bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin
Authors: Weiss Felix D. , Calderon Lesly , Wang Yi-Fang , Georgieva Radina , Guo Ya , Cvetesic Nevena , Kaur Maninder , Dharmalingam Gopuraja , Krantz Ian D. , Lenhard Boris , Fisher Amanda G. , Merkenschlager Matthias 
Published: May 2021

AbstractCornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS.
Rheology of rounded mammalian cells over continuous high-frequencies
Authors: Fläschner Gotthold , Roman Cosmin I. , Strohmeyer Nico , Martinez-Martin David , Müller Daniel J. 
Published: May 2021

AbstractUnderstanding the viscoelastic properties of living cells and their relation to cell state and morphology remains challenging. Low-frequency mechanical perturbations have contributed considerably to the understanding, yet higher frequencies promise to elucidate the link between cellular and molecular properties, such as polymer relaxation and monomer reaction kinetics. Here, we introduce an assay, that uses an actuated microcantilever to confine a single, rounded cell on a second microcantilever, which measures the cell mechanical response across a continuous frequency range ≈ 1–40 kHz. Cell mass measurements and optical microscopy are co-implemented. The fast, high-frequency measurements are applied to rheologically monitor cellular stiffening. We find that the rheology of rounded HeLa cells obeys a cytoskeleton-dependent power-law, similar to spread cells. Cell size and viscoelasticity are uncorrelated, which contrasts an assumption based on the Laplace law. Together with the presented theory of mechanical de-embedding, our assay is generally applicable to other rheological experiments.
Relaxed selection underlies genome erosion in socially parasitic ant species
Authors: Schrader Lukas , Pan Hailin , Bollazzi Martin , Schiøtt Morten , Larabee Fredrick J. , Bi Xupeng , Deng Yuan , Zhang Guojie , Boomsma Jacobus J. , Rabeling Christian 
Published: May 2021

AbstractInquiline ants are highly specialized and obligate social parasites that infiltrate and exploit colonies of closely related species. They have evolved many times convergently, are often evolutionarily young lineages, and are almost invariably rare. Focusing on the leaf-cutting ant genus Acromyrmex, we compared genomes of three inquiline social parasites with their free-living, closely-related hosts. The social parasite genomes show distinct signatures of erosion compared to the host lineages, as a consequence of relaxed selective constraints on traits associated with cooperative ant colony life and of inquilines having very small effective population sizes. We find parallel gene losses, particularly in olfactory receptors, consistent with inquiline species having highly reduced social behavioral repertoires. Many of the genomic changes that we uncover resemble those observed in the genomes of obligate non-social parasites and intracellular endosymbionts that branched off into highly specialized, host-dependent niches.
Molecular exclusion limits for diffusion across a porous capsid
Authors: Selivanovitch Ekaterina , LaFrance Benjamin , Douglas Trevor 
Published: May 2021

AbstractMolecular communication across physical barriers requires pores to connect the environments on either side and discriminate between the diffusants. Here we use porous virus-like particles (VLPs) derived from bacteriophage P22 to investigate the range of molecule sizes able to gain access to its interior. Although there are cryo-EM models of the VLP, they may not accurately depict the parameters of the molecules able to pass across the pores due to the dynamic nature of the P22 particles in the solution. After encapsulating the enzyme AdhD within the P22 VLPs, we use a redox reaction involving PAMAM dendrimer modified NADH/NAD+ to examine the size and charge limitations of molecules entering P22. Utilizing the three different accessible morphologies of the P22 particles, we determine the effective pore sizes of each and demonstrate that negatively charged substrates diffuse across more readily when compared to those that are neutral, despite the negatively charge exterior of the particles.
Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome
Authors: Wang Li-Qiu , Liu Tao , Yang Shuai , Sun Lin , Zhao Zhi-Yao , Li Li-Yue , She Yuan-Chu , Zheng Yan-Yan , Ye Xiao-Yan , Bao Qing , Dong Guang-Hui , Li Chun-Wei , Cui Jun 
Published: May 2021

AbstractPerfluoroalkyl substances (PFAS) are widely used in various manufacturing processes. Accumulation of these chemicals has adverse effects on human health, including inflammation in multiple organs, yet how PFAS are sensed by host cells, and how tissue inflammation eventually incurs, is still unclear. Here, we show that the double-stranded DNA receptor AIM2 is able to recognize perfluorooctane sulfonate (PFOS), a common form of PFAS, to trigger IL-1β secretion and pyroptosis. Mechanistically, PFOS activates the AIM2 inflammasome in a process involving mitochondrial DNA release through the Ca2+-PKC-NF-κB/JNK-BAX/BAK axis. Accordingly, Aim2−/− mice have reduced PFOS-induced inflammation, as well as tissue damage in the lungs, livers, and kidneys in both their basic condition and in an asthmatic exacerbation model. Our results thus suggest a function of AIM2 in PFOS-mediated tissue inflammation, and identify AIM2 as a major pattern recognition receptor in response to the environmental organic pollutants.
Joint inference of CFC lifetimes and banks suggests previously unidentified emissions
Authors: Lickley Megan , Fletcher Sarah , Rigby Matt , Solomon Susan 
Published: May 2021

AbstractChlorofluorocarbons (CFCs) are harmful ozone depleting substances and greenhouse gases. CFC production was phased-out under the Montreal Protocol, however recent studies suggest new and unexpected emissions of CFC-11. Quantifying CFC emissions requires accurate estimates of both atmospheric lifetimes and ongoing emissions from old equipment (i.e. ‘banks’). In a Bayesian framework we simultaneously infer lifetimes, banks and emissions of CFC-11, 12 and 113 using available constraints. We find lifetimes of all three gases are likely shorter than currently recommended values, suggesting that best estimates of inferred emissions are larger than recent evaluations. Our analysis indicates that bank emissions are decreasing faster than total emissions, and we estimate new, unexpected emissions during 2014-2016 were 23.2, 18.3, and 7.8 Gg/yr for CFC-11, 12 and 113, respectively. While recent studies have focused on unexpected CFC-11 emissions, our results call for further investigation of potential sources of emissions of CFC-12 and CFC-113, along with CFC-11.
In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy
Authors: Becker Kolja , Klein Holger , Simon Eric , Viollet Coralie , Haslinger Christian , Leparc German , Schultheis Christian , Chong Victor , Kuehn Markus H. , Fernandez-Albert Francesc , Bakker Remko A. 
Published: May 2021

AbstractDiabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.
Transformation of microbiology data into a standardised data representation using OpenEHR
Authors: Wulff Antje , Baier Claas , Ballout Sarah , Tute Erik , Sommer Kim Katrin , Kaase Martin , Sargeant Anneka , Drenkhahn Cora ,   Infection Control Study Group, Fehling Patrick , Rey Sabine , Suhr Markus , Eichel Vanessa M. , Mutters Nico T. , Heeg Klaus , Gastmeier Petra , Behnke Michael , Diaz Luis Alberto Peña , Thun Sylvia , Eils Roland , Mellmann Alexander , Tönnies Hauke , Zacher Benedikt , Eckmanns Tim , Sztyler Timo , Malone Brandon , Merzweiler Angela , Dugas Martin , Storck Michael , Wunderlich Marcel , von Landesberger Tatiana , Gebel Benjamin , Klingen Thorsten , Glöckner Stephan , Schlüter Dirk , Marschollek Michael , Scheithauer Simone 
Published: May 2021

AbstractThe spread of multidrug resistant organisms (MDRO) is a global healthcare challenge. Nosocomial outbreaks caused by MDRO are an important contributor to this threat. Computer-based applications facilitating outbreak detection can be essential to address this issue. To allow application reusability across institutions, the various heterogeneous microbiology data representations needs to be transformed into standardised, unambiguous data models. In this work, we present a multi-centric standardisation approach by using openEHR as modelling standard. Data models have been consented in a multicentre and international approach. Participating sites integrated microbiology reports from primary source systems into an openEHR-based data platform. For evaluation, we implemented a prototypical application, compared the transformed data with original reports and conducted automated data quality checks. We were able to develop standardised and interoperable microbiology data models. The publicly available data models can be used across institutions to transform real-life microbiology reports into standardised representations. The implementation of a proof-of-principle and quality control application demonstrated that the new formats as well as the integration processes are feasible. Holistic transformation of microbiological data into standardised openEHR based formats is feasible in a real-life multicentre setting and lays the foundation for developing cross-institutional, automated outbreak detection systems.
Super-resolution imaging of platelet-activation process and its quantitative analysis
Authors: Chung Jinkyoung , Jeong Dokyung , Kim Geun-ho , Go Seokran , Song Jaewoo , Moon Eunyoung , Huh Yang Hoon , Kim Doory 
Published: May 2021

AbstractUnderstanding the platelet activation molecular pathways by characterizing specific protein clusters within platelets is essential to identify the platelet activation state and improve the existing therapies for hemostatic disorders. Here, we employed various state-of-the-art super-resolution imaging and quantification methods to characterize the platelet spatiotemporal ultrastructural change during the activation process due to phorbol 12-myristate 13-acetate (PMA) stimuli by observing the cytoskeletal elements and various organelles at nanoscale, which cannot be done using conventional microscopy. Platelets could be spread out with the guidance of actin and microtubules, and most organelles were centralized probably due to the limited space of the peripheral thin regions or the close association with the open canalicular system (OCS). Among the centralized organelles, we provided evidence that granules are fused with the OCS to release their cargo through enlarged OCS. These findings highlight the concerted ultrastructural reorganization and relative arrangements of various organelles upon activation and call for a reassessment of previously unresolved complex and multi-factorial activation processes.
Hot-carrier dynamics in InAs/AlAsSb multiple-quantum wells
Authors: Piyathilaka Herath P. , Sooriyagoda Rishmali , Esmaielpour Hamidreza , Whiteside Vincent R. , Mishima Tetsuya D. , Santos Michael B. , Sellers Ian R. , Bristow Alan D. 
Published: May 2021

AbstractA type-II InAs/AlAs$$_{0.16}$$

0.16

Sb$$_{0.84}$$

0.84

multiple-quantum well sample is investigated for the photoexcited carrier dynamics as a function of excitation photon energy and lattice temperature. Time-resolved measurements are performed using a near-infrared pump pulse, with photon energies near to and above the band gap, probed with a terahertz probe pulse. The transient terahertz absorption is characterized by a multi-rise, multi-decay function that captures long-lived decay times and a metastable state for an excess-photon energy of $$>100$$

>
100

meV. For sufficient excess-photon energy, excitation of the metastable state is followed by a transition to the long-lived states. Excitation dependence of the long-lived states map onto a nearly-direct band gap ($$E{_g}$$

E

g

) density of states with an Urbach tail below $$E{_g}$$

E

g

. As temperature increases, the long-lived decay times increase $$<E{_g}$$

<
E

g

, due to the increased phonon interaction of the unintentional defect states, and by phonon stabilization of the hot carriers $$>E{_g}$$

>
E

g

. Additionally, Auger (and/or trap-assisted Auger) scattering above the onset of the plateau may also contribute to longer hot-carrier lifetimes. Meanwhile, the initial decay component shows strong dependence on excitation energy and temperature, reflecting the complicated initial transfer of energy between valence-band and defect states, indicating methods to further prolong hot carriers for technological applications.
STAT3 determines IL-4 signalling outcomes in naïve T cells
Authors: Deimel Lachlan P. , Li Zheyi , Roy Sreeja , Ranasinghe Charani 
Published: May 2021

AbstractIL-4 production is associated with low-avidity, poorly cytotoxic T cell induction that contributes to viral immune evasion and the failure of T cell-based vaccines. Yet, the precise mechanisms that regulate IL-4 signalling in T cells remain elusive. Mounting evidence indicates that cells can dynamically alter their IL-4/IL-13 receptor signature to modulate downstream immune outcomes upon pathogen encounter. Here, we describe how naïve (CD62L+CD44lo–mid) CD4 and CD8 T cells distinctly engage both STAT6 and STAT3 in response to IL-4. We further show that IL-4R⍺ expression is both time- and IL-4 concentration-dependent. Remarkably, our findings reveal that STAT3 inhibition can ablate IL-4R⍺ and affect transcriptional expression of other Stat and Jak family members. By extension, the loss of STAT3 lead to aberrant STAT6 phosphorylation, revealing an inter-regulatory relationship between the two transcription factors. Moreover, IL-4 stimulation down-regulated TGF-β1 and IFN-γR1 expression on naïve T cells, possibly signifying the broad regulatory implications of IL-4 in conditioning lineage commitment decisions during early infection. Surprisingly, naïve T cells were unresponsive to IL-13 stimulation, unlike dendritic cells. Collectively, these findings could be exploited to inform more efficacious vaccines, as well as design treatments against IL-4/IL-13-associated disease conditions.
Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach
Authors: Fourman Lindsay T. , Stanley Takara L. , Billingsley James M. , Sui Shannan J. Ho , Feldpausch Meghan N. , Boutin Autumn , Zheng Isabel , McClure Colin M. , Corey Kathleen E. , Torriani Martin , Kleiner David E. , Hadigan Colleen M. , Chung Raymond T. , Grinspoon Steven K. 
Published: May 2021

AbstractNAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log2-fold change − 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, − 0.35 ± 0.56 vs. − 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, − 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV.
Clinical Trials Registry Number: NCT02196831
The miR-378c-Samd1 circuit promotes phenotypic modulation of vascular smooth muscle cells and foam cells formation in atherosclerosis lesions
Authors: Tian Shengya , Cao Yang , Wang Jinliang , Bi Yongjun , Zhong Jingquan , Meng Xiangbin , Sun Wenyu , Yang Ruixue , Gan Luping , Wang Xuping , Li Hongshi , Wang Rong 
Published: May 2021

AbstractMicroRNAs have emerged as key regulators in vascular diseases and are involved in the formation of atherosclerotic lesions. However, the atherosclerotic-specific MicroRNAs and their functional roles in atherosclerosis are unclear. Here, we report that miR-378c protects against atherosclerosis by directly targeting Sterile Alpha Motif Domain Containing 1 (Samd1), a predicted transcriptional repressor. miR-378c was strikingly reduced in atherosclerotic plaques and blood of acute coronary syndrome (ACS) patients relative to healthy controls. Suppression of miR-378c promoted vascular smooth muscle cells (VSMCs) phenotypic transition during atherosclerosis. We also reported for the first time that Samd1 prolonged immobilization of LDL on the VSMCs, thus facilitated LDL oxidation and subsequently foam cell formation. Further, we found that Samd1 contains predicted DNA binding domain and directly binds to DNA regions as a transcriptional repressor. Together, we uncovered a novel mechanism whereby miR-378c-Samd1 circuit participates in two key elements of atherosclerosis, VSMCs phenotypic transition and LDL oxidation. Our results provided a better understanding of atherosclerosis pathophysiology and potential therapeutic management by targeting miR-378c-Samd1 circuit.
X-chromosome variants are associated with aldosterone producing adenomas
Authors: Dutta Ravi Kumar , Larsson Malin , Arnesen Thomas , Heie Anette , Walz Martin , Alesina Piero , Gimm Oliver , Söderkvist Peter 
Published: May 2021

AbstractAldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. Several mutations have been identified in ion channels or ion channel-associated genes that result in APAs. To date, no studies have used a genome-wide association study (GWAS) approach to search for predisposing loci for APAs. Thus, we investigated Scandinavian APA cases (n = 35) and Swedish controls (n = 60) in a GWAS and discovered a susceptibility locus on chromosome Xq13.3 (rs2224095, OR = 7.9, 95% CI = 2.8–22.4, P = 1 × 10–7) in a 4-Mb region that was significantly associated with APA. Direct genotyping of sentinel SNP rs2224095 in a replication cohort of APAs (n = 83) and a control group (n = 740) revealed persistently strong significance (OR = 6.1, 95% CI = 3.5–10.6, p < 0.0005). We sequenced an adjacent gene, MAGEE1, of the sentinel SNP and identified a rare variant in one APA, p.Gly327Glu, which is complementary to other mutations in our primary cohort. Expression quantitative trait loci (eQTL) were investigated on the X-chromosome, and 24 trans-eQTL were identified. Some of the genes identified by trans-eQTL point towards a novel mechanistic explanation for the association of the SNPs with APAs. In conclusion, our study provides further insights into the genetic basis of APAs.
Photothermal therapy via a gold nanoparticle-coated stent for treating stent-induced granulation tissue formation in the rat esophagus
Authors: Cho Young Chul , Kang Jeon Min , Park Wooram , Kim Dong-Hyun , Shin Ji Hoon , Kim Do Hoon , Park Jung-Hoon 
Published: May 2021

AbstractMinimally invasive therapies using stent technology are currently limited by stent-induced granulation tissue formation adjacent to the stent. The effectiveness of photothermal therapy (PTT) using a gold nanoparticle (AuNP)-coated stent for treating stent-induced granulation tissue formation in the rat esophagus was investigated. All experiments were approved by the animal research committee of our institution. An AuNP-coated, self-expandable metallic stent (SEMS) was produced to conduct PTT under near-infrared laser irradiation. Forty rats were randomly divided into four groups (10 rats each). The animals in group A (non-coated SEMS) and group B (AuNP-coated SEMS with local heating at 65 °C at 4 weeks) were sacrificed 4 weeks after stent placement. The rats in group C (AuNP-coated SEMS with local heating at 65 °C at 4 weeks) and group D (AuNP-coated SEMS with local heating at 65 °C at 4 and 8 weeks) were sacrificed 8 weeks after stent placement. The effectiveness of local heating was assessed by histopathology. All procedures were successful in all of the animals. Seven rats were excluded because of stent migration (n = 2) and death (n = 5). Granulation tissue formation-related variables were significantly higher in group A than in groups B–D (all p < 0.05). Heat-shock protein 70 (HSP70) and TUNEL expression were significantly lower in group A than in groups B–D (all p < 0.05). Granulation tissue formation-related variables were significantly higher in group C than in groups B and D (all p < 0.05). PTT using AuNP-coated SEMS successfully treated granulation tissue formation after stent placement in the rat esophagus.