bluuebunny/crossref_metadata_2025 huggingface dataset:
Underlying Climate Controls in Triple Oxygen (16 O, 17 O, 18 O) and Hydrogen (1 H, 2 H) Isotopes Composition of Rainfall (Central Pyrenees)
Authors: Giménez Reyes , Bartolomé Miguel , Gázquez Fernando , Iglesias Miguel , Moreno Ana
Published: May 2021

Studies of rainfall isotopic composition in the Iberian Peninsula are scarce, and to date, none of them have provided analyses of the triple oxygen isotopes, preventing from the complete understanding of current atmospheric processes in this region. We investigate the rainwater δ17O, δ18O, and δD and derived parameters 17O-excess and d-excess in a mountain site in the Central South Pyrenees (Villanúa, Huesca, Spain) to identify the main factors (regional and local) controlling the isotopic composition of precipitation at event scale. The samples were collected on a rainfall-event basis during 2 years (from July 2017 to June 2019), and meteorological variables [temperature, relative humidity (RH), and rainfall amount] were monitored at the sampling site. The δ17O, δ18O, and δD values were higher during summer and lower during the rest of the year. In contrast, the 17O-excess and d-excess were lower during summer and higher during the remaining months. We found that the isotopic parameters are weakly correlated with rainfall amount during each event, but they strongly depend on changes in air temperature and moderately on RH. We consider other factors affecting the isotopic composition of rainfall events that resulted to have an important role, such as the influence of the moisture source and trajectory throughout the variations in the synoptic pattern during rainfall events. This dataset can be useful for further comprehensive atmospheric and hydrological studies, with application to paleoclimatic investigations.
The Emerging Roles of Endocrine Hormones in Different Arthritic Disorders
Authors: Bertoldo Eugenia , Adami Giovanni , Rossini Maurizio , Giollo Alessandro , Orsolini Giovanni , Viapiana Ombretta , Gatti Davide , Fassio Angelo
Published: May 2021

The relationship between endocrine hormones and the spectrum of rheumatic conditions has long been discussed in the literature, focusing primarily on sexual hormones, such as estrogens, androgens, prolactin (PRL). Estrogens are indeed involved in the pathogenesis of the main inflammatory arthritis thanks to their effects on the immune system, both stimulatory and inhibitory. The PRL system has been discovered in synovial tissue of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), patients and has been propose as a new potential therapeutic target. Besides sexual hormones, in the last years scientific interest about the crosstalk of immune system with other class of hormones has grown. Hormones acting on the bone tissue (i.e. parathyroid hormone, vitamin D) and modulators of the Wnt pathway (i.e. Dickkopf-1) have been demonstrated to play active role in inflammatory arthritis course, defining a new field of research named osteoimmunology. PTH, which is one of the main determinants of Dkkopf-1, plays a crucial role in bone erosions in RA and a correlation between PTH, Trabecular Bone Score (TBS) and disease activity has been found in ankylosing spondylitis (AS). In PSA is under studying the interaction among IL-17 and bone metabolism. The purpose of this review is to discuss and summarize the recent data about the interaction between endocrine hormone and immune system in the main rheumatic disorders, covering in particular the role of bone-related hormones and cytokines. We will describe this relationship from a biochemical, diagnostic and therapeutic perspective, with a particular focus on RA, PsA and AS.
Screening for Mutations in Isolated Central Hypothyroidism Reveals a Novel Mutation in Insulin Receptor Substrate 4
Authors: Patyra Konrad , Makkonen Kristiina , Haanpää Maria , Karppinen Sinikka , Viikari Liisa , Toppari Jorma , Reeve Mary Pat , Kero Jukka
Published: May 2021

Background

Central hypothyroidism (CeH) is a rare condition affecting approximately 1:16 000- 100 000 individuals. Congenital forms can harm normal development if not detected and treated promptly. Clinical and biochemical diagnosis, especially of isolated CeH, can be challenging. Cases are not usually detected in neonatal screening, which, in most countries, is focused on detection of the more prevalent primary hypothyroidism. Until now, five genetic causes for isolated CeH have been identified. Here we aimed to identify the genetic cause in two brothers with impaired growth diagnosed with CeH at the age of 5 years. We further evaluated the candidate gene variants in a large genetic database.

Methods

Clinical and biochemical characterization together with targeted next-generation sequencing (NGS) was used to identify the genetic cause in a family of two brothers presenting with CeH. Screening of insulin receptor substrate 4 (IRS4) variants was carried out in the FinnGen database.

Results

A novel monoallelic frameshift mutation c.1712_1713insT, p.Gly572Trp fs*32 in the X-linked IRS4 gene was identified by NGS analysis in both affected males and confirmed using Sanger sequencing. Their mother was an unaffected carrier. In addition to the declined growth at presentation, central hypothyroidism and blunted TRH test, no other phenotypic alterations were found. Diagnostic tests included head MRI, thyroid imaging, bone age, and laboratory tests for thyroid autoantibodies, glucose, insulin and glycosylated hemoglobin levels. Examination of the IRS4 locus in FinnGen (R5) database revealed the strongest associations to a rare Finnish haplotype associated with thyroid disorders (p = 1.3e-7) and hypothyroidism (p = 8.3e-7).

Conclusions

Here, we identified a novel frameshift mutation in an X-linked IRS4 gene in two brothers with isolated CeH. Furthermore, we demonstrate an association of IRS4 gene locus to a general thyroid disease risk in the FinnGen database. Our findings confirm the role of IRS4 in isolated central hypothyroidism.
New Hybrid Organic-Inorganic Thin Films by Molecular Layer Deposition for Rechargeable Batteries
Authors: Liu Jian , Wang Jiajun
Published: May 2021

The design of multifunctional thin films holds the key to manipulate the surface and interface structure of the electrode and electrolyte in rechargeable batteries and achieve desirable performance for various applications. Molecular layer deposition (MLD) is an emerging thin-film technique with exclusive advantages of depositing hybrid organic-inorganic materials at a nanoscale level and with well tunable and unique properties that conventional thin films might not have. Herein, we provide a timely mini-review on the most recent progress in the surface chemistry and MLD process of novel hybrid organic-inorganic thin films and their applications as the anode, cathode, and solid electrolytes in lithium-ion batteries. Perspectives for future research in designing new MLD process and precursors, enriching MLD material library, and expanding their potential applications in other energy storage systems, are discussed at the end.
How Loud Can you go? Physical and Physiological Constraints to Producing High Sound Pressures in Animal Vocalizations
Authors: Jakobsen Lasse , Christensen-Dalsgaard Jakob , Juhl Peter Møller , Elemans Coen P. H.
Published: May 2021

Sound is vital for communication and navigation across the animal kingdom and sound communication is unrivaled in accuracy and information richness over long distances both in air and water. The source level (SL) of the sound is a key factor in determining the range at which animals can communicate and the range at which echolocators can operate their biosonar. Here we compile, standardize and compare measurements of the loudest animals both in air and water. In air we find a remarkable similarity in the highest SLs produced across the different taxa. Within all taxa we find species that produce sound above 100 dBpeak re 20 μPa at 1 m, and a few bird and mammal species have SLs as high as 125 dBpeak re 20 μPa at 1 m. We next used pulsating sphere and piston models to estimate the maximum sound pressures generated in the radiated sound field. These data suggest that the loudest species within all taxa converge upon maximum pressures of 140–150 dBpeak re 20 μPa in air. In water, the toothed whales produce by far the loudest SLs up to 240 dBpeak re 1 μPa at 1 m. We discuss possible physical limitations to the production, radiation and propagation of high sound pressures. Furthermore, we discuss physiological limitations to the wide variety of sound generating mechanisms that have evolved in air and water of which many are still not well-understood or even unknown. We propose that in air, non-linear sound propagation forms a limit to producing louder sounds. While non-linear sound propagation may play a role in water as well, both sperm whale and pistol shrimp reach another physical limit of sound production, the cavitation limit in water. Taken together, our data suggests that both in air and water, animals evolved that produce sound so loud that they are pushing against physical rather than physiological limits of sound production, radiation and propagation.
Flowers of Deceptive Aristolochia microstoma Are Pollinated by Phorid Flies and Emit Volatiles Known From Invertebrate Carrion
Authors: Rupp Thomas , Oelschlägel Birgit , Rabitsch Katharina , Mahfoud Hafez , Wenke Torsten , Disney R. Henry L. , Neinhuis Christoph , Wanke Stefan , Dötterl Stefan
Published: May 2021

Deceptive flowers decoy pollinators by advertising a reward, which finally is not provided. Numerous deceptive plants are pollinated by Diptera, but the attractive cues and deceptive strategies are only identified in a few cases. A typical fly-deceptive plant genus is Aristolochia, which evolved sophisticated trap flowers to temporarily capture pollinators. Though rarely demonstrated by experimental approaches, Aristolochia species are believed to chemically mimic brood sites, food sources for adult flies, or utilize sexual deception. Indeed, for most species, studies on scent composition and attractive signals are lacking. In this study, we focused on Aristolochia microstoma, a peculiar Greek endemic with flowers that are presented at ground level in the leaf litter or between rocks and are characterized by a unique morphology. We analyzed flower visitor and pollinator spectra and identified the floral scent composition using dynamic headspace and gas chromatography coupled to mass spectrometry (GC/MS). Female and male phorid flies (Phoridae) are the exclusive pollinators, although the flowers are also frequently visited by Sciaridae, as well as typical ground-dwelling arthropods, such as Collembola and arachnids. The carrion-like floral scent mainly consists of the oligosulphide dimethyldisulfide and the nitrogen-bearing compound 2,5-dimethylpyrazine. These compounds together are known to be released from decomposing insects, and thus, we conclude that pollinators are likely deceived by chemical imitation of invertebrate carrion, a deceptive strategy not described from another plant species so far.
Omics Profiling of S2P Mutant Fibroblasts as a Mean to Unravel the Pathomechanism and Molecular Signatures of X-Linked MBTPS2 Osteogenesis Imperfecta
Authors: Lim Pei Jin , Marfurt Severin , Lindert Uschi , Opitz Lennart , Ndarugendamwo Timothée , Srikanthan Pakeerathan , Poms Martin , Hersberger Martin , Langhans Claus-Dieter , Haas Dorothea , Rohrbach Marianne , Giunta Cecilia
Published: May 2021

Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by low bone density, bone fragility and recurrent fractures. The characterization of its heterogeneous genetic basis has allowed the identification of novel players in bone development. In 2016, we described the first X-linked recessive form of OI caused by hemizygous MBTPS2 missense variants resulting in moderate to severe phenotypes. MBTPS2 encodes site-2 protease (S2P), which activates transcription factors involved in bone (OASIS) and cartilage development (BBF2H7), ER stress response (ATF6) and lipid metabolism (SREBP) via regulated intramembrane proteolysis. In times of ER stress or sterol deficiency, the aforementioned transcription factors are sequentially cleaved by site-1 protease (S1P) and S2P. Their N-terminal fragments shuttle to the nucleus to activate gene transcription. Intriguingly, missense mutations at other positions of MBTPS2 cause the dermatological spectrum condition Ichthyosis Follicularis, Atrichia and Photophobia (IFAP) and Keratosis Follicularis Spinulosa Decalvans (KFSD) without clinical overlap with OI despite the proximity of some of the pathogenic variants. To understand how single amino acid substitutions in S2P can lead to non-overlapping phenotypes, we aimed to compare the molecular features of MBTPS2-OI and MBTPS2-IFAP/KFSD, with the ultimate goal to unravel the pathomechanisms underlying MBTPS2-OI. RNA-sequencing-based transcriptome profiling of primary skin fibroblasts from healthy controls (n = 4), MBTPS2-OI (n = 3), and MBTPS2-IFAP/KFSD (n = 2) patients was performed to identify genes that are differentially expressed in MBTPS2-OI and MBTPS2-IFAP/KFSD individuals compared to controls. We observed that SREBP-dependent genes are more downregulated in OI than in IFAP/KFSD. This is coupled to alterations in the relative abundance of fatty acids in MBTPS2-OI fibroblasts in vitro, while no consistent alterations in the sterol profile were observed. Few OASIS-dependent genes are suppressed in MBTPS2-OI, while BBF2H7- and ATF6-dependent genes are comparable between OI and IFAP/KFSD patients and control fibroblasts. Importantly, we identified genes involved in cartilage physiology that are differentially expressed in MBTPS2-OI but not in MBTPS2-IFAP/KFSD fibroblasts. In conclusion, our data provide clues to how pathogenic MBTPS2 mutations cause skeletal deformities via altered fatty acid metabolism or cartilage development that may affect bone development, mineralization and endochondral ossification.
Elevated Expression of PDZD11 Is Associated With Poor Prognosis and Immune Infiltrates in Hepatocellular Carcinoma
Authors: Chen Yao , Xie Haifeng , Xie Ting , Yang Xunjun , Pang Yilin , Ye SongDao
Published: May 2021

Epithelial cells are held together by tight and adherent junctions, which are destroyed by the activation of epithelial-to-mesenchymal transition (EMT). The PLEKHA7-PDZD11 complex has been reported to be important for epithelial cell adhesion and connecting tissues. However, there is no research regarding the expression and role of PDZD11 in liver hepatocellular carcinoma (LIHC) progression. Here, we analyzed PDZD11 mRNA expression and its clinical results in LIHC patient RNA sequencing data based on different open databases. Furthermore, we examined differences in PDZD11 expression in LIHC tissues and cell lines using western blotting and real-time qPCR. These results are the first to report that the mRNA and protein levels of PDZD11 are significantly overexpressed in LIHC. Moreover, high expression of PDZD11 was correlated with poor overall survival in patients with LIHC. Gene regulatory network analysis suggested that PDZD11 is mainly involved in copper ion homeostasis, proteasome, and oxidative phosphorylation pathways. Interestingly, we found that PDZD11 levels were positively correlated with the abundance of immune infiltrates. In particular, higher infiltration levels of CD4+ T cells and macrophage subsets significantly affected LIHC patient prognosis. Taken together, these results demonstrate that PDZD11 could be a potential diagnostic and prognostic biomarker in LIHC.
Efficacy of Electroacupuncture Therapy in Patients With Postherpetic Neuralgia: Study Protocol for a Multicentre, Randomized, Controlled, Assessor-Blinded Trial
Authors: Hu Hantong , Shen Yejing , Li Xinwei , Tian Hongfang , Li XingLing , Li Yang , Cheng Yingying , Wu Lei , Han Dexiong
Published: May 2021

Introduction: The efficacy of conventional treatments for treating postherpetic neuralgia (PHN) remains unsatisfactory. Thus, this multicentre, randomized controlled, assessor-blinded trial aims to investigate the efficacy and safety of electroacupuncture (EA) therapy in patients with PHN.

Methods and Analysis: This multicentre randomized controlled trial will enroll 132 patients with PHN from 3 hospitals. All patients will be randomly assigned to either the EA combined with medication group or medication group through a computerized central randomization system in a 1:1 ratio. Outcome measures will be assessed before intervention, at 2, 4, 6 weeks after intervention and at the end of 8-week follow-up. Primary outcomes will be sensory thresholds and pain intensity. Secondary outcomes will include dosage of analgetic, quality of life, anxiety, and depression severity and sleep quality. All adverse effects will be assessed during the trial.

Conclusions: This study will provide evidence to ascertain whether EA is effective and safe for treating PHN.

Ethics and Dissemination: Ethics approval (No.ZSLL-KY-2017-025) has been obtained from the Ethics Committee of The Third Affiliated Hospital of Zhejiang Chinese Medical University. Informed consent will be signed prior to subject enrolment. The results will be submitted to international peer-reviewed journals and presented at international conferences.

Trial Registration Number: The study protocol has been registered in the clinicaltrials registry with the identification code NCT04594226.
Publication Trends of Research on Retinoblastoma During 2001–2021: A 20-Year Bibliometric Analysis
Authors: Gu Xiang , Xie Minyue , Jia Renbing , Ge Shengfang
Published: May 2021

Background: Retinoblastoma is the most common primary intraocular malignancy of childhood. Despite high survival and eye salvage as the result of various types of therapies, retinoblastoma remains a disease that places a considerable burden on developing countries. Our study attempted to analyse the research trends in retinoblastoma research and compare contributions from different countries, institutions, journals, and authors.

Methods: We extracted all publications concerning retinoblastoma from 2001 to 2021 from the Web of Science database. Microsoft Excel and VOSviewer were employed to collect publication data, analyse publication trends, and visualize relevant results.

Results: A total of 1,675 publications with 30,148 citations were identified. The United States contributed the most publications (643) and citations (16,931 times) with the highest H-index value (67) as of February 4, 2021. China ranked second in the number of publications (259), while ranking fourth in both citations (2,632 times) and the H-index (26) ranked fourth. The British Journal of Ophthalmology was the most productive journal concerning retinoblastoma, and Abramson DH had published the most papers in the field. Keywords were categorized into three clusters; tumor-related research, clinical research, and management-related research. The keywords “intravitreal,” “intraarterial,” and “intravenous” appeared the most frequently, with the average appearing year being 2018.1, 2017.7, and 2017.1, respectively. Management-related research has been recognized as a heavily researched topic in the field.

Conclusion: We conclude that the United States, China, and India made the most exceptional contributions in the field of retinoblastoma research, while China still has a disparity between the quantity and quality of publications. Management-related research, including intravitreal, intraarterial, and intravenous chemotherapy was considered as a potential focus for future research.
Enterococcus faecalis Readily Adapts Membrane Phospholipid Composition to Environmental and Genetic Perturbation
Authors: Woodall Brittni M. , Harp John R. , Brewer William T. , Tague Eric D. , Campagna Shawn R. , Fozo Elizabeth M.
Published: May 2021

The bacterial lipid membrane, consisting both of fatty acid (acyl) tails and polar head groups, responds to changing conditions through alteration of either the acyl tails and/or head groups. This plasticity is critical for cell survival as it allows maintenance of both the protective nature of the membrane as well as functioning membrane protein complexes. Bacteria that live in fatty-acid rich environments, such as those found in the human host, can exploit host fatty acids to synthesize their own membranes, in turn, altering their physiology. Enterococcus faecalis is such an organism: it is a commensal of the mammalian intestine where it is exposed to fatty-acid rich bile, as well as a major cause of hospital infections during which it is exposed to fatty acid containing-serum. Within, we employed an untargeted approach to detect the most common phospholipid species of E. faecalis OG1RF via ultra-high performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS). We examined not only how the composition responds upon exposure to host fatty acids but also how deletion of genes predicted to synthesize major polar head groups impact lipid composition. Regardless of genetic background and differing basal lipid composition, all strains were able to alter their lipid composition upon exposure to individual host fatty acids. Specific gene deletion strains, however, had altered survival to membrane damaging agents. Combined, the enterococcal lipidome is highly resilient in response to both genetic and environmental perturbation, likely contributing to stress survival.
CRISPR-Cas9-Based Discovery of the Verrucosidin Biosynthesis Gene Cluster in Penicillium polonicum
Authors: Valente Silvia , Piombo Edoardo , Schroeckh Volker , Meloni Giovanna Roberta , Heinekamp Thorsten , Brakhage Axel A. , Spadaro Davide
Published: May 2021

Penicillium polonicum, commonly found on food matrices, is a mycotoxigenic species able to produce a neurotoxin called verrucosidin. This methylated α-pyrone polyketide inhibits oxidative phosphorylation in mitochondria and thereby causes neurological diseases. Despite the importance of verrucosidin as a toxin, its biosynthetic genes have not been characterized yet. By similarity analysis with the polyketide synthase (PKS) genes for the α-pyrones aurovertin (AurA) and citreoviridin (CtvA), 16 PKS genes for putative α-pyrones were identified in the P. polonicum genome. A single PKS gene, verA, was found to be transcribed under verrucosidin-producing growth conditions. The annotated functions of the genes neighboring verA correspond to those required for verrucosidin biosynthesis. To prove the involvement of verA in verrucosidin biosynthesis, the clustered regularly interspaced short palindrome repeats (CRISPR) technology was applied to P. polonicum. In vitro reconstituted CRISPR-Cas9 was used to induce targeted gene deletions in P. polonicum. This approach allowed identifying and characterizing the verrucosidin biosynthetic gene cluster. VerA deletion mutants were no longer able to produce verrucosidin, whereas they were displaying morphological characteristics comparable with the wild-type strain. The available CRISPR-Cas9 technology allows characterizing the biosynthetic potential of P. polonicum as a valuable source of novel compounds.
An Oligosaccharide Rich Diet Increases Akkermansia spp. Bacteria in the Equine Microbiota
Authors: Lindenberg Frederikke Christine , Lützhøft Ditte Olsen , Krych Lukasz , Fielden James , Kot Witold , Frøkiær Hanne , van Galen Gaby , Nielsen Dennis Sandris , Hansen Axel Kornerup
Published: May 2021

Some oligosaccharides induce growth of anti-inflammatory bacterial species and induce regulatory immunity in humans as well as animals. We have shown that the equine gut microbiota and the immune-microbial homeostasis largely stabilize within the first 50 days of life. Furthermore, we have previously established that certain bacterial species in the equine gut correlated with regulatory immunity. Accordingly, we hypothesized that an oligosaccharide rich diet fed to foals during the first 50 days would increase the abundance of bacterial species associated with regulatory immunity, and that this would influence immune responses in the foals. Eight pregnant mares and their foals were fed an oligosaccharide rich diet from 4 weeks before expected parturition until 49 days post-partum. Six mares and foals served as control. Fecal microbiota from mares and foals was characterized using 16S rRNA gene amplicon high throughput sequencing. On Day 49 the test foals had significantly higher abundances of Akkermansia spp. Blood sampled from the foals in the test group on Day 7, 28, and 49 showed non-significant increases in IgA, and decreases in IgG on Day 49. In BALB/cBomTac mice inoculated with gut microbiota from test and control foals we found increased species richness, increased relative abundance of several species identified as potentially anti-inflammatory in horses, which were unclassified Clostridiales, Ruminococcaceae, Ruminococcus, Oscilospira, and Coprococcus. We also found increased il10 expression in the ileum if inoculated with test foal microbiota. We conclude that an oligosaccharide diet fed to foals in the “window of opportunity,” the first 50 days of life, increases the abundance of anti-inflammatory species in the microbiota with potentially anti-inflammatory effects on regulatory immunity.
Health-Promoting Properties of Lactobacilli in Fermented Dairy Products
Authors: Widyastuti Yantyati , Febrisiantosa Andi , Tidona Flavio
Published: May 2021

Bacteria of the genus Lactobacillus have been employed in food fermentation for decades. Fermented dairy products, such as cheese and yogurt, are products of high value known as functional food and widely consumed due to their positive health impact. Fermentation was originally based on conversion of carbohydrate into organic acids, mostly lactic acid, intended to preserve nutrient in milk, but then it develops in other disclosure of capabilities associates with health benefit. It is expected that during the manufacture of fermented dairy products, some bioactive peptides from milk protein are released through proteolysis. Lactobacilli have been recognized and received increasing attention as probiotics by balancing gut microbial population. Information of molecular mechanisms of genome sequence focusing on the microbial that normally inhabit gut may explain as to how these bacteria positively give impact on improving host health. Recent post-biotics concept revealed that health benefit can also be associated after bacterial lysis. This mini review focuses on the contribution of lactobacilli in dairy fermentation with health-promoting properties on human health.
Bayesian Random Tomography of Particle Systems
Authors: Vakili Nima , Habeck Michael
Published: May 2021

Random tomography is a common problem in imaging science and refers to the task of reconstructing a three-dimensional volume from two-dimensional projection images acquired in unknown random directions. We present a Bayesian approach to random tomography. At the center of our approach is a meshless representation of the unknown volume as a mixture of spherical Gaussians. Each Gaussian can be interpreted as a particle such that the unknown volume is represented by a particle cloud. The particle representation allows us to speed up the computation of projection images and to represent a large variety of structures accurately and efficiently. We develop Markov chain Monte Carlo algorithms to infer the particle positions as well as the unknown orientations. Posterior sampling is challenging due to the high dimensionality and multimodality of the posterior distribution. We tackle these challenges by using Hamiltonian Monte Carlo and a global rotational sampling strategy. We test the approach on various simulated and real datasets.
Novel Insights into the Potential Diagnostic Value of Circulating Exosomal IncRNA-Related Networks in Large Artery Atherosclerotic Stroke
Authors: Zhang Shuai , Wang Jing , Qu Mei Jie , Wang Kun , Ma Ai Jun , Pan Xu Dong , Zhu Xiao Yan
Published: May 2021

Exosomes show diagnostic and therapeutic promise as carriers of ncRNAs in diseases. LncRNAs in exosomes have been identified as being stable and avoided degradation by nucleolytic enzymes. Although lncRNAs have been confirmed to be important in cancers, no studies for exo-lncRNAs have been reported in LAA stroke. High-throughput sequencing was performed to detect the differential expression profiles of lncRNAs in five paired plasma-derived exosome samples from patients with LAA stroke and controls (matched on vascular risk factors). Exo-lncRNA-associated networks were predicted with a combination of multiple databases. The expression of the selected genes in the networks was confirmed by qRT-PCR in a validation set (LAA vs. controls = 30:30). Furthermore, ROC analysis was used to evaluate the diagnostic performance of the lncRNA-related networks. A total of 1,020 differentially expressed lncRNAs were identified in LAA stroke patients. GO and KEGG pathway analyses indicated that their target genes are involved in atherosclerosis-related pathways, including inflammation, cell adhesion, and cell migration. qRT-PCR confirmed that the expression trend of differential expressed genes was consistent with RNA-seq. Furthermore, the AUCs of the lnc_002015-related network and lnc_001350-related network were 0.959 and 0.97, respectively, in LAA stroke. Our study showed the differential expression of lncRNAs in plasma exosomes and presented related diagnostic networks for LAA stroke for the first time. The results suggested that exosomal lncRNA-related networks could be potential diagnostic tools in LAA stroke.
Marked Mild Cognitive Deficits in Humanized Mouse Model of Alzheimer’s-Type Tau Pathology
Authors: Cho Joshua D. , Kim Yoon A. , Rafikian Elizabeth E. , Yang Mu , Santa-Maria Ismael
Published: May 2021

Hyperphosphorylation and the subsequent aggregation of tau protein into neurofibrillary tangles (NFTs) are well-established neuropathological hallmarks of Alzheimer’s disease (AD) and associated tauopathies. To further examine the impact and progression of human tau pathology in neurodegenerative contexts, the humanized tau (htau) mouse model was originally created. Despite AD-like tau pathological features recapitulated in the htau mouse model, robustness of behavioral phenotypes has not been fully established. With the ultimate goal of evaluating the htau mouse model as a candidate for testing AD therapeutics, we set out to verify, in-house, the presence of robust, replicable cognitive deficits in the htau mice. The present study shows behavioral data collected from a carefully curated battery of learning and memory tests. Here we report a significant short-term spatial memory deficit in aged htau mice, representing a novel finding in this model. However, we did not find salient impairments in long-term learning and memory previously reported in this mouse model. Here, we attempted to understand the discrepancies in the literature by highlighting the necessity of scrutinizing key procedural differences across studies. Reported cognitive deficits in the htau model may depend on task difficulty and other procedural details. While the htau mouse remains a unique and valuable animal model for replicating late onset AD-like human tau pathology, its cognitive deficits are modest under standard testing conditions. The overarching message is that before using any AD mouse model to evaluate treatment efficacies, it is imperative to first characterize and verify the presence of behavioral deficits in-house.
A Comparison of Safety and Effectiveness Between Wingspan and Neuroform Stents in Patients With Middle Cerebral Artery Stenosis
Authors: Zhou Kai , Cao Yuan , He Xiao-Hui , Qiu Zhong-Ming , Liu Shuai , Gong Zi-Li , Shuai Jie , Yang Qing-Wu
Published: May 2021

Background: Percutaneous transluminal angioplasty and stenting with the Wingspan stent has proven safe and effective in patients with middle cerebral artery stenosis (MCAS), but the off-label use of the Neuroform stent might be an alternative treatment. This study aimed to compare the safety and effectiveness of the above two intracranial stents in patients with MCAS.

Methods: We retrospectively analyzed consecutive patients with symptomatic MCAS who had been treated with the Neuroform EZ or the Wingspan stent. A propensity score was generated to control for differences in baseline characteristics. The endpoints were the rate of peri-procedural complications within 30 days after stenting, the in-stent restenosis rate, and any target-vessel-related stroke or deaths during follow-up.

Results: After matching for propensity score, the peri-procedural complication rate in the Wingspan group was 7.4% compared with 5.6% in the Neuroform group (p = 1.00), while the follow-up in-stent restenosis rates were 23.3 vs. 14.3%, respectively (p = 0.41). In the restenosis group, the patients tended to be younger (p < 0.01) and the degree of artery stenosis before stenting was higher (p < 0.01).

Conclusion: This study indicated that in patients with symptomatic MCAS, Neuroform EZ stents are an alternative to Wingspan. Moreover, younger age and higher degree of artery stenosis before stenting might be a risk factor of in-stent restenosis.
Prevalence of Vestibular Disorders in Independent People Over 50 That Experience Dizziness
Authors: Figtree William V. C. , Menant Jasmine C. , Chau Allan T. , Hübner Patrick P. , Lord Stephen R. , Migliaccio Americo A.
Published: May 2021

People aged over 50 are the most likely to present to a physician for dizziness. It is important to identify the main cause of dizziness in order to develop the best treatment approach. Our goal was to determine the prevalence of benign paroxysmal positional vertigo (BPPV), and peripheral and central vestibular function in people that had experienced dizziness within the past year aged over 50. One hundred and ninety three community-dwelling participants aged 51–92 (68 ± 8.7 years; 117 females) were tested using the clinical and video head impulse test (cHIT and vHIT) to test high-frequency vestibular organ function; the head thrust dynamic visual acuity (htDVA) test to test high-frequency visual-stability; the dizziness handicap inventory (DHI) to measure the impact of dizziness; as well as sinusoidal and unidirectional rotational chair testing to test low- to mid-frequency peripheral and central vestibular function. From these assessments we computed the following measures: HIT gain; htDVA score; DHI score; sinusoidal (whole-body; 0.1–2 Hz with 30°/s peak-velocity) vestibulo-ocular reflex (VOR) gain and phase; transient (whole-body, 150°/s2 acceleration to 50°/s constant velocity) VOR gain and time constant; optokinetic nystagmus (OKN) gain and time constant (whole-body, 50°/s constant velocity rotation). Our study showed that BPPV, and peripheral or central vestibular hypofunction were present in 34% of participants, suggesting a vestibular cause to their dizziness. Over half (57%) of these with a likely vestibular cause had BPPV, which is more than twice the percentage reported in other dizzy clinic studies. Our findings suggest that the physical DHI score and VOR time constant were best at detecting those with non-BPPV vestibular loss, but should always be used in conjunction with cHIT or vHIT, and that the htDVA score and vHIT gain were best at detecting differences between ipsilesional and contralesional sides.
Angiotensin-(1-7) Central Mechanisms After ICV Infusion in Hypertensive Transgenic (mRen2)27 Rats
Authors: Kangussu Lucas M. , Melo-Braga Marcella Nunes , de Souza Lima Bruna Soares , Santos Robson A. S. , de Andrade Hélida Monteiro , Campagnole-Santos Maria José
Published: May 2021

Graphical Abstract

Hypothalamic mechanisms induced by ICV infusion of angiotensin-(1-7) in the transgenic (mRen2)27 hypertensive animals. Ang-(1-7) treatment modulated components of the renin-angiotensin system (RAS), attenuating increased levels of AT1 and ACE activity, and negatively modulated inflammatory profile, by increasing anti-inflammatory IL-10 and decreasing TNFα and iNOS in the hypothalamus. Further, altered oxidative stress/inflammation by ROS mediator, decreasing Uchl1 (ubiquitin carboxyl-terminal hydrolase isozyme L1) while increasing antioxidant peroxiredoxin 1 (figure was created with pictures from biorender.com).
Effects of Anaerobic Fermentation on Black Garlic Extract by Lactobacillus: Changes in Flavor and Functional Components
Authors: Ma Li , Zhao Chengying , Chen Jifeng , Zheng Jinkai
Published: May 2021

The purpose of this study is to investigate the potential application of probiotics in the development of novel functional foods based on black garlic. The single-factor analysis (extraction temperatures, solid-to-liquid ratios, and extraction times) and the response surface methodology were firstly used to optimize hot water extraction of soluble solids from black garlic. The optimal extraction conditions were temperature 99.96°C, solid-to-liquid ratio 1:4.38 g/ml, and extracting 2.72 h. The effects of Lactobacillus (Lactobacillus plantarum, Lactobacillus rhamnosus, and co-culture of them) fermentation on the physicochemical properties of black garlic extract broth were studied for the first time. Artificial and electronic sensory evaluations demonstrated that fermentation significantly influenced the sensory characteristics. The variations of metabolites in different broth samples (S1, unfermented; S2, 1-day fermentation by L. plantarum; S3, 2-day fermentation by L. rhamnosus; and S4, 1-day fermentation by co-cultured Lactobacillus) were further investigated by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry/mass spectrometry analysis. As a result, Lactobacillus fermentation significantly reduced the pH; increased the contents of the total acid, amino nitrogen, total polyphenol, and total flavonoid; and reduced the content of 5-hydroxymethylfurfural (a carcinogenic component) by 25.10–40.81% in the black garlic extract. The contents of several components with unpleasant baking flavors (e.g., furfural, 2-acetylfuran, and 5-methyl furfural) were reduced, whereas the contents of components with green grass, floral, and fruit aromas were increased. More importantly, the contents of several functional components including lactic acid, Gly-Pro-Glu, sorbose, and α-CEHC (3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-propanoic acid) were increased after Lactobacillus fermentation. The results demonstrated the potential of probiotic fermentation to improve the quality of black garlic. This work will provide an insight into the strategic design of novel black garlic products and facilitate the application of black garlic in functional foods.
A Dynamic Transcription Factor Signature Along the Colorectal Adenoma-Carcinoma Sequence in Patients With Co-Occurrent Adenoma and Carcinoma
Authors: Pan Zongfu , He Ying , Zhu Wenjuan , Xu Tong , Hu Xiaoping , Huang Ping
Published: May 2021

Background

Colorectal carcinoma (CRC) often arises from benign adenoma after a stepwise accumulation of genetic alterations. Here, we profiled the dynamic landscapes of transcription factors (TFs) in the mucosa-adenoma-carcinoma progression sequence.

Methods

The transcriptome data of co-occurrent adenoma, carcinoma, and normal mucosa samples were obtained from GSE117606. Identification of differentially expressed TFs (DE-TFs) and subsequent function annotation were conducted in R software. Expression patterns of DE-TFs were clustered by Short Time-series Expression Miner software. Thereafter, modular co-expression analysis, Kaplan-Meier survival analysis, mutation profiling, and gene set enrichment analysis were conducted to investigate TF dynamics in colorectal tumorigenesis. Finally, tissue microarrays, including 51 tumors, 32 adenomas, and 53 normal tissues, were employed to examine the expression of significant candidates by immunohistochemistry staining.

Results

Compared to normal tissues, 20 (in adenoma samples) and 29 (in tumor samples) DE-TFs were identified. During the disease course, 28 expression patterns for DE-TFs and four co-expression modules were clustered. Notably, six DE-TFs, DACH1, GTF2IRD1, MEIS2, NR3C2, SOX9, and SPIB, were identified as having a dynamic signature along the colorectal adenoma-carcinoma sequence. The dynamic signature was of significance in GO enrichment, prognosis, and co-expression analysis. Among the 6-TF signature, the roles of GTF2IRD1, SPIB and NR3C2 in CRC progression are unclear. Immunohistochemistry validation showed that GTF2IRD1 enhanced significantly throughout the mucosa-adenoma-carcinoma sequence, while SPIB and NR3C2 kept decreasing in stroma during the disease course.

Conclusions

Our study provided a dynamic 6-TF signature throughout the course of colorectal mucosa-adenoma-carcinoma. These findings deepened the understanding of colorectal cancer pathogenesis.
Case Report: Transformation From Non-Small Cell Lung Cancer to Small Cell Lung Cancer During Anti-PD-1 Therapy: A Report of Two Cases
Authors: Shen Qian , Qu Jingjing , Sheng Lingyan , Gao Qiqi , Zhou Jianying
Published: May 2021

Background

Histological transformation of lung cancer to small cell lung cancer (SCLC) is uncommon. It is a small subset of the possible resistance mechanisms, even in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Reports on programmed cell death-1 (PD-1) inhibitors are rare. We report two cases of lung squamous carcinomas that transformed to SCLC during anti-PD-1 therapy, and present a detailed description of histological examination of the pre-and post-transformation tissues, hitherto absent from reports on the topic.

Case Presentation

Case 1: A 69-year-old man was diagnosed with stage IVa squamous cell carcinoma of the lung. He had a programmed cell death-ligand 1 tumor proportion score ≥50%. He achieved partial response after four cycles of sintilimab as first-line treatment. However, sintilimab was discontinued because of severe decrease in hemoglobin levels and platelet counts. Moreover, the occurrence of pleural effusion favored disease progression. Interestingly, bone marrow puncture and biopsy showed transformation to SCLC. Case 2: A 71-year-old man diagnosed with stage IIIa lung squamous cell carcinoma received neoadjuvant chemotherapy, underwent radical surgery, and finally received adjuvant chemotherapy. Five months later, he presented with tumor recurrence. He was treated with nivolumab, though disease progression was observed after four cycles. Notably, a subsequent computed tomography-guided biopsy showed SCLC.

Conclusion

Phenotypic transformation to SCLC is a potential mechanism of resistance to immunotherapy in squamous cell carcinomas of the lung. Disease progression should prompt re-biopsy to diagnose potential histological changes to assess the requirement for change in treatment.
Variation of Long Non-Coding RNA And mRNA Profiles in Breast Cancer Cells With Influences of Adipocytes
Authors: Cao Xin-Hui , Yang Kai , Liang Ming-Xing , Ma Pei , Xu Di , Fei Yin-Jiao , Zhang Wei , Chen Xiu , Tang Jin-Hai
Published: May 2021

Background

It is well known that obesity is one of the risks for incurrence and development in breast cancer patients. Long non-coding RNAs (lncRNAs) are reported to participate in the composition of tumor microenvironment and to regulate breast cancer cell metabolic activities. However, there was rare study focused on the lncRNAs in breast cancer with the influences of adipocytes. The study aimed to investigate lncRNAs expression profiles and discover potential biomarkers to predict the incidence and progression of adipocyte-associated-breast cancer.

Methods

We co-cultured adipocytes with breast cancer cells and profiled the expression of lncRNAs as well as mRNAs by using the RNA-sequencing method. Wound Healing, Migration assays and Invasion assays were applied to verify the invasion and metastasis of cancer cells.

Results

MDA-MB-231/Hpa-V and SK-BR-3/Hpa-V cells showed elevated migration and invasiveness compared to the control group. A sum of 371 mRNAs (181 upregulated and 190 downregulated) and 850 lncRNAs(414 upregulated and 436 downregulated) were differentially expressed in MDA-MB-231/Hpa-V comparing to MDA-MB-231(P < 0.05; |log2 (fold change)|>1.2). GO enrichment, KEGG pathway and interaction networks demonstrated that differentially expressed lncRNAs were involved in functional categories, such as material metabolism, which might lead to the progression of breast cancer.

Conclusion

Our study detected a lncRNA profile in breast cancer cells affecting by adipocytes and provided a better understanding of the tumor microenvironment. LncRNAs may be helpful to predict the therapeutic responses and prognosis of obese breast cancer patients.
Overexpression of LINC00673 Promotes the Proliferation of Cervical Cancer Cells
Authors: Huang Sheng-Kai , Ni Ruo-Xuan , Wang Wen-Jie , Wang Di , Zhao Mei , Lei Cheng-Zhi , Sun Xiao-Jie , Huang Chang-Zhi , Bai Ping , Che Yi-Qun , Xu Jian-Ping
Published: May 2021

Objective

To study the expression of LINC00673 in cervical cancer and cervical intraepithelial neoplasia (CIN) and to explore the role of LINC00673 in the development of cervical cancer.

Methods

The expression of LINC00673 in serum from cervical cancer patients, CIN patients, and healthy participants was detected by RT-qPCR. The function of LINC00673 in cervical cancer cells was analyzed using in vitro and in vivo experiments.

Results

Our results revealed that serum LINC00673 levels were highest in cervical cancer patients, followed by patients with CIN and healthy controls. In vitro experiments demonstrated that overexpression of LINC00673 enhanced the proliferation and cell cycle progression of HeLa and SiHa cells. In vivo experiments showed that the tumor weight and volume of nude mice subcutaneously injected with LINC00673-overexpressing HeLa cells were larger than those of nude mice injected with control cells (P < 0.05). Western blotting showed that cell cycle-related proteins cyclin A2 and cyclin E and interstitial-associated proteins Snail and N-cadherin were upregulated and p53 signaling pathway-related proteins were downregulated in LINC00673-overexpressing HeLa and SiHa cells.

Conclusion

LINC00673 plays an important role in the development of cervical cancer and may serve as a new therapeutic target for cervical cancer.
Synchrotron X-Ray Radiation-Induced Bystander Effect: An Impact of the Scattered Radiation, Distance From the Irradiated Site and p53 Cell Status
Authors: Lobachevsky Pavel , Forrester Helen B. , Ivashkevich Alesia , Mason Joel , Stevenson Andrew W. , Hall Chris J. , Sprung Carl N. , Djonov Valentin G. , Martin Olga A.
Published: May 2021

Synchrotron radiation, especially microbeam radiotherapy (MRT), has a great potential to improve cancer radiotherapy, but non-targeted effects of synchrotron radiation have not yet been sufficiently explored. We have previously demonstrated that scattered synchrotron radiation induces measurableγ-H2AX foci, a biomarker of DNA double-strand breaks, at biologically relevant distances from the irradiated field that could contribute to the apparent accumulation of bystander DNA damage detected in cells and tissues outside of the irradiated area. Here, we quantified an impact of scattered radiation to DNA damage response in “naïve” cells sharing the medium with the cells that were exposed to synchrotron radiation. To understand the effect of genetic alterations in naïve cells, we utilised p53-null and p53-wild-type human colon cancer cells HCT116. The cells were grown in two-well chamber slides, with only one of nine zones (of equal area) of one well irradiated with broad beam or MRT.γ-H2AX foci per cell values induced by scattered radiation in selected zones of the unirradiated well were compared to the commensurate values from selected zones in the irradiated well, with matching distances from the irradiated zone. Scattered radiation highly impacted the DNA damage response in both wells and a pronounced distance-independent bystander DNA damage was generated by broad-beam irradiations, while MRT-generated bystander response was negligible. For p53-null cells, a trend for a reduced response to scattered irradiation was observed, but not to bystander signalling. These results will be taken into account for the assessment of genotoxic effects in surrounding non-targeted tissues in preclinical experiments designed to optimise conditions for clinical MRT and for cancer treatment in patients.