bluuebunny/crossref_metadata_2025 huggingface dataset:
Widespread transcriptional disruption of the microRNA biogenesis machinery in brain and peripheral tissues of individuals with schizophrenia
Authors: Rey Romain , Suaud-Chagny Marie-Françoise , Dorey Jean-Michel , Teyssier Jean-Raymond , d’Amato Thierry
Published: November 2020

In schizophrenia, altered transcription in brain and peripheral tissues may be due to altered expression of the microRNA biogenesis machinery genes. In this study, we explore the expression of these genes both at the cerebral and peripheral levels. We usedshinyGEO application to analyze gene expression from ten Gene Expression Omnibus datasets, in order to perform differential expression analyses for eight genes encoding the microRNA biogenesis machinery. First, we compared expression of the candidate genes between control subjects and individuals with schizophrenia in postmortem cerebral samples from seven different brain regions. Then, we compared the expression of the candidate genes between control subjects and individuals with schizophrenia in three peripheral tissues. In brain and peripheral tissues of individuals with schizophrenia, we report distinct altered expression patterns of the microRNA biogenesis machinery genes. In the dorsolateral prefrontal cortex, associative striatum and cerebellum of individuals with schizophrenia, we observed an overexpression pattern of some candidate genes suggesting a heightened miRNA production in these brain regions. Additionally, mixed transcriptional abnormalities were identified in the hippocampus. Moreover, in the blood and olfactory epithelium of individuals with schizophrenia, we observed distinct aberrant transcription patterns of the candidate genes. Remarkably, in individuals with schizophrenia, we report DICER1 overexpression in the dorsolateral prefrontal cortex, hippocampus and cerebellum as well as a congruent DICER1 upregulation in the blood compartment suggesting that it may represent a peripheral marker. Transcriptional disruption of the miRNA biogenesis machinery may contribute to schizophrenia pathogenesis both in brain and peripheral tissues.
Anti-bacterial antibodies in multiple myeloma patients at disease presentation, in response to therapy and in remission: implications for patient management
Authors: Chicca Ilaria J. , Heaney Jennifer L. J. , Iqbal Gulnaz , Dunn Janet A. , Bowcock Stella , Pratt Guy , Yong Kwee L. , Planche Timothy D. , Richter Alex , Drayson Mark T.
Published: November 2020

Multiple myeloma (MM) is associated with increased risk of infection, but little is known regarding antibody levels against specific bacteria. We assessed levels of polyclonal immunoglobulin and antibacterial antibodies in patients recruited to the TEAMM trial, a randomised trial of antibiotic prophylaxis at the start of anti-myeloma treatment. Polyclonal IgG, IgA and IgM levels were below the reference range in 71%, 83% and 90% of 838 MM patients at diagnosis. Anti-vaccine targeted tetanus toxoid antibodies were protective in 95% of 193 healthy controls but only 41% of myeloma patients. In healthy controls, protective antibodies against 6/12 pneumococcal serotypes, haemophilus and meningococcus A were present in 67%, 41% and 56% compared to just 15%, 21% and 17% of myeloma patients. By 1 year, myeloma patients IgG levels had recovered for 57% of patients whilst the proportion with protective levels of IgG against thymus-dependent protein antigen tetanus toxoid had changed little. In contrast the proportions of patients with protective levels against thymus independent polysaccharide antigens pneumococcus, haemophilus and meningococcus had fallen from 15 to 7%, 21 to 0% and 17 to 11%. Findings highlight the need for strategies to protect patients against bacterial infections during therapy and vaccination programmes during remission.
Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX
Authors: Kaufman Jonathan L. , Dimopoulos Meletios A. , White Darrell , Benboubker Lotfi , Cook Gordon , Leiba Merav , Morton James , Joy Ho P. , Kim Kihyun , Takezako Naoki , Moreau Philippe , Sutherland Heather J. , Magen Hila , Iida Shinsuke , Kim Jin Seok , Miles Prince H. , Cochrane Tara , Oriol Albert , Bahlis Nizar J. , Chari Ajai , O’Rourke Lisa , Trivedi Sonali , Casneuf Tineke , Krevvata Maria , Ukropec Jon , Kobos Rachel , Avet-Loiseau Hervé , Usmani Saad Z. , San-Miguel Jesus
Published: November 2020

High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.
Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients
Authors: Fotiou Despina , Roussou Maria , Gakiopoulou Charikleia , Psimenou Erasmia , Gavriatopoulou Maria , Migkou Magdalini , Kanellias Nikolaos , Dialoupi Ioanna , Eleutherakis-Papaiakovou Evangelos , Giannouli Stavroula , Delavinia Christina , Efstathiou Kostantinos , Kontogiannis Sofoklis , Terpos Evangelos , Dimopoulos Meletios A. , Kastritis Efstathios
Published: November 2020

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ.
Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer
Authors: Dwyer Amy R. , Truong Thu H. , Kerkvliet Carlos Perez , Paul Kiran V. , Kabos Peter , Sartorius Carol A. , Lange Carol A.
Published: November 2020

Background

Progesterone receptors (PR) are potent modifiers of endocrine responses. In aberrant signalling cancer contexts, phosphorylation events dramatically alter steroid hormone receptor action.

Methods

The transcriptomes of primary tumours and metastases in mice harbouring ER+ breast cancer patient-derived xenografts (PDXs) were analysed following single-cell RNAseq. In vitro assays were employed to delineate mechanisms of endocrine resistance and stemness.

Results

A 16-gene phospho-Ser294 PR (p-PR) signature predicted poor outcome in ER+ breast cancer. Relative to primary PDX tumours, metastatic lesions expressed abundant p-PR and exhibited an activated PR gene programme with elevated expression of PGR and IRS-1. Breast cancer models of activated PR lost the expression of IGF1R and acquired insulin hypersensitivity with tamoxifen insensitivity. Activated p-PR+ breast cancer cells formed increased tumourspheres with enlarged ALDH+ and CD24−/CD44 populations. E2 induced PR/IRS-1 interaction and exchange of IGF1Rβ for IRS-1 in p-PR-containing transcriptional complexes. Inhibition of IRS-1 or IR and inducible IRS-1 knockdown reduced tumourspheres. Endocrine-resistant models of luminal B breast cancer induced p-PR in 3D cultures and required PR and IRS-1 for tumoursphere formation.

Conclusions

Phospho-PR-B cooperates with IRS-1 to promote outgrowth of endocrine-resistant and stem-like breast cancer cells. Targeting phospho-PR/IRS-1 crosstalk may block the emergence of endocrine resistance.
Effects of social distancing and isolation on epidemic spreading modeled via dynamical density functional theory
Authors: te Vrugt Michael , Bickmann Jens , Wittkowski Raphael
Published: November 2020

For preventing the spread of epidemics such as the coronavirus disease COVID-19, social distancing and the isolation of infected persons are crucial. However, existing reaction-diffusion equations for epidemic spreading are incapable of describing these effects. In this work, we present an extended model for disease spread based on combining a susceptible-infected-recovered model with a dynamical density functional theory where social distancing and isolation of infected persons are explicitly taken into account. We show that the model exhibits interesting transient phase separation associated with a reduction of the number of infections, and allows for new insights into the control of pandemics.
Site-specific spectroscopic measurement of spin and charge in (LuFeO3)m/(LuFe2O4)1 multiferroic superlattices
Authors: Fan Shiyu , Das Hena , Rébola Alejandro , Smith Kevin A. , Mundy Julia , Brooks Charles , Holtz Megan E. , Muller David A. , Fennie Craig J. , Ramesh Ramamoorthy , Schlom Darrell G. , McGill Stephen , Musfeldt Janice L.
Published: November 2020

Interface materials offer a means to achieve electrical control of ferrimagnetism at room temperature as was recently demonstrated in (LuFeO3)m/(LuFe2O4)1 superlattices. A challenge to understanding the inner workings of these complex magnetoelectric multiferroics is the multitude of distinct Fe centres and their associated environments. This is because macroscopic techniques characterize average responses rather than the role of individual iron centres. Here, we combine optical absorption, magnetic circular dichroism and first-principles calculations to uncover the origin of high-temperature magnetism in these superlattices and the charge-ordering pattern in the m = 3 member. In a significant conceptual advance, interface spectra establish how Lu-layer distortion selectively enhances the Fe2+ →  Fe3+ charge-transfer contribution in the spin-up channel, strengthens the exchange interactions and increases the Curie temperature. Comparison of predicted and measured spectra also identifies a non-polar charge ordering arrangement in the LuFe2O4 layer. This site-specific spectroscopic approach opens the door to understanding engineered materials with multiple metal centres and strong entanglement.
Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons
Authors: Hauberg Mads E. , Creus-Muncunill Jordi , Bendl Jaroslav , Kozlenkov Alexey , Zeng Biao , Corwin Chuhyon , Chowdhury Sarah , Kranz Harald , Hurd Yasmin L. , Wegner Michael , Børglum Anders D. , Dracheva Stella , Ehrlich Michelle E. , Fullard John F. , Roussos Panos
Published: November 2020

The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability. Transcription factor footprinting implicates cell-specific transcriptional regulators and infers cell-specific regulation of protein-coding genes, long intergenic noncoding RNAs and microRNAs. In vivo transgenic mouse experiments validate the cell type specificity of several of these human-derived regulatory sequences. We find that open chromatin regions in glutamatergic neurons are enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Integration of cell-specific chromatin data with a bulk tissue study of schizophrenia brains increases statistical power and confirms that glutamatergic neurons are most affected. These findings illustrate the utility of studying the cell-type-specific epigenome in complex tissues like the human brain, and the potential of such approaches to better understand the genetic basis of human brain function.
Distance makes a difference in crystalline photoluminescence
Authors: Gan Zibao , Liu Yungui , Wang Lin , Jiang Shuqing , Xia Nan , Yan Zhipeng , Wu Xiang , Zhang Junran , Gu Wanmiao , He Lizhong , Dong Jingwu , Ma Xuedan , Kim Jaeyong , Wu Zhongyan , Xu Yixuan , Li Yanchun , Wu Zhikun
Published: November 2020

Crystallization-induced photoluminescence weakening was recently revealed in ultrasmall metal nanoparticles. However, the fundamentals of the phenomenon are not understood yet. By obtaining conformational isomer crystals of gold nanoclusters, we investigate crystallization-induced photoluminescence weakening and reveal that the shortening of interparticle distance decreases photoluminescence, which is further supported by high-pressure photoluminescence experiments. To interpret this, we propose a distance-dependent non-radiative transfer model of excitation electrons and support it with additional theoretical and experimental results. This model can also explain both aggregation-induced quenching and aggregation-induced emission phenomena. This work improves our understanding of aggregated-state photoluminescence, contributes to the concept of conformational isomerism in nanoclusters, and demonstrates the utility of high pressure studies in nanochemistry.
Hormonal contraception alters vaginal microbiota and cytokines in South African adolescents in a randomized trial
Authors: Balle Christina , Konstantinus Iyaloo N. , Jaumdally Shameem Z. , Havyarimana Enock , Lennard Katie , Esra Rachel , Barnabas Shaun L. , Happel Anna-Ursula , Moodie Zoe , Gill Katherine , Pidwell Tanya , Karaoz Ulas , Brodie Eoin , Maseko Venessa , Gamieldien Hoyam , Bosinger Steven E. , Myer Landon , Bekker Linda-Gail , Passmore Jo-Ann S. , Jaspan Heather B.
Published: November 2020

Young women in sub-Saharan Africa are disproportionally affected by HIV infection and unintended pregnancies. However, hormonal contraceptive (HC) use may influence HIV risk through changes in genital tract microbiota and inflammatory cytokines. To investigate this, 130 HIV negative adolescent females aged 15–19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and contraceptive product preference as a proxy for HIV prevention delivery methods. Participants were randomized to injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) or etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR) for 16 weeks, then crossed over to another HC for 16 weeks. Cervicovaginal samples were collected at baseline, crossover and exit for characterization of the microbiota and measurement of cytokine levels; primary endpoints were cervical T cell activation, vaginal microbial diversity and cytokine concentrations. Adolescents randomized to COCs had lower vaginal microbial diversity and relative abundance of HIV risk-associated taxa compared to Net-En or CCVR. Cervicovaginal inflammatory cytokine concentrations were significantly higher in adolescents randomized to CCVR compared to COC and Net-En. This suggests that COC use may induce an optimal vaginal ecosystem by decreasing bacterial diversity and inflammatory taxa, while CCVR use is associated with genital inflammation.
Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis
Authors: Moreira-Teixeira Lúcia , Stimpson Philippa J. , Stavropoulos Evangelos , Hadebe Sabelo , Chakravarty Probir , Ioannou Marianna , Aramburu Iker Valle , Herbert Eleanor , Priestnall Simon L. , Suarez-Bonnet Alejandro , Sousa Jeremy , Fonseca Kaori L. , Wang Qian , Vashakidze Sergo , Rodríguez-Martínez Paula , Vilaplana Cristina , Saraiva Margarida , Papayannopoulos Venizelos , O’Garra Anne
Published: November 2020

Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Transcriptional signatures associated with type I IFN signalling and neutrophilic inflammation were shown to correlate with disease severity in mouse models of TB. Here we show that similar transcriptional signatures correlate with increased bacterial loads and exacerbate pathology during Mycobacterium tuberculosis infection upon GM-CSF blockade. Loss of GM-CSF signalling or genetic susceptibility to TB (C3HeB/FeJ mice) result in type I IFN-induced neutrophil extracellular trap (NET) formation that promotes bacterial growth and promotes disease severity. Consistently, NETs are present in necrotic lung lesions of TB patients responding poorly to antibiotic therapy, supporting the role of NETs in a late stage of TB pathogenesis. Our findings reveal an important cytokine-based innate immune effector network with a central role in determining the outcome of M. tuberculosis infection.
Metabolite signatures of diverse Camellia sinensis tea populations
Authors: Yu Xiaomin , Xiao Jiajing , Chen Si , Yu Yuan , Ma Jianqiang , Lin Yuzhen , Li Ruizi , Lin Jun , Fu Zhijun , Zhou Qiongqiong , Chao Qianlin , Chen Liang , Yang Zhenbiao , Liu Renyi
Published: November 2020

The tea plant (Camellia sinensis) presents an excellent system to study evolution and diversification of the numerous classes, types and variable contents of specialized metabolites. Here, we investigate the relationship among C. sinensis phylogenetic groups and specialized metabolites using transcriptomic and metabolomic data on the fresh leaves collected from 136 representative tea accessions in China. We obtain 925,854 high-quality single-nucleotide polymorphisms (SNPs) enabling the refined grouping of the sampled tea accessions into five major clades. Untargeted metabolomic analyses detect 129 and 199 annotated metabolites that are differentially accumulated in different tea groups in positive and negative ionization modes, respectively. Each phylogenetic group contains signature metabolites. In particular, CSA tea accessions are featured with high accumulation of diverse classes of flavonoid compounds, such as flavanols, flavonol mono-/di-glycosides, proanthocyanidin dimers, and phenolic acids. Our results provide insights into the genetic and metabolite diversity and are useful for accelerated tea plant breeding.
Author Correction: Light-powered Escherichia coli cell division for chemical production
Authors: Ding Qiang , Ma Danlei , Liu Gao-Qiang , Li Yang , Guo Liang , Gao Cong , Hu Guipeng , Ye Chao , Liu Jia , Liu Liming , Chen Xiulai
Published: November 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Modelling and manufacturing of 3D-printed, patient-specific, and anthropomorphic gastric phantoms: a pilot study
Authors: Kwon Jinhee , Choi Joonmyeong , Lee Sangwook , Kim Minkyeong , Park Yoon Kyung , Park Do Hyun , Kim Namkug
Published: November 2020

Interventional devices including intragastric balloons are widely used to treat obesity. This study aims to develop 3D-printed, patient-specific, and anthropomorphic gastric phantoms with mechanical properties similar to those of human stomach. Using computed tomography gastrography (CTG) images of three patients, gastric phantoms were modelled through shape registration to align the stomach shapes of three different phases. Shape accuracies of the original gastric models versus the 3D-printed phantoms were compared using landmark distances. The mechanical properties (elongation and tensile strength), number of silicone coatings (0, 2, and 8 times), and specimen hardness (50, 60, and 70 Shore A) of three materials (Agilus, Elastic, and Flexa) were evaluated. Registration accuracy was significantly lower between the arterial and portal phases (3.16 ± 0.80 mm) than that between the portal and delayed phases (8.92 ± 0.96 mm). The mean shape accuracy difference was less than 10 mm. The mean elongations and tensile strengths of the Agilus, Elastic, and Flexa were 264%, 145%, and 146% and 1.14, 1.59, and 2.15 MPa, respectively, and their mechanical properties differed significantly (all p < 0.05). Elongation and tensile strength assessments, CTG image registration and 3D printing resulted in highly realistic and patient-specific gastric phantoms with reasonable shape accuracies.
Umbilical cord tissue is a robust source for mesenchymal stem cells with enhanced myogenic differentiation potential compared to cord blood
Authors: Mishra Shivangi , Sevak Jayesh Kumar , Das Anamica , Arimbasseri G. Aneeshkumar , Bhatnagar Shinjini , Gopinath Suchitra D.
Published: November 2020

Differentiation of mesenchymal stem cells (MSCs) derived from two different sources of fetal tissues such as umbilical cord blood (UCB) and tissue (UCT) into skeletal muscle have remained underexplored. Here, we present a comparative analysis of UCB and UCT MSCs, in terms of surface markers, proliferation and senescence marker expression. We find that CD45−CD34− MSCs obtained from UCT and UCB of term births display differences in the combinatorial expression of key MSC markers CD105 and CD90. Importantly, UCT MSCs display greater yield, higher purity, shorter culture time, and lower rates of senescence in culture compared to UCB MSCs. Using a robust myogenic differentiation protocol, we show that UCT MSCs differentiate more robustly into muscle than UCB MSCs by transcriptomic sequencing and specific myogenic markers. Functional assays reveal that CD90, and not CD105 expression promotes myogenic differentiation in MSCs and could explain the enhanced myogenic potential of UCT MSCs. These results suggest that in comparison to large volumes of UCB that are routinely used to obtain MSCs and with limited success, UCT is a more reliable, robust, and convenient source of MSCs to derive cells of the myogenic lineage for both therapeutic purposes and increasing our understanding of developmental processes.
Full strength and toughness recovery after repeated cracking and healing in bone-like high temperature ceramics
Authors: Osada Toshio , Watabe Aiko , Yamamoto Joji , Brouwer Johannes C. , Kwakernaak Cees , Ozaki Shingo , van der Zwaag Sybrand , Sloof Willem G.
Published: November 2020

Bones of humans and animals combine two unique features, namely: they are brittle yet have a very high fracture toughness linked to the tortuosity of the crack path and they have the ability to repeatedly heal local fissures such that full recovery of overall mechanical properties is obtained even if the local bone structure is irreversibly changed by the healing process. Here it is demonstrated that Ti2AlC MAX phase metallo-ceramics also having a bone-like hierarchical microstructure and also failing along zig-zag fracture surfaces similarly demonstrate repeated full strength and toughness recovery at room temperature, even though the (high temperature) healing reaction involves the local formation of dense and brittle alumina within the crack. Full recovery of the fracture toughness depends on the healed zone thickness and process zone size formed in the alumina reaction product. A 3-dimensional finite element method (FEM) analysis of the data obtained from a newly designed wedge splitting test allowed full extraction of the local fracture properties of the healed cracks.
Nasal respiration is necessary for ketamine-dependent high frequency network oscillations and behavioral hyperactivity in rats
Authors: Wróbel Jacek , Średniawa Władysław , Jurkiewicz Gabriela , Żygierewicz Jarosław , Wójcik Daniel K. , Whittington Miles Adrian , Hunt Mark Jeremy
Published: November 2020

Changes in oscillatory activity are widely reported after subanesthetic ketamine, however their mechanisms of generation are unclear. Here, we tested the hypothesis that nasal respiration underlies the emergence of high-frequency oscillations (130–180 Hz, HFO) and behavioral activation after ketamine in freely moving rats. We found ketamine 20 mg/kg provoked “fast” theta sniffing in rodents which correlated with increased locomotor activity and HFO power in the OB. Bursts of ketamine-dependent HFO were coupled to “fast” theta frequency sniffing. Theta coupling of HFO bursts were also found in the prefrontal cortex and ventral striatum which, although of smaller amplitude, were coherent with OB activity. Haloperidol 1 mg/kg pretreatment prevented ketamine-dependent increases in fast sniffing and instead HFO coupling to slower basal respiration. Consistent with ketamine-dependent HFO being driven by nasal respiration, unilateral naris blockade led to an ipsilateral reduction in ketamine-dependent HFO power compared to the control side. Bilateral nares blockade reduced ketamine-induced hyperactivity and HFO power and frequency. These findings suggest that nasal airflow entrains ketamine-dependent HFO in diverse brain regions, and that the OB plays an important role in the broadcast of this rhythm.
Extracellular vesicles report on the MET status of their cells of origin regardless of the method used for their isolation
Authors: Useckaite Zivile , Mukhopadhya Anindya , Moran Barry , O’Driscoll Lorraine
Published: November 2020

MET pathway is an important actionable target across many solid tumour types and several MET inhibitors have been developed. Extracellular vesicles (EVs) are proposed to be mini-maps of their cells of origin. However, the potential of EVs to report on the MET status of their cells of origin is unknown. After applying three proposed methods of EV separation from medium conditioned by three cell lines of known MET status, this study used an extensive range of methodologies to fundamentally characterise the resulting particles (nanoparticle tracking analysis, TEM, flow cytometry, immunoblotting) and their MET status (RT-qPCR and ELISAs). The results indicated that ultracentrifugation on density-gradient (UC-DG) consistently produced the most reliable data with regards to purest EVs. EV cargo reflected MET mRNA, total MET and pMET status of their cells of origin. In conclusion, to simply determine if the general contents of conditioned medium reflect the MET status of the conditioning cells, choice of method for initial EV separation may not be crucial. However, to be confident of specifically studying EVs and thus EV-MET cargo, UC-DG followed by extensive EV characterisation is necessary.
Changes in electrophysiological static and dynamic human brain functional architecture from childhood to late adulthood
Authors: Coquelet N. , Wens V. , Mary A. , Niesen M. , Puttaert D. , Ranzini M. , Vander Ghinst M. , Bourguignon M. , Peigneux P. , Goldman S. , Woolrich M. , De Tiège X.
Published: November 2020

This magnetoencephalography study aimed at characterizing age-related changes in resting-state functional brain organization from mid-childhood to late adulthood. We investigated neuromagnetic brain activity at rest in 105 participants divided into three age groups: children (6–9 years), young adults (18–34 years) and healthy elders (53–78 years). The effects of age on static resting-state functional brain integration were assessed using band-limited power envelope correlation, whereas those on transient functional brain dynamics were disclosed using hidden Markov modeling of power envelope activity. Brain development from childhood to adulthood came with (1) a strengthening of functional integration within and between resting-state networks and (2) an increased temporal stability of transient (100–300 ms lifetime) and recurrent states of network activation or deactivation mainly encompassing lateral or medial associative neocortical areas. Healthy aging was characterized by decreased static resting-state functional integration and dynamic stability within the primary visual network. These results based on electrophysiological measurements free of neurovascular biases suggest that functional brain integration mainly evolves during brain development, with limited changes in healthy aging. These novel electrophysiological insights into human brain functional architecture across the lifespan pave the way for future clinical studies investigating how brain disorders affect brain development or healthy aging.
Genome wide association study of passive immunity and disease traits in beef-suckler and dairy calves on Irish farms
Authors: Johnston Dayle , Mukiibi Robert , Waters Sinéad M. , McGee Mark , Surlis Carla , McClure Jennifer C. , McClure Matthew C. , Todd Cynthia G. , Earley Bernadette
Published: November 2020

Calves with lower concentrations of immunoglobulin G (IgG) in their blood, have a greater risk of developing diseases. There is a lack of knowledge on genetic markers known to be associated with immunological variability or disease resistance. Therefore, the objective of this study was to identify SNP markers associated with passive immunity measures (serum IgG, serum protein, albumin, globulin and total protein concentrations, total solids Brix percentage, zinc sulphate turbidity units) and disease (pneumonia, diarrhoea, crude illness) traits in Irish commercial beef-suckler and dairy calves through genome wide association studies (GWAS). Genotyping was performed on DNA samples from beef-suckler (n = 698) and dairy (n = 1178) calves, using the IDBv3 chip. Heritability of passive immunity associated traits (range 0.02–0.22) and the disease traits (range 0.03–0.20) were low-to-moderate. Twenty-five and fifteen SNPs approached genome wide significance (P < 5 × 10−5) for the passive immunity and the disease traits, respectively. One SNP “ARS-BFGL-BAC-27914” reached Bonferroni genome wide significance (P < 1.15 × 10−6) for an association with serum IgG concentration in beef calves. Further work will evaluate these SNPs in larger cattle populations and assess their contribution to genomic selection breeding strategies, aimed towards producing more disease resistant livestock.
Risk of dengue virus infection according to serostatus in individuals from dengue endemic areas of Mexico
Authors: Amaya-Larios I. Y. , Martínez-Vega R. A. , Diaz-Quijano F. A. , Sarti E. , Puentes-Rosas E. , Chihu L. , Ramos-Castañeda J.
Published: November 2020

The variability in the host immune response directed against dengue virus (DENV) has demonstrated the need to understand the immune response associated with protection in incident infection. The objective was to estimate the association between serostatus and the risk of incident DENV infection. We used a prospective study from 2014 to 2016 in the localities of Axochiapan and Tepalcingo, Morelos, Mexico. We recruited 966 participants, of which, according to their infection history registered were categorized in four groups. To accomplish the objectives of this study, we selected to 400 participants older than 5 years of age were followed for 2.5 years. Blood samples were taken every 6 months to measure serological status and infection by ELISA. In individuals with at least two previous infections the risk of new infection was lower compared to a seronegative group (hazard ratio adjusted 0.49, 95% CI 0.24–0.98), adjusted for age and locality. Therefore, individuals who have been exposed two times or more to a DENV infection have a lower risk of re-infection, thus showing the role of cross-immunity and its association with protection.
High voltage generation from wastewater by microbial fuel cells equipped with a newly designed low voltage booster multiplier (LVBM)
Authors: Koffi N’Dah Joel , Okabe Satoshi
Published: November 2020

Although microbial fuel cells (MFCs) can produce renewable energy from wastewater, the generated power is practically unusable. To extract usable power from an MFC fed with wastewater, we newly developed a low voltage booster multiplier (LVBM), which is composed of a self-oscillating LVB and multistage voltage multiplier circuits (VMCs). The low output MFC voltage (ca. 0.4 V) was successfully boosted up to 99 ± 2 V, which was the highest voltage that has been ever reported, without voltage reversal by connecting an LVB with 20-stage VMCs. Moreover, the boosted voltage (81 ± 1 V) was stably maintained for > 40 h even after disconnecting the LVBM from the MFC. The energy harvesting efficiency of LVBM was > 80% when an LVB with 4-stage VMCs was charged to 9.3 V. These results clearly suggest that the proposed LVBM system is an efficient and self-starting energy harvester and storage for low-power generating MFCs.
Mapping O2 concentration in ex-vivo tissue samples on a fast PLIM macro-imager
Authors: Sen Rajannya , Zhdanov Alexander V. , Bastiaanssen Thomaz F. S. , Hirvonen Liisa M. , Svihra Peter , Fitzgerald Patrick , Cryan John F. , Andersson-Engels Stefan , Nomerotski Andrei , Papkovsky Dmitri B.
Published: November 2020

O2 PLIM microscopy was employed in various studies, however current platforms have limitations in sensitivity, image acquisition speed, accuracy and general usability. We describe a new PLIM imager based on the Timepix3 camera (Tpx3cam) and its application for imaging of O2 concentration in various tissue samples stained with a nanoparticle based probe, NanO2-IR. Upon passive staining of mouse brain, lung or intestinal tissue surface with minute quantities of NanO2-IR or by microinjecting the probe into the lumen of small or large intestine fragments, robust phosphorescence intensity and lifetime signals were produced, which allow mapping of O2 in the tissue within 20 s. Inhibition of tissue respiration or limitation of O2 diffusion to tissue produced the anticipated increases or decreases in O2 levels, respectively. The difference in O2 concentration between the colonic lumen and air-exposed serosal surface was around 140 µM. Furthermore, subcutaneous injection of 5 µg of the probe in intact organs (a paw or tail of sacrificed mice) enabled efficient O2 imaging at tissue depths of up to 0.5 mm. Overall, the PLIM imager holds promise for metabolic imaging studies with various ex vivo models of animal tissue, and also for use in live animals.
Epitope similarity cannot explain the pre-formed T cell immunity towards structural SARS-CoV-2 proteins
Authors: Stervbo Ulrik , Rahmann Sven , Roch Toralf , Westhoff Timm H. , Babel Nina
Published: November 2020

The current pandemic is caused by the SARS-CoV-2 virus and large progress in understanding the pathology of the virus has been made since its emergence in late 2019. Several reports indicate short lasting immunity against endemic coronaviruses, which contrasts studies showing that biobanked venous blood contains T cells reactive to SARS-CoV-2 S-protein even before the outbreak in Wuhan. This suggests a preformed T cell memory towards structural proteins in individuals not exposed to SARS-CoV-2. Given the similarity of SARS-CoV-2 to other members of the Coronaviridae family, the endemic coronaviruses appear likely candidates to generate this T cell memory. However, given the apparent poor immunological memory created by the endemic coronaviruses, immunity against other common pathogens might offer an alternative explanation. Here, we utilize a combination of epitope prediction and similarity to common human pathogens to identify potential sources of the SARS-CoV-2 T cell memory. Although beta-coronaviruses are the most likely candidates to explain the pre-existing SARS-CoV-2 reactive T cells in uninfected individuals, the SARS-CoV-2 epitopes with the highest similarity to those from beta-coronaviruses are confined to replication associated proteins—not the host interacting S-protein. Thus, our study suggests that the observed SARS-CoV-2 pre-formed immunity to structural proteins is not driven by near-identical epitopes.
Unraveling the adult cell progeny of early postnatal progenitor cells
Authors: Sánchez-González Rebeca , Salvador Nieves , López-Mascaraque Laura
Published: November 2020

NG2-glia, also referred to as oligodendrocyte precursor cells or polydendrocytes, represent a large pool of proliferative neural cells in the adult brain that lie outside of the two major adult neurogenic niches. Although their roles are not fully understood, we previously reported significant clonal expansion of adult NG2-cells from embryonic pallial progenitors using the StarTrack lineage-tracing tool. To define the contribution of early postnatal progenitors to the specific NG2-glia lineage, we used NG2-StarTrack. A temporal clonal analysis of single postnatal progenitor cells revealed the production of different glial cell types in distinct areas of the dorsal cortex but not neurons. Moreover, the dispersion and size of the different NG2 derived clonal cell clusters increased with age. Indeed, clonally-related NG2-glia were located throughout the corpus callosum and the deeper layers of the cortex. In summary, our data reveal that postnatally derived NG2-glia are proliferative cells that give rise to NG2-cells and astrocytes but not neurons. These progenitors undergo clonal cell expansion and dispersion throughout the adult dorsal cortex in a manner that was related to aging and cell identity, adding new information about the ontogeny of these cells. Thus, identification of clonally-related cells from specific progenitors is important to reveal the NG2-glia heterogeneity.
Reappraisal of anoxic spreading depolarization as a terminal event during oxygen–glucose deprivation in brain slices in vitro
Authors: Juzekaeva Elvira , Gainutdinov Azat , Mukhtarov Marat , Khazipov Roustem
Published: November 2020

Anoxic spreading depolarization (aSD) has been hypothesized as a terminal event during oxygen–glucose deprivation (OGD) in submerged cortical slices in vitro. However, mechanical artifacts caused by aSD-triggered edema may introduce error in the assessment of neuronal viability. Here, using continuous patch-clamp recordings from submerged rat cortical slices, we first confirmed that vast majority of L4 neurons permanently lost their membrane potential during OGD-induced aSD. In some recordings, spontaneous transition from whole-cell to out-side out configuration occurred during or after aSD, and only a small fraction of neurons survived aSD with reperfusion started shortly after aSD. Secondly, to minimize artifacts caused by OGD-induced edema, cells were short-term patched following OGD episodes of various duration. Nearly half of L4 cells maintained membrane potential and showed the ability to spike-fire if reperfusion started less than 10 min after aSD. The probability of finding live neurons progressively decreased at longer reperfusion delays at a rate of about 2% per minute. We also found that neurons in L2/3 show nearly threefold higher resistance to OGD than neurons in L4. Our results suggest that in the OGD ischemia model, aSD is not a terminal event, and that the “commitment point” of irreversible damage occurs at variable delays, in the range of tens of minutes, after OGD-induced aSD in submerged cortical slices.
Methane breath tests and blood sugar tests in children with suspected carbohydrate malabsorption
Authors: Schneider Christof , Wutzke Klaus D. , Däbritz Jan
Published: November 2020

Carbohydrate malabsorption and subsequent gastrointestinal symptoms are a common clinical problem in pediatrics. Hydrogen (H2) and methane (CH4) breath tests are a cheap and non-invasive procedure for diagnosing fructose and lactose malabsorption (FM/LM) but test accuracy and reliability as well as the impact of non-hydrogen producers (NHP) is unclear. CH4 breath tests (MBT), blood sugar tests (BST) and clinical symptoms were compared with H2 breath tests (HBT) for FM/LM. 187/82 tests were performed in children (2 to 18 years) with unclear chronic/recurrent abdominal pain and suspected FM/LM. In FM and LM, we found a significant correlation between HBT and MBT/BST. In LM, MBT differentiated most of the patients correctly and BST might be used as an exclusion test. However, additional MBT and BST had no diagnostic advantage in FM. NHP still remain a group of patients, which cannot be identified using the recommended CH4 cut-off values in FM or LM. Reported symptoms during breath tests are not a reliable method to diagnose FM/LM. Overall a combined test approach might help in diagnosing children with suspected carbohydrate malabsorption.
Loss of PHF6 leads to aberrant development of human neuron-like cells
Authors: Fliedner Anna , Gregor Anne , Ferrazzi Fulvia , Ekici Arif B. , Sticht Heinrich , Zweier Christiane
Published: November 2020

Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females. To investigate the mechanisms behind overlapping but distinct clinical aspects between genders, we assessed the consequences of individual variants with structural modelling and molecular techniques. We found evidence that de novo variants occurring in females are more severe and result in loss of PHF6, while inherited variants identified in males might be hypomorph or have weaker effects on protein stability. This might contribute to the different phenotypes in male versus female individuals with BFLS. Furthermore, we used CRISPR/Cas9 to induce knockout of PHF6 in SK-N-BE (2) cells which were then differentiated to neuron-like cells in order to model nervous system related consequences of PHF6 loss. Transcriptome analysis revealed a broad deregulation of genes involved in chromatin and transcriptional regulation as well as in axon and neuron development. Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration. Impairment of these processes might therefore contribute to the neurodevelopmental and cognitive dysfunction in BFLS.
Singular manifolds of proteomic drivers to model the evolution of inflammatory bowel disease status
Authors: Morilla Ian , Léger Thibaut , Marah Assiya , Pic Isabelle , Zaag Hatem , Ogier-Denis Eric
Published: November 2020

The conditions used to describe the presence of an immune disease are often represented by interaction graphs. These informative, but intricate structures are susceptible to perturbations at different levels. The mode in which that perturbation occurs is still of utmost importance in areas such as cell reprogramming and therapeutics models. In this sense, module identification can be useful to well characterise the global graph architecture. To help us with this identification, we perform topological overlap-related measures. Thanks to these measures, the location of highly disease-specific module regulators is possible. Such regulators can perturb other nodes, potentially causing the entire system to change behaviour or collapse. We provide a geometric framework explaining such situations in the context of inflammatory bowel diseases (IBD). IBD are severe chronic disorders of the gastrointestinal tract whose incidence is dramatically increasing worldwide. Our approach models different IBD status as Riemannian manifolds defined by the graph Laplacian of two high throughput proteome screenings. It also identifies module regulators as singularities within the manifolds (the so-called singular manifolds). Furthermore, it reinterprets the characteristic nonlinear dynamics of IBD as compensatory responses to perturbations on those singularities. Then, particular reconfigurations of the immune system could make the disease status move towards an innocuous target state.
Circulating expression of Hsa_circRNA_102893 contributes to early gestational diabetes mellitus detection
Authors: Yang Hongling , Ye Weitao , Chen Ruihua , Zeng Fangling , Long Yan , Zhang Xiaoyan , Ma Jun , Gan Qiangsheng , Rehemutula Rehemayi , Zhu Chunyan
Published: November 2020

Due to a poor availability of reliable biomarkers, detecting gestational diabetes mellitus (GDM) in early pregnancy remains a challenge. Novel biomarkers like Circular RNAs (circRNAs) may be a promising diagnostic tool. The aim of this study was (a) to identify circRNAs deregulated in GDM and (b) evaluate the potential of circRNAs in detecting GDM. The circRNAs expression profiling in 6 paired women (with and without GDM) was measured by microarray. The levels of five most relevant circRNAs were validated in 12 paired participants by qRT-PCR. To verify the reproducibility of qRT-PCR, significantly differential expressed circRNA levels were confirmed in 18 paired participants. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value. The areas under ROC curves of hsa_circRNA_102893 were 0.806 (95% CI 0.594–0.937) and 0.741 (0.568–0.872) in training set and test set, respectively. Circulating circRNAs reflect the presence of GDM. Hsa_circRNA_102893 may be a potential novel and stable noninvasive biomarker for detecting GDM in early pregnancy.
Investigation of associations between Piezo1 mechanoreceptor gain-of-function variants and glaucoma-related phenotypes in humans and mice
Authors: Baxter Sally L. , Keenan William T. , Athanas Argus J. , Proudfoot James A. , Zangwill Linda M. , Ayyagari Radha , Liebmann Jeffrey M. , Girkin Christopher A. , Patapoutian Ardem , Weinreb Robert N.
Published: November 2020

Glaucoma disproportionately affects individuals of African descent. Prior studies of the PIEZO1 mechanoreceptor have suggested a possible role in glaucoma pathophysiology. Here, we investigated associations between a Piezo1 gain-of-function variant common in individuals of African descent with glaucoma-related phenotypes. We analyzed whole genome sequences to identify Piezo1 variants and their frequencies among 1565 human participants. For the most common variant (e756del), we compared phenotypes between heterozygotes, homozygotes, and wildtypes. Longitudinal mixed effects models of visual field mean deviation (MD) and retinal nerve fiber layer (RNFL) thickness were used to evaluate progression. Based on trends in the models, further investigation was conducted using Piezo1 gain-of-function mice. About 30% of African descent individuals had at least one e756del allele. There were trends suggesting e756del was associated with higher IOPs, thinner RNFLs, lower optic nerve head capillary densities, and greater decreases in MD and RNFL thickness over time, but these did not reach statistical significance. Among mice, increased Piezo1 activity was not significantly associated with IOP or retinal ganglion cell density. Our study confirms that the Piezo1 e756del gain-of-function variant is a frequent polymorphism present in African descent individuals but is unrelated to examined differences in glaucoma phenotypes. Ongoing work is needed to elucidate the role of Piezo1-mediated mechanotransduction in glaucoma.