhiwei , Xie Yinyin , Liu Dan , Liu Ping , Li Fei , Zhang Zhanglin , Zhang Mengmeng , Wang Xiaolin , Zhang Yuanliang , Sun Xiaojian , Huang Qiuhua
Published: July 2021

Background

Leukemic stem cell (LSC) is thought to be responsible for chronic myelogenous leukemia (CML) initiation and relapse. However, the inherent regulation of LSCs remains largely obscure. Herein, we integratedly analyzed miRNA and gene expression alterations in bone marrow (BM) Lin-Sca1+c-Kit+ cells (LSKs) of a tet-off inducible CML mouse model, Scl/tTA-BCR/ABL (BA).

Methods

Scl/tTA and TRE-BA transgenic mice were crossed in the presence of doxycycline to get double transgenic mice. Both miRNA and mRNA expression profiles were generated from BM LSKs at 0 and 3 weeks after doxycycline withdrawal. The target genes of differentially expressed miRNAs were predicted, followed by the miRNA-mRNA network construction. In vitro and in vivo experiments were further performed to elucidate their regulation and function in CML progression.

Results

As a result of the integrated analysis and experimental validation, an anti-apoptotic pathway emerged from the fog. miR-142a was identified to be downregulated by enhanced ERK-phosphorylation in BA-harboring cells, thereby relieving its repression on Ciapin1, an apoptosis inhibitor. Moreover, miR-142a overexpression could partially rescue the abnormal anti-apoptotic phenotype and attenuate CML progression.

Conclusion

Taken together, this study explored the miRNA-mRNA regulatory networks in murine CML LSKs and demonstrated that ERK-miR-142a-Ciapin1 axis played an essential role in CML pathogenesis.
Successful Treatment With Intrathecal and Intravenous Polymyxin B-Based Combination Against MDR Acinetobacter baumannii Meningitis in Pediatric Patient: A Case Report
Authors: Xing Haiyan , Cheng Caiyi , Zhang Yihua , Cai Yongqing , Wang Xianfeng , Deng Dongmei , Xu Lunshan , Xu Minhui , Chen Jianhong
Published: July 2021

Background: Nosocomial meningitis with multidrug-resistant (MDR) or extensively drug-resistant (XDR) Acinetobacter baumannii is a life-threatening complication in neurosurgery. Treatment of these infections is challenging because of poor penetration of the available antibiotics into the cerebrospinal fluid (CSF). Intrathecal (ITH) or intraventricular (IVT) administration of antibiotics is increasingly used as the last treatment option against MDR/XDR Gram-negative bacteria meningitis not responding to intravenous (IV) regimens. However, pertinent data in pediatric patients is scarce.

Case Presentation: A 14-year-old male patient developed meningitis from an MDR strain of A. baumannii following endoscopic endonasal resection of craniopharyngioma. Despite a combination therapy involving IV tigecycline, we observed clinical and bacteriologic failure. The patient was then successfully treated with an ITH and IV polymyxin B-based combination. Quantification of tigecycline and polymyxin B in CSF was performed with two-dimensional high-performance liquid chromatography (2D-HPLC) and HDLC coupled with tandem mass spectrometry (HPLC-MS/MS), respectively. Adverse drug reactions (neurotoxicity and skin hyperpigmentation), probably induced by polymyxin B, were acceptable and reversible.

Conclusions: The case illustrates ITH and IV Polymyxin B-based combination is an optimal therapeutic option against MDR A. baumannii meningitis in this pediatric patient. In the future, real-time PK/PD data obtained from patients during ITH/IVT polymyxin B therapy should be required to optimize polymyxin use with maximal efficacy and minimal adverse effects.
A Review of Infections After Hematopoietic Cell Transplantation Requiring PICU Care: Transplant Timeline Is Key
Authors: Ferdjallah Asmaa , Young Jo-Anne H. , MacMillan Margaret L.
Published: July 2021

Despite major advances in antimicrobial prophylaxis and therapy, opportunistic infections remain a major cause of morbidity and mortality after pediatric hematopoietic cell transplant (HCT). Risk factors associated with the development of opportunistic infections include the patient's underlying disease, previous infection history, co-morbidities, source of the donor graft, preparative therapy prior to the graft infusion, immunosuppressive agents, early and late toxicities after transplant, and graft-vs.-host disease (GVHD). Additionally, the risk for and type of infection changes throughout the HCT course and is greatly influenced by the degree and duration of immunosuppression of the HCT recipient. Hematopoietic cell transplant recipients are at high risk for rapid clinical decompensation from infections. The pediatric intensivist must remain abreast of the status of the timeline from HCT to understand the risk for different infections. This review will serve to highlight the infection risks over the year-long course of the HCT process and to provide key clinical considerations for the pediatric intensivist by presenting a series of hypothetical HCT cases.
Neuroprotective Effects of Dexmedetomidine on the Ketamine-Induced Disruption of the Proliferation and Differentiation of Developing Neural Stem Cells in the Subventricular Zone
Authors: Sha Huanhuan , Peng Peipei , Wei Guohua , Wang Juan , Wu Yuqing , Huang He
Published: July 2021

Background: Ketamine disrupts the proliferation and differentiation of developing neural stem cells (NSCs). Therefore, the safe use of ketamine in pediatric anesthesia has been an issue of increasing concern among anesthesiologists and children's parents. Dexmedetomidine (DEX) is widely used in sedation as an antianxiety agent and for analgesia. DEX has recently been shown to provide neuroprotection against anesthetic-induced neurotoxicity in the developing brain. The aim of this in vivo study was to investigate whether DEX exerted neuroprotective effects on the proliferation and differentiation of NSCs in the subventricular zone (SVZ) following neonatal ketamine exposure.

Methods: Postnatal day 7 (PND-7) male Sprague-Dawley rats were equally divided into the following five groups: control group (n = 8), ketamine group (n = 8), 1 μg/kg DEX+ketamine group (n = 8), 5 μg/kg DEX+ketamine group (n = 8) and 10 μg/kg DEX+ketamine group (n = 8). Immediately after treatment, rats received a single intraperitoneal injection of BrdU, and the proliferation and differentiation of NSCs in the SVZ were assessed using immunostaining at 24 h after the BrdU injection. In the olfactory behavioral tests, rats in each group were raised until 2 months old, and the buried food test and olfactory memory test were performed.

Results: The proliferation of NSCs and astrocytic differentiation in the SVZ were significantly inhibited at 24 h after repeated ketamine exposure in the neonatal period, and neuronal differentiation was markedly increased. Furthermore, pretreatment with moderately high (5 μg/kg) or high doses (10 μg/kg) of DEX reversed ketamine-induced disturbances in the proliferation and differentiation of NSCs. In the behavior tests, repeated neonatal ketamine exposure induced olfactory cognitive dysfunction in the adult stage, and moderately high and high doses of DEX reversed the olfactory cognitive dysfunction induced by ketamine.

Conclusions: Based on the present findings, pretreatment with a moderately high (5 μg/kg) or high dose (10 μg/kg) of DEX may alleviate the developmental neurogenesis disorder in the SVZ at 24 h after repeated ketamine exposure and improve olfactory cognitive dysfunction in adulthood.
Chondro-Protective Effects of Shikimic Acid on Osteoarthritis via Restoring Impaired Autophagy and Suppressing the MAPK/NF-κB Signaling Pathway
Authors: You Hongbo , Zhang Rui , Wang Lingying , Pan Qiyong , Mao Zekai , Huang Xiaojian
Published: July 2021

Osteoarthritis (OA) is a major cause of cartilage pain and limited mobility in middle-aged and elderly individuals. The degeneration of cartilage induced by inflammation and cartilage anabolic and catabolic disorder plays a key role in OA. Shikimic acid (SA), a natural ingredient extracted from Illicium verum, has been shown to exert notable anti-inflammatory effects in previous studies, suggesting its potential effects in the treatment of OA. In this study, we revealed that the pretreatment of SW1353 human chondrocytes with SA before interleukin 1β (IL-1β) stimulation effectively decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, matrix metalloproteinases (MMPs; MMP3 and MMP13), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, type X collagen, and p62; increased the expression of type II collagen, ATG7, Beclin-1, and LC3; and increased the autophagic flux. Mechanistically, we found that SA suppressed the IL-1β-induced activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) pathways. Furthermore, the results of safranin O staining and toluidine blue staining of primary rat cartilage chondrocytes and a trauma-induced rat model of OA showed that SA alleviated progression of OA in vivo. Collectively, our research enhances understanding of the mechanism of protective effect of SA against the progression of OA, which involves amelioration of cartilage degeneration, thereby providing new evidence for the use of SA as a therapy to prevent the development of OA.
Antiatherogenic Effects of Quercetin in the THP-1 Macrophage Model In Vitro, With Insights Into Its Signaling Mechanisms Using In Silico Analysis
Authors: Huwait Etimad A. , Saddeek Salma Y. , Al-Massabi Rehab F. , Almowallad Sanaa J. , Pushparaj Peter Natesan , Kalamegam Gauthaman
Published: July 2021

Background: Atherosclerosis (AS), a major risk factor for stroke and brain tissue destruction, is an inflammatory disease of the blood vessels, and the underlying pathology is inflammation mediated by various chemokines and cytokines. Quercetin, a natural flavonol, is reported to have both anti-inflammatory and antioxidant properties. As such, in the present study, we evaluated the antiatherogenic effects of quercetin in a human THP-1 cell line in vitro and also the signaling mechanisms using in silico analysis.

Materials and Methods: THP-1 macrophages exposed to different concentrations of quercetin (5–100 μM for 24 h) were tested for cytotoxicity. Real-time gene expression assay for intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) was carried out following treatment with quercetin at 15 and 30 μM for 24 h either in the absence or presence of interferon (IFN-γ) for 3 h to induce inflammation. Monocyte migration and cholesterol efflux were also assessed.

Results: Quercetin did not exert any cytotoxic effects on THP-1 cells at the various concentrations tested. The gene expression assay showed a significant decrease in ICAM-1 (by 3.05 and 2.70) and MCP-1 (by 22.71 and 27.03), respectively. Quercetin at 15 µM decreased THP-1 monocyte migration by 33% compared to the MCP-1-treated cells. It also increased cholesterol efflux significantly by1.64-fold and 1.60-fold either alone or in combination with IFN-γ, respectively. Ingenuity Pathway Analysis of the molecular interactions of quercetin identified canonical pathways directly related to lipid uptake and cholesterol efflux. Furthermore, CD36, SR-A, and LXR-α also demonstrated significant increases by 72.16-, 149.10-, and 29.68-fold, respectively.

Conclusion: Our results from both in vitro and in silico studies identified that quercetin inhibited the THP-1 monocyte migration, MCP-1, and ICAM-1 and increased cholesterol efflux probably mediated via the LXR/RXR signaling pathway. Therefore, quercetin will help prevent cell infiltration in atherosclerotic plaques and reduce the risk of stroke or brain destruction.
Elabela Protects Spontaneously Hypertensive Rats From Hypertension and Cardiorenal Dysfunctions Exacerbated by Dietary High-Salt Intake
Authors: Sainsily Xavier , Coquerel David , Giguère Hugo , Dumont Lauralyne , Tran Kien , Noll Christophe , Ionescu Andrei L. , Côté Jérôme , Longpré Jean-Michel , Carpentier André , Marsault Éric , Lesur Olivier , Sarret Philippe , Auger-Messier Mannix
Published: July 2021

Objectives: Arterial hypertension, when exacerbated by excessive dietary salt intake, worsens the morbidity and mortality rates associated with cardiovascular and renal diseases. Stimulation of the apelinergic system appears to protect against several circulatory system diseases, but it remains unknown if such beneficial effects are conserved in severe hypertension. Therefore, we aimed at determining whether continuous infusion of apelinergic ligands (i.e., Apelin-13 and Elabela) exerted cardiorenal protective effects in spontaneously hypertensive (SHR) rats receiving high-salt diet.

Methods: A combination of echocardiography, binding assay, histology, and biochemical approaches were used to investigate the cardiovascular and renal effects of Apelin-13 or Elabela infusion over 6 weeks in SHR fed with normal-salt or high-salt chow.

Results: High-salt intake upregulated the cardiac and renal expression of APJ receptor in SHR. Importantly, Elabela was more effective than Apelin-13 in reducing high blood pressure, cardiovascular and renal dysfunctions, fibrosis and hypertrophy in high-salt fed SHR. Unlike Apelin-13, the beneficial effects of Elabela were associated with a counter-regulatory role of the ACE/ACE2/neprilysin axis of the renin-angiotensin-aldosterone system (RAAS) in heart and kidneys of salt-loaded SHR. Interestingly, Elabela also displayed higher affinity for APJ in the presence of high salt concentration and better resistance to RAAS enzymes known to cleave Apelin-13.

Conclusion: These findings highlight the protective action of the apelinergic system against salt-induced severe hypertension and cardiorenal failure. As compared with Apelin-13, Elabela displays superior pharmacodynamic and pharmacokinetic properties that warrant further investigation of its therapeutic use in cardiovascular and kidney diseases.
Characterisation, Chain Conformation and Antifatigue Effect of Steamed Ginseng Polysaccharides With Different Molecular Weight
Authors: Jiao Lili , Li Junming , Liu Furao , Wang Jing , Jiang Peng , Li Bo , Li Hui , Chen Changbao , Wu Wei
Published: July 2021

Two polysaccharides were obtained from steamed ginseng via ultrafiltration, and their physical–chemical properties, solution properties and antifatigue activities were studied. WSGP-S3 and WSGP-G3 were acid heteropolysaccharides with the molecular weights of 2.03 × 104 and 4.86 × 104, respectively. They were composed of different molar ratios of the monosaccharides Rha, GlcA, GalA, Glc, Gal, and Ara. The results of size-exclusion chromatography–multiangle laser light scattering analysis, Conge red staining and Circular dichroism spectroscopy revealed that WSGP-S3 exhibited a random conformation of branched clusters in solution. By contrast, WSGP-G3 exhibited an ordered conformation, including helix-like conformations in aqueous solution. Antifatigue activity tests proved that WSGP-S3 markedly prolonged the exhaustive swimming time of fatigued mice; increased liver and muscle glycogen levels and superoxide dismutase, catalase, glutathione peroxidase activities and decreased blood lactic acid, nitrogen and malondialdehyde levels compared with the control treatment. Moreover, it enhanced spleen cell proliferation in fatigued mice. By contrast, WSGP-G3 had no significant effect on fatigued mice. The results showed that WSGP-S3 might have a major contribution to the antifatigue effects of steamed ginseng polysaccharides and could be a potential anti-fatigue polysaccharide.