bluuebunny/crossref_metadata_2025 huggingface dataset:
Accessing Livestock Resources in Ensembl
Authors: Martin Fergal J. , Gall Astrid , Szpak Michal , Flicek Paul
Published: April 2021

Genome assembly is cheaper, more accurate and more automated than it has ever been. This is due to a combination of more cost-efficient chemistries, new sequencing technologies and better algorithms. The livestock community has been at the forefront of this new wave of genome assembly, generating some of the highest quality vertebrate genome sequences. Ensembl’s goal is to add functional and comparative annotation to these genomes, through our gene annotation, genomic alignments, gene trees, regulatory, and variation data. We run computationally complex analyses in a high throughput and consistent manner to help accelerate downstream science. Our livestock resources are continuously growing in both breadth and depth. We annotate reference genome assemblies for newly sequenced species and regularly update annotation for existing genomes. We are the only major resource to support the annotation of breeds and other non-reference assemblies. We currently provide resources for 13 pig breeds, maternal and paternal haplotypes for hybrid cattle and various other non-reference or wild type assemblies for livestock species. Here, we describe the livestock data present in Ensembl and provide protocols for how to view data in our genome browser, download via it our FTP site, manipulate it via our tools and interact with it programmatically via our REST API.
Epilepsy-Associated UBE3A Deficiency Downregulates Retinoic Acid Signalling Pathway
Authors: Fang Meimiao , Li Yali , Ren Jin , Hu Ronggui , Gao Xiaobo , Chen Liang
Published: April 2021

Ubiquitin-protein ligase E3A (UBE3A) has dual functions as a E3 ubiquitin-protein ligase and coactivator of nuclear hormone receptors. Mutations or deletions of the maternally inherited UBE3A gene cause Angelman syndrome. Here, we performed transcriptome profiling in the hippocampus of Ube3am+/p+ and Ube3am–/p+ mice, and determined that the expression of the retinoic acid (RA) signalling pathway was downregulated in Ube3a-deficient mice compared to WT mice. Furthermore, we demonstrated that UBE3A directly interacts with RARα and may function as a coactivator of the nuclear receptor RARα to participate in the regulation of gene expression. Loss of UBE3A expression caused the downregulation of the expression of RA-related genes, including Erbb4, Dpysl3, Calb1, Pten, and Arhgap5 in Ube3am–/p+ mice brain tissues. This work revealed a new role for UBE3A in regulating retinoic acid (RA) signalling downstream genes and hopefully to shed light on the potential drug target of AS.
Stimulation of α7 Nicotinic Acetylcholine Receptor by Nicotine Suppresses Decidual M1 Macrophage Polarization Against Inflammation in Lipopolysaccharide-Induced Preeclampsia-Like Mouse Model
Authors: Han Xinjia , Li Wei , Li Ping , Zheng Zheng , Lin Baohua , Zhou Bei , Guo Kaimin , He Ping , Yang Jinying
Published: April 2021

Changes in decidual macrophage polarization affect local inflammatory microenvironment and lead to adverse pregnancy outcomes. However, the regulatory mechanism of macrophage polarization in preeclampsia (PE) remains unclear. In this study, we found that α7nAChR expression was significantly down-regulated in decidual macrophages in PE patients compared to normal pregnant women, accompanied by a reduced proportion of M2 phenotype and an increased proportion of M1 phenotype; these results suggested that the reduced α7nAChR activity might contribute to changes in the polarization of decidual macrophages. Then, we further investigated the regulatory role of α7nAChR activation by nicotine on decidual macrophage polarization and placental remodeling in the PE-like mouse model. The PE mice were obtained by i.p. injection of 10 µg/kg lipopolysaccharide (LPS) gestational day (GD) 13, and 40 µg/kg LPS daily until GD16. Subcutaneous injection of 1.0 mg/kg nicotine was administrated from GD14 to GD18. Nicotine treatment increased the decreased M2 phenotype and inhibited the increased M1 phenotype in decidua of pregnant mice induced by LPS. The levels of pro-inflammatory cytokines in decidua were higher but the levels of anti-inflammatory cytokines were lower in PE mice compared to the controls, nicotine reversed these changes. The level of choline acetyltransferase (CHAT) was reduced in the LPS-treated group, it was increased following nicotine treatment. Damage of spiral artery remodeling and down-regulation of markers related to trophoblast invasion in placentas were found in PE mice; nicotine improved these pathological structures of placentas. α-bungarotoxin (α-BGT) which is specific antagonist for α7nAChR could abolish the effects of nicotine on decidual macrophage polarization, trophoblast arrangement and vascular structure in placental tissue in PE mice. These results suggest that α7nAChR plays an important regulatory role in maternal-fetal inflammation and placental remodeling in preeclampsia and may provide a theoretical basis for the discovery of new strategies for preeclampsia.
Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients
Authors: Morikis Vasilios A. , Hernandez Alfredo A. , Magnani John L. , Sperandio Markus , Simon Scott I.
Published: April 2021

Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels. Recently, we reported that recognition of sLex on L-selectin by E-selectin during neutrophil rolling initiates shear force resistant catch-bonds that facilitate tethering to endothelium and activation of integrin bond clusters that anchor cells to the vessel wall. Evidence indicates that blocking this important signaling cascade prevents the congestion and ischemia in microvasculature that occurs from neutrophil capture of sickled red blood cells, which are normally deformable ellipses that flow easily through small blood vessels. Two recently completed clinical trials of therapies targeting selectins and their effect on neutrophil activation in small blood vessels reveal the importance of mechanoregulation that in health is an immune adaption facilitating rapid and proportional leukocyte adhesion, while sustaining tissue perfusion. We provide a timely perspective on the mechanism underlying vaso-occlusive crisis (VOC) with a focus on new drugs that target selectin mediated integrin adhesive bond formation.
Novel Combinatorial MicroRNA-Binding Sites in AAV Vectors Synergistically Diminish Antigen Presentation and Transgene Immunity for Efficient and Stable Transduction
Authors: Muhuri Manish , Zhan Wei , Maeda Yukiko , Li Jia , Lotun Anoushka , Chen Jennifer , Sylvia Katelyn , Dasgupta Ishani , Arjomandnejad Motahareh , Nixon Thomas , Keeler Allison M. , Manokaran Sangeetha , He Ran , Su Qin , Tai Phillip W. L. , Gao Guangping
Published: April 2021

Recombinant adeno-associated virus (rAAV) platforms hold promise for in vivo gene therapy but are undermined by the undesirable transduction of antigen presenting cells (APCs), which in turn can trigger host immunity towards rAAV-expressed transgene products. In light of recent adverse events in patients receiving high systemic AAV vector doses that were speculated to be related to host immune responses, development of strategies to mute innate and adaptive immunity is imperative. The use of miRNA binding sites (miR-BSs) to confer endogenous miRNA-mediated regulation to detarget transgene expression from APCs has shown promise for reducing transgene immunity. Studies have shown that designing miR-142BSs into rAAV1 vectors were able to repress costimulatory signals in dendritic cells (DCs), blunt the cytotoxic T cell response, and attenuate clearance of transduced muscle cells in mice to allow sustained transgene expression in myofibers with negligible anti-transgene IgG production. In this study, we screened individual and combinatorial miR-BS designs against 26 miRNAs that are abundantly expressed in APCs, but not in skeletal muscle. The highly immunogenic ovalbumin (OVA) transgene was used as a proxy for foreign antigens. In vitro screening in myoblasts, mouse DCs, and macrophages revealed that the combination of miR-142BS and miR-652-5pBS strongly mutes transgene expression in APCs but maintains high myoblast and myocyte expression. Importantly, rAAV1 vectors carrying this novel miR-142/652-5pBS cassette achieve higher transgene levels following intramuscular injections in mice than previous detargeting designs. The cassette strongly inhibits cytotoxic CTL activation and suppresses the Th17 response in vivo. Our approach, thus, advances the efficiency of miRNA-mediated detargeting to achieve synergistic reduction of transgene-specific immune responses and the development of safe and efficient delivery vehicles for gene therapy.
Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy
Authors: Shaver Kari A. , Croom-Perez Tayler J. , Copik Alicja J.
Published: April 2021

Cancer immunotherapy is a highly successful and rapidly evolving treatment modality that works by augmenting the body’s own immune system. While various immune stimulation strategies such as PD-1/PD-L1 or CTLA-4 checkpoint blockade result in robust responses, even in patients with advanced cancers, the overall response rate is low. While immune checkpoint inhibitors are known to enhance cytotoxic T cells’ antitumor response, current evidence suggests that immune responses independent of cytotoxic T cells, such as Natural Killer (NK) cells, play crucial role in the efficacy of immunotherapeutic interventions. NK cells hold a distinct role in potentiating the innate immune response and activating the adaptive immune system. This review highlights the importance of the early actions of the NK cell response and the pivotal role NK cells hold in priming the immune system and setting the stage for successful response to cancer immunotherapy. Yet, in many patients the NK cell compartment is compromised thus lowering the chances of successful outcomes of many immunotherapies. An overview of mechanisms that can drive NK cell dysfunction and hinder immunotherapy success is provided. Rather than relying on the likely dysfunctional endogenous NK cells to work with immunotherapies, adoptive allogeneic NK cell therapies provide a viable solution to increase response to immunotherapies. This review highlights the advances made in development of NK cell therapeutics for clinical application with evidence supporting their combinatorial application with other immune-oncology approaches to improve outcomes of immunotherapies.
Deciphering the Fine-Tuning of the Retinoic Acid-Inducible Gene-I Pathway in Teleost Fish and Beyond
Authors: Jami Raphaël , Mérour Emilie , Lamoureux Annie , Bernard Julie , Millet Jean K. , Biacchesi Stéphane
Published: April 2021

Interferons are the first lines of defense against viral pathogen invasion during the early stages of infection. Their synthesis is tightly regulated to prevent excessive immune responses and possible deleterious effects on the host organism itself. The RIG-I-like receptor signaling cascade is one of the major pathways leading to the production of interferons. This pathway amplifies danger signals and mounts an appropriate innate response but also needs to be finely regulated to allow a rapid return to immune homeostasis. Recent advances have characterized different cellular factors involved in the control of the RIG-I pathway. This has been most extensively studied in mammalian species; however, some inconsistencies remain to be resolved. The IFN system is remarkably well conserved in vertebrates and teleost fish possess all functional orthologs of mammalian RIG-I-like receptors as well as most downstream signaling molecules. Orthologs of almost all mammalian regulatory components described to date exist in teleost fish, such as the widely used zebrafish, making fish attractive and powerful models to study in detail the regulation and evolution of the RIG-I pathway.
Effects of Different Strain Rates on the Impact Properties of Recycled Aggregate Concrete Modified With Nanosilica Solution and Polyvinyl Alcohol Fiber
Authors: Wang Xingguo , Jiang Maolin , Zhang Xianggang , Cheng Zhaoxia , Gong Jian , Cheng Fei
Published: April 2021

The recycled aggregate (RA) was modified by 2% nanosilica solution, and the split Hopkinson pressure bar (SHPB) test device was used to study the dynamic impact properties of the modified recycled aggregate concrete (RAC) mixed with polyvinyl alcohol (PVA) fibers. The RA replacement percentage, the amount of PVA fiber, and the strain rate were variables. The failure pattern, the stress–strain curve of the nanosilica solution, and PVA fiber-modified RAC were shown under different strain rate conditions. Dynamic peak stress, peak strain, and dynamic increase factor (DIF) of the specimens are discussed. The results showed that the stress and dynamic peak strain value of the specimen increased with the increase of the strain rate; moreover, with the increase of the RA replacement percentage and the PVA fiber content, the dynamic peak stress of the specimen decreases, while the dynamic peak strain and the DIF value increase. The incorporation of nanosilica-modified RA is beneficial to the improvement of the impact performance of RAC, and the incorporation of an appropriate amount of the PVA fiber effectively improves the deformability of RAC.
Association of Serum Immunoglobulins Levels With Specific Disease Phenotypes of Crohn's Disease: A Multicenter Analysis in China
Authors: Song Dong Juan , Shen Jun , Chen Min Hu , Liu Zhan Ju , Cao Qian , Hu Pin Jin , Gao Xiang , Qian Jia Ming , Wu Kai Chun , Lai Li Jie , Ran Zhi Hua
Published: April 2021

Background and Aim:Serum immunoglobulins were reported to be associated with clinical characteristics of inflammatory bowel disease. However, whether a difference exists in the serum immunoglobulins levels in patients with Crohn's disease (CD) with different disease location and behavior phenotypes remains unclear. Therefore, this study aimed to explore the associations of serum immunoglobulins levels with specific CD phenotypes.

Methods:Patients with CD having recorded serum immunoglobulins levels were recruited through multicenter collaborative efforts. The associations between serum immunoglobulins levels and distinct phenotypes of CD were evaluated using multiple logistic regression models.

Results:A total of 608 patients with CD were included in the study. Elevated (above the upper limit of normal) serum immunoglobulin G (IgG), IgA, IgM, and IgG4 were identified in 24.5, 17.4, 2.1, and 8.2% of patients, respectively. Elevated serum IgG4 levels negatively correlated with complicated disease behavior [odds ratio (OR) 0.49, 95% confidence interval (CI) 0.26–0.92]. Elevated serum IgG was linked to isolated ileal disease with an OR of 0.37 (95% CI 0.23–0.61). The ORs of isolated ileal disease progressively reduced across increasing quartiles of IgG (Pfor trend < 0.001). The adjusted ORs of isolated ileal disease for increasing quartiles of IgM were 1.82 (1.07–3.1), 1.92 (1.14–3.24), 1.17 (0.69–1.98), and 1 (Pfor trend = 0.008). Besides, serum IgA and IgG levels significantly correlated with several disease activity indices.

Conclusions:These results suggested that certain serum immunoglobulins were associated with specific disease phenotypes of CD. Further investigations to account for the associations are warranted.
Treatment of Behçet's Disease: An Algorithmic Multidisciplinary Approach
Authors: Alpsoy Erkan , Leccese Pietro , Emmi Giacomo , Ohno Shigeaki
Published: April 2021

Behçet's disease (BD) is a chronic, relapsing inflammatory, multisystem disease of unknown etiology. The disease has a wide clinical spectrum of mucocutaneous lesions and ocular, vascular, articular, neurologic, gastrointestinal and cardiac involvement. Although the number of effective drugs used in the disease's treatment has increased in recent years, BD is still associated with severe morbidity because of mainly mucocutaneous, articular and ocular symptoms and an increased mortality because of large vessel, neurological, gastrointestinal and cardiac involvement. Many factors are associated with a more serious course, such as male gender and a younger age of onset. While the severity of the disease is more pronounced in the first years of the disease, it decreases in most patients after the age of forties. The primary goal of treatment should be the prevention of irreversible organ damage. Therefore, early diagnosis and appropriate treatment and close follow-up are mandatory to reduce the morbidity and mortality of the disease. Treatment varies depending on the organ involved and the severity of the involvement. For all these reasons, the treatment should be personalized and arranged with a multidisciplinary approach according to the organs involved. Treatment is mainly based on suppression of the inflammatory attacks of the disease using local and systemic immunomodulatory and immunosuppressive drugs. In this review, based on the mainly controlled studies and personal experience in clinical practice and basic research in this field, we propose a stepwise, symptom-based, algorithmic approach for the management of BD with a holistic perspective.
Microbial Degradation of Citric Acid in Low Level Radioactive Waste Disposal: Impact on Biomineralization Reactions
Authors: Byrd Natalie , Lloyd Jonathan R. , Small Joe S. , Taylor Frank , Bagshaw Heath , Boothman Christopher , Morris Katherine
Published: April 2021

Organic complexants are present in some radioactive wastes and can challenge waste disposal as they may enhance subsurface mobility of radionuclides and contaminant species via chelation. The principal sources of organic complexing agents in low level radioactive wastes (LLW) originate from chemical decontamination activities. Polycarboxylic organic decontaminants such as citric and oxalic acid are of interest as currently there is a paucity of data on their biodegradation at high pH and under disposal conditions. This work explores the biogeochemical fate of citric acid, a model decontaminant, under high pH anaerobic conditions relevant to disposal of LLW in cementitious disposal environments. Anaerobic microcosm experiments were set up, using a high pH adapted microbial inoculum from a well characterized environmental site, to explore biodegradation of citrate under representative repository conditions. Experiments were initiated at three different pH values (10, 11, and 12) and citrate was supplied as the electron donor and carbon source, under fermentative, nitrate-, Fe(III)- and sulfate- reducing conditions. Results showed that citrate was oxidized using nitrate or Fe(III) as the electron acceptor at > pH 11. Citrate was fully degraded and removed from solution in the nitrate reducing system at pH 10 and pH 11. Here, the microcosm pH decreased as protons were generated during citrate oxidation. In the Fe(III)-reducing systems, the citrate removal rate was slower than in the nitrate reducing systems. This was presumably as Fe(III)-reduction consumes fewer moles of citrate than nitrate reduction for the same molar concentrations of electron acceptor. The pH did not change significantly in the Fe(III)-reducing systems. Sulfate reduction only occurred in a single microcosm at pH 10. Here, citrate was fully removed from solution, alongside ingrowth of acetate and formate, likely fermentation products. The acetate and lactate were subsequently used as electron donors during sulfate-reduction and there was an associated decrease in solution pH. Interestingly, in the Fe(III) reducing experiments, Fe(II) ingrowth was observed at pH values recorded up to 11.7. Here, TEM analysis of the resultant solid Fe-phase indicated that nanocrystalline magnetite formed as an end product of Fe(III)-reduction under these extreme conditions. PCR-based high-throughput 16S rRNA gene sequencing revealed that bacteria capable of nitrate Fe(III) and sulfate reduction became enriched in the relevant, biologically active systems. In addition, some fermentative organisms were identified in the Fe(III)- and sulfate-reducing systems. The microbial communities present were consistent with expectations based on the geochemical data. These results are important to improve long-term environmental safety case development for cementitious LLW waste disposal.
A High Rate of Recurrent Vulvovaginal Candidiasis and Therapeutic Failure of Azole Derivatives Among Iranian Women
Authors: Arastehfar Amir , Kargar Melika Laal , Mohammadi Shahla Roudbar , Roudbary Maryam , Ghods Nayereh , Haghighi Ladan , Daneshnia Farnaz , Tavakoli Mahin , Jafarzadeh Jalal , Hedayati Mohammad Taghi , Wang Huiwei , Fang Wenjie , Carvalho Agostinho , Ilkit Macit , Perlin David S. , Lass-Flörl Cornelia
Published: April 2021

Recurrent vulvovaginal candidiasis (RVVC) is one of the most prevalent fungal infections in humans, especially in developing countries; however, it is underestimated and regarded as an easy-to-treat condition. RVVC may be caused by dysbiosis of the microbiome and other host-, pathogen-, and antifungal drug-related factors. Although multiple studies on host-related factors affecting the outcome have been conducted, such studies on Candida-derived factors and their association with RVVC are lacking. Thus, fluconazole-tolerant (FLZT) isolates may cause fluconazole therapeutic failure (FTF), but this concept has not been assessed in the context of Candida-associated vaginitis. Iran is among the countries with the highest burden of RVVC; however, comprehensive studies detailing the clinical and microbiological features of this complication are scarce. Therefore, we conducted a 1-year prospective study with the aim to determine the RVVC burden among women referred to a gynecology hospital in Tehran, the association of the previous exposure to clotrimazole and fluconazole with the emergence of FLZT and fluconazole-resistant (FLZR) Candida isolates, and the relevance of these phenotypes to FTF. The results indicated that about 53% of the patients (43/81) experienced RVVC. Candida albicans and C. glabrata constituted approximately 90% of the yeast isolates (72 patients). Except for one FLZT C. tropicalis isolate, FLZR and FLZT phenotypes were detected exclusively in patients with RVVC; among them, 27.9% (12/43) harbored FLZR strains. C. albicans constituted 81.2% of FLZR (13/16) and 100% of the FLZT (13/13) isolates, respectively, and both phenotypes were likely responsible for FTF, which was also observed among patients with RVVC infected with fluconazole-susceptible isolates. Thus, FTF could be due to host-, drug-, and pathogen-related characteristics. Our study indicates that FLZT and FLZR isolates may arise following the exposure to over-the-counter (OTC) topical azole (clotrimazole) and that both phenotypes can cause FTF. Therefore, the widespread use of OTC azoles can influence fluconazole therapeutic success, highlighting the necessity of controlling the use of weak topical antifungals among Iranian women.
Identification of Molecular Subtypes and Key Genes of Atherosclerosis Through Gene Expression Profiles
Authors: Yang Yujia , Cai Yue , Zhang Yuan , Yi Xu , Xu Zhiqiang
Published: April 2021

Atherosclerotic cardiovascular disease (ASCVD) caused by atherosclerosis (AS) is one of the highest causes of mortality worldwide. Although there have been many studies on AS, its etiology remains unclear. In order to carry out molecular characterization of different types of AS, we retrieved two datasets composed of 151 AS samples and 32 normal samples from the Gene Expression Omnibus database. Using the non-negative matrix factorization (NMF) algorithm, we successfully divided the 151 AS samples into two subgroups. We then compared the molecular characteristics between the two groups using weighted gene co-expression analysis (WGCNA) and identified six key modules associated with the two subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis were used to identify the potential functions and pathways associated with the modules. In addition, we used the cytoscape software to construct and visualize protein–protein networks so as to identify key genes in the modules of interest. Three hub genes including PTGER3, GNAI1, and IGFBP5 were further screened using the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms. Since the modules were associated with immune pathways, we performed immune cell infiltration analysis. We discovered a significant difference in the level of immune cell infiltration by naïve B cells, CD8 T cells, T regulatory cells (Tregs), resting NK cells, Monocytes, Macrophages M0, Macrophages M1, and Macrophages M2 between the two subgroups. In addition, we observed the three hub genes were positively correlated with Tregs but negatively correlated with Macrophages M0. We also found that the three key genes are differentially expressed between normal and diseased tissue, as well as in the different subgroups. Receiver operating characteristic (ROC) results showed a good performance in the validation dataset. These results may provide novel insight into cellular and molecular characteristics of AS and potential markers for diagnosis and targeted therapy.
Family Planning Decision Making in People With Multiple Sclerosis
Authors: Bonavita Simona , Lavorgna Luigi , Worton Hilary , Russell Susan , Jack Dominic
Published: April 2021

Introduction: The majority of people diagnosed with MS are of childbearing or child fathering age, therefore family planning is an important issue for both women and men with MS. Fertility and the course of pregnancy are not affected by MS; however, people with MS (pwMS) may have concerns that there will be a greater risk of complications to the mother and/or adverse pregnancy outcomes either due to the disease or to ongoing medication. This survey aimed to understand family planning decision making in pwMS and related unmet educational needs.

Methods: A total of 332 pwMS across the USA, UK, France, Germany, Italy, and Spain were recruited from a specialist patient panel agency to participate in a smartphone-enabled standing panel. The 80-question survey focussed on decision making and information sources for pwMS regarding family planning, as well as behavior during and after pregnancy. Male patients with MS did not respond to specific questions on pregnancy. Survey results were directly compared with the 2016 US and 2010 UN census data.

Results: pwMS were more likely to have no children than the general population, particularly in the subgroup of patients aged 36–45 years. A total of 56% of pwMS reported that the disease affected, with different degrees of impact, their family planning decision making. Of these, 21% significantly changed their plans for timing of pregnancy and the number of children, and 14% decided against having children. Participants indicated that healthcare professionals were the primary source of information on family planning (81% of responses). The timing of planned pregnancy was not considered when selecting treatment by 78% of participants.

Conclusion: MS was found to significantly impact family planning decision making, with pwMS significantly less likely to have children in comparison with the general population.
Wavelet Autoregulation Monitoring Identifies Blood Pressures Associated With Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy
Authors: Liu Xiuyun , Tekes Aylin , Perin Jamie , Chen May W. , Soares Bruno P. , Massaro An N. , Govindan Rathinaswamy B. , Parkinson Charlamaine , Chavez-Valdez Raul , Northington Frances J. , Brady Ken M. , Lee Jennifer K.
Published: April 2021

Dysfunctional cerebrovascular autoregulation may contribute to neurologic injury in neonatal hypoxic-ischemic encephalopathy (HIE). Identifying the optimal mean arterial blood pressure (MAPopt) that best supports autoregulation could help identify hemodynamic goals that support neurologic recovery. In neonates who received therapeutic hypothermia for HIE, we hypothesized that the wavelet hemoglobin volume index (wHVx) would identify MAPopt and that blood pressures closer to MAPopt would be associated with less brain injury on MRI. We also tested a correlation-derived hemoglobin volume index (HVx) and single- and multi-window data processing methodology. Autoregulation was monitored in consecutive 3-h periods using near infrared spectroscopy in an observational study. The neonates had a mean MAP of 54 mmHg (standard deviation: 9) during hypothermia. Greater blood pressure above the MAPopt from single-window wHVx was associated with less injury in the paracentral gyri (p = 0.044; n = 63), basal ganglia (p = 0.015), thalamus (p = 0.013), and brainstem (p = 0.041) after adjustments for sex, vasopressor use, seizures, arterial carbon dioxide level, and a perinatal insult score. Blood pressure exceeding MAPopt from the multi-window, correlation HVx was associated with less injury in the brainstem (p = 0.021) but not in other brain regions. We conclude that applying wavelet methodology to short autoregulation monitoring periods may improve the identification of MAPopt values that are associated with brain injury. Having blood pressure above MAPopt with an upper MAP of ~50–60 mmHg may reduce the risk of brain injury during therapeutic hypothermia. Though a cause-and-effect relationship cannot be inferred, the data support the need for randomized studies of autoregulation and brain injury in neonates with HIE.
Sex Differences in Re-experiencing Symptoms Between Husbands and Wives Who Lost Their Only Child in China: A Resting-State Functional Connectivity Study of Hippocampal Subfields
Authors: Luo Yifeng , Liu Yu , Qing Zhao , Zhang Li , Weng Yifei , Zhang Xiaojie , Shan Hairong , Li Lingjiang , Qi Rongfeng , Cao Zhihong , Lu Guangming
Published: April 2021

Background: Losing one’s only child may lead to post-traumatic stress disorder (PTSD), of which re-experiencing is the core symptom. However, neuroimaging studies of sex differences in re-experiencing in the context of the trauma of losing one’s only child and PTSD are scarce; comparisons of the functional networks from the hippocampal subfields to the thalamus might clarify the neural basis.

Methods: Thirty couples without any psychiatric disorder who lost their only child (non-PTSD group), 55 patients with PTSD, and 50 normal controls underwent resting-state functional magnetic resonance imaging. The functional connectivity (FC) from the hippocampal subregions to the thalamus and the correlations of FC with re-experiencing symptoms were analyzed within and between the sexes.

Results: Compared with husbands without PTSD, wives without PTSD had higher re-experiencing symptoms and weaker FC between the right hippocampal cornu ammonis 3 (RCA3) and the right thalamus (RT; RCA3-RT). Moreover, only the correlation between the RCA3-RT FC and re-experiencing in wives without PTSD was significant. Among the three groups, only the RCA3-RT FC in female subjects was markedly different. Additionally, the RCA3-RT FC in wives without PTSD was remarkably lower relative to female patients with PTSD.

Conclusion: Wives without PTSD who lost their only child had worse re-experiencing symptoms relative to their husbands, which was associated with the FC alteration between the hippocampal subregions and the thalamus. Importantly, the low level of the RCA3-RT FC may play a potentially protective role against the development of PTSD in wives who have lost their only child.
Neural Tracking of Sound Rhythms Correlates With Diagnosis, Severity, and Prognosis of Disorders of Consciousness
Authors: Xu Chuan , Zou Jiajie , He Fangping , Wen Xinrui , Li Jingqi , Gao Jian , Ding Nai , Luo Benyan
Published: April 2021

Effective diagnosis and prognosis of patients with disorders of consciousness (DOC) provides a basis for family counseling, decision-making, and the design of rehabilitation programs. However, effective and objective bedside evaluation is a challenging problem. In this study, we explored electroencephalography (EEG) response tracking sound rhythms as potential neural markers for DOC evaluation. We analyzed the responses to natural speech and tones modulated at 2 and 41 Hz. At the population level, patients with positive outcomes (DOC-P) showed higher cortical synchronization to modulated tones at 41 Hz compared with patients with negative outcomes (DOC-N). At the individual level, phase coherence to modulated tones at 41 Hz was significantly correlated with Coma Recovery Scale-Revised (CRS-R) and Glasgow Outcome Scale-Extended (GOS-E) scores. Furthermore, SVM classifiers, trained using phase coherences in higher frequency bands or combination of the low frequency aSSR and speech tracking responses, performed very well in diagnosis and prognosis of DOC. These findings show that EEG response to auditory rhythms is a potential tool for diagnosis, severity, and prognosis of DOC.
Characteristics of Idiopathic Sensory Processing Disorder in Young Children
Authors: Mulligan Shelley , Douglas Sarah , Armstrong Caitlin
Published: April 2021

This study described the developmental and behavioral characteristics of children identified with idiopathic sensory processing disorder (SPD) as well as the relations among specific types of SPD as proposed by the nosology presented by Miller et al. (2007), adaptive behavior profiles, and behaviors associated with mental functioning. A retrospective, non-experimental design applying descriptive and correlational analyses was used. Data were obtained from clinic medical records of 78 children ages 2 to 7 years who were identified with sensory processing problems affecting daily life, but who did not meet criteria for any other neurodevelopmental or mental disorders following a comprehensive diagnostic evaluation. Results revealed that all SPD types as described by current typologies were well represented with the most common being the over-responsivity sensory modulation subtype. Within the sample, 53% of the children displayed more than one SPD type. Atypical externalizing and internalizing behavior scores associated with various mental disorders as measured by the child behavior checklist (CBCL) fell in the borderline dysfunctional range. Adaptive behavior for all developmental domains was below average, and the severity of SPD symptoms moderately and positively correlated with behaviors associated with mental disorders, and with lower adaptive behavior performance. It was concluded that symptoms characteristic of the various types of idiopathic SPD overlap substantially suggesting that current typologies may include more types/subtypes than are necessary or clinically useful. Children with SPD share similar, but often less severe pathological behaviors associated with other mental or related neurodevelopmental disorders. Psychometrically sound measures of SPD are needed, and further study of the neural mechanisms involved in sensory processing deficits is vital for validating idiopathic SPD as its own diagnostic entity.
A Neural Model of Intrinsic and Extrinsic Hippocampal Theta Rhythms: Anatomy, Neurophysiology, and Function
Authors: Grossberg Stephen
Published: April 2021

This article describes a neural model of the anatomy, neurophysiology, and functions of intrinsic and extrinsic theta rhythms in the brains of multiple species. Topics include how theta rhythms were discovered; how theta rhythms organize brain information processing into temporal series of spatial patterns; how distinct theta rhythms occur within area CA1 of the hippocampus and between the septum and area CA3 of the hippocampus; what functions theta rhythms carry out in different brain regions, notably CA1-supported functions like learning, recognition, and memory that involve visual, cognitive, and emotional processes; how spatial navigation, adaptively timed learning, and category learning interact with hippocampal theta rhythms; how parallel cortical streams through the lateral entorhinal cortex (LEC) and the medial entorhinal cortex (MEC) represent the end-points of the What cortical stream for perception and cognition and the Where cortical stream for spatial representation and action; how the neuromodulator acetylcholine interacts with the septo-hippocampal theta rhythm and modulates category learning; what functions are carried out by other brain rhythms, such as gamma and beta oscillations; and how gamma and beta oscillations interact with theta rhythms. Multiple experimental facts about theta rhythms are unified and functionally explained by this theoretical synthesis.
Chronic Fructose Substitution for Glucose or Sucrose in Food or Beverages and Metabolic Outcomes: An Updated Systematic Review and Meta-Analysis
Authors: Zafar Mohammad Ishraq , Frese Michael , Mills Kerry E.
Published: April 2021

Despite the publication of several of meta-analyses in recent years, the effects of fructose on human health remains a topic of debate. We previously undertook two meta-analyses on post-prandial and chronic responses to isoenergetic replacement of fructose for sucrose or glucose in food or beverages (Evans et al. 2017, AJCN 106:506–518 & 519–529). Here we report on the results of an updated search with a complete re-extraction of previously identified studies and a new and more detailed subgroup-analysis and meta-regression. We identified two studies that were published after our previous analyses, which slightly altered effect sizes and conclusions. Overall, the isoenergetic substitution of fructose for glucose resulted in a statistically significant but clinically irrelevant reduction in fasting blood glucose, insulin, and triglyceride concentrations. A subgroup analysis by diabetes status revealed much larger reductions in fasting blood glucose in people with impaired glucose tolerance and type 2 diabetes. However, each of these subgroups contained only a single study. In people with a healthy body mass index, fructose consumption was associated with statistically significant, but clinically irrelevant reductions in fasting blood glucose and fasting blood insulin. Meta-regression of the outcomes by a number of pre-identified andpost-hoccovariates revealed some sources of heterogeneity, such as year of publication, age of the participants at baseline, and participants' sex. However, the small number of studies and the large number of potential covariates precluded detailed investigations of effect sizes in different subpopulations. For example, well-controlled, high quality studies in people with impaired glucose tolerance and type 2 diabetes are still lacking. Taken together, the available data suggest that chronic consumption of fructose is neither more beneficial, nor more harmful than equivalent doses of sucrose or glucose for glycemic and other metabolic outcomes.
Altered T Follicular Helper Cell Subsets and Function in Chronic Lymphocytic Leukemia
Authors: Wu Xun , Fajardo-Despaigne J. Ernesto , Zhang Christine , Neppalli Vishala , Banerji Versha , Johnston James B. , Gibson Spencer B. , Marshall Aaron J.
Published: April 2021

Follicular helper T cells (TFH) have specialized properties in promoting normal B cell activation but their role in chronic lymphocytic leukemia (CLL) is unknown. We find that TFH cells are elevated in CLL patients and are phenotypically abnormal, expressing higher levels of PD-1, TIGIT, CD40L, IFNγ and IL-21, and exhibiting abnormal composition of TFH1, TFH2 and TFH17 subsets. Frequencies of CD4-positive T cells expressing TFH1 markers and IL-21 were positively correlated with patient lymphocyte counts and RAI stage, suggesting that accumulation of abnormal TFH cells is concomitant with expansion of the leukemic B cell clone. Treatment with ibrutinib led to normalization of TFH frequencies and phenotype. TFH cells identified in CLL bone marrow display elevated expression of several functional markers compared to blood TFH cells. CLL T cell-B cell co-culture experiments revealed a correlation of patient TFH frequencies with functional ability of their CD4-positive T cells to promote CLL proliferation. Conversely, CLL cells can preferentially activate the TFH cell subset in co-culture. Together our results indicate that CLL development is associated with expansion of abnormal TFH populations that produce elevated levels of cytokines and costimulatory molecules which may help support CLL proliferation.
Performance of PRISM III, PELOD-2, and P-MODS Scores in Two Pediatric Intensive Care Units in China
Authors: Zhang Lidan , Wu Yuhui , Huang Huimin , Liu Chunyi , Cheng Yucai , Xu Lingling , Tang Wen , Luo Xuequn
Published: April 2021

Objective: The performances of the pediatric risk of mortality score III (PRISM III), pediatric logistic organ dysfunction score-2 (PELOD-2), and pediatric multiple organ dysfunction score (P-MODS) in Chinese patients are unclear. This study aimed to assess the performances of these scores in predicting mortality in critically ill pediatric patients.

Methods: This retrospective observational study was conducted at two tertiary-care PICUs of teaching hospitals in China. A total of 1,253 critically ill pediatric patients admitted to the two Pediatric Intensive Care Units (PICUs) of the First Affiliated Hospital, Sun Yat-Sen University from August 2014 to December 2019 and Shen-Zhen Children's Hospital from January 2019 to December 2019 were analyzed. The indexes of discrimination and calibration were applied to evaluate score performance for the three models (PRISM III, PELOD-2, and P-MODS scores). The receiver operating characteristic (ROC) curve was plotted, and the efficiency of PRISM III, PELOD-2, and P-MODS in predicting death were evaluated by the area under ROC curve (AUC). Hosmer–Lemeshow goodness-of-fit test was used to evaluate the degree of fitting between the mortality predictions of each scoring system and the actual mortality.

Results: A total of 1,253 pediatric patients were eventually enrolled in this study (median age, 38 months; overall mortality rate, 8.9%; median length of PICU stay, 8 days). Compared to the survival group, the non-survival group showed significantly higher PRISM III, PELOD-2, and P-MODS scores [PRISM III: 18 (12, 23) vs. 11 (0, 16); PELOD-2, 8 (4, 10) vs. 4 (0, 6); and P-MODS: 5 (4, 9) vs. 3 (0, 4), all P < 0.001]. ROC curve analysis showed that the AUCs of PRISM III, PELOD-2, and P-MODS for predicting the death of critically ill children were 0.858, 0.721, and 0.596, respectively. Furthermore, in the Hosmer–Lemeshow goodness-of-fit test, PRISM III and PELOD-2 showed the better calibration between predicted mortality and observed mortality (PRISM III: χ2 = 5.667, P = 0.368; PELOD-2: χ2 = 9.582, P = 0.276; P-MODS: χ2 = 12.449, P = 0.015).

Conclusions: PRISM III and PELOD-2 can discriminate well between survivors and non-survivors. PRISM III and PELOD-2 showed the better calibration between predicted and observed mortality, while P-MODS showed poor calibration.
PPARγ in Ischemia-Reperfusion Injury: Overview of the Biology and Therapy
Authors: Huang Ruizhen , Zhang Chiyu , Wang Xing , Hu Honglin
Published: April 2021

Ischemia-reperfusion injury (IRI) is a complex pathophysiological process that is often characterized as a blood circulation disorder caused due to various factors (such as traumatic shock, surgery, organ transplantation, burn, and thrombus). Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. Theoretically, IRI can occur in various tissues and organs, including the kidney, liver, myocardium, and brain, among others. The advances made in research regarding restoring tissue perfusion in ischemic areas have been inadequate with regard to decreasing the mortality and infarct size associated with IRI. Hence, the clinical treatment of patients with severe IRI remains a thorny issue. Peroxisome proliferator-activated receptor γ (PPARγ) is a member of a superfamily of nuclear transcription factors activated by agonists and is a promising therapeutic target for ameliorating IRI. Therefore, this review focuses on the role of PPARγ in IRI. The protective effects of PPARγ, such as attenuating oxidative stress, inhibiting inflammatory responses, and antagonizing apoptosis, are described, envisaging certain therapeutic perspectives.
Modeling Crossing Random Seas by Fully Non-Linear Numerical Simulations
Authors: Wang Jinghua , Ma Qingwei , Yan Shiqiang , Liang Bingchen
Published: April 2021

Bimodal spectrum wave conditions, known as crossing seas, can produce extreme waves which are hostile to humans during oceanic activities. This study reports some new findings of the probability of extreme waves in deep crossing random seas in response to the variation of spectral bandwidth through fully non-linear numerical simulations. Two issues are addressed, namely (i) the impacts of the spectral bandwidth on the changes of extreme wave statistics, i.e., the kurtosis and crest exceedance probability, and (ii) the suitability of theoretical distribution models for accurately describing the wave crest height exceedance probability in crossing seas. The numerical results obtained by simulating a large number of crossing sea conditions on large spatial-temporal scale with a variety of spectral bandwidth indicate that the kurtosis and crest height exceedance probability will be enhanced when the bandwidth of each wave train becomes narrower, suggesting a higher probability of encountering extreme waves in narrowband crossing seas. Meanwhile, a novel empirical formula is suggested to predict the kurtosis in crossing seas provided the bandwidth is known in advance. In addition, the Rayleigh and second-order Tayfun distribution underestimate the crest height exceedance probability, while the third-order Tayfun distribution only yields satisfactory predictions for cases with relatively broader bandwidth regarding the wave conditions considered in this study. For crossing seas with narrower bandwidth, all the theoretical distribution models failed to accurately describe the crest height exceedance probability of extreme waves.
A Thermodynamic Framework for Stretching Processes in Fiber Materials
Authors: Arango-Restrepo A. , Rubi J. M. , Pradhan Srutarshi
Published: April 2021

Fiber breakage process involves heat exchange with the medium and energy dissipation in the form of heat, sound, and light, among others. A purely mechanical treatment is therefore in general not enough to provide a complete description of the process. We have proposed a thermodynamic framework which allows us to identify new alarming signals before the breaking of the whole set of fibers. The occurrence of a maximum of the reversible heat, a minimum of the derivative of the dissipated energy, or a minimum in the stretching velocity as a function of the stretch can prevent us from an imminent breakage of the fibers which depends on the nature of the fiber material and on the load applied. The proposed conceptual framework can be used to analyze how dissipation and thermal fluctuations affect the stretching process of fibers in systems as diverse as single-molecules, textile and muscular fibers, and composite materials.