bluuebunny/crossref_metadata_2025 huggingface dataset:
Maladaptive alterations of resting state cortical network in Tinnitus: A directed functional connectivity analysis of a larger MEG data set
Authors: Paraskevopoulos Evangelos , Dobel Christian , Wollbrink Andreas , Salvari Vasiliki , Bamidis Panagiotis D. , Pantev Christo
Published: October 2019

The present study used resting state MEG whole-head recordings to identify how chronic tonal tinnitus relates to altered functional connectivity of brain’s intrinsic cortical networks. Resting state MEG activity of 40 chronic tinnitus patients and 40 matched human controls was compared identifying significant alterations in intrinsic networks of the tinnitus population. Directed functional connectivity of the resting brain, at a whole cortex level, was estimated by means of a statistical comparison of the estimated phase Transfer Entropy (pTE) between the time-series of cortical activations, as reconstructed by LORETA. As pTE identifies the direction of the information flow, a detailed analysis of the connectivity differences between tinnitus patients and controls was possible. Results indicate that the group of tinnitus patients show increased connectivity from right dorsal prefrontal to right medial temporal areas. Our results go beyond previous findings by indicating that the role of the left para-hippocampal area is dictated by a modulation from dmPFC; a region that is part of the dorsal attention network (DAN), as well as implicated in the regulation of emotional processing. Additionally, this whole cortex analysis showed a crucial role of the left inferior parietal cortex, which modulated the activity of the right superior temporal gyrus, providing new hypotheses for the role of this area within the context of current tinnitus models. Overall, these maladaptive alterations of the structure of intrinsic cortical networks show a decrease in efficiency and small worldness of the resting state network of tinnitus patients, which is correlated to tinnitus distress.
Broad North Atlantic distribution of a meiobenthic annelid – against all odds
Authors: Worsaae Katrine , Kerbl Alexandra , Vang Áki , Gonzalez Brett C.
Published: October 2019

DNA barcoding and population genetic studies have revealed an unforeseen hidden diversity of cryptic species among microscopic marine benthos, otherwise exhibiting highly similar and simple morphologies. This has led to a paradigm shift, rejecting cosmopolitism of marine meiofauna until genetically proven and challenging the “Everything is Everywhere, but the environment selects” hypothesis that claims ubiquitous distribution of microscopic organisms. With phylogenetic and species delimitation analyses of worldwide genetic samples of the meiofaunal family Dinophilidae (Annelida) we here resolve three genera within the family and showcase an exceptionally broad, boreal, North Atlantic distribution of a single microscopic marine species with no obvious means of dispersal besides vicariance. With its endobenthic lifestyle, small size, limited migratory powers and lack of pelagic larvae, the broad distribution ofDinophilus vorticoidesseems to constitute a “meiofaunal paradox”. This species feasts in the biofilm among sand grains, but also on macroalgae and ice within which it can likely survive long-distance rafting dispersal due to its varying lifecycle stages; eggs encapsulated in cocoons and dormant encystment stages. Though often neglected and possibly underestimated among marine microscopic species, dormancy may be a highly significant factor for explaining wide distribution patterns and a key to solving this meiofaunal paradox.
Machine Friendly Machine Learning: Interpretation of Computed Tomography Without Image Reconstruction
Authors: Lee Hyunkwang , Huang Chao , Yune Sehyo , Tajmir Shahein H. , Kim Myeongchan , Do Synho
Published: October 2019

Recent advancements in deep learning for automated image processing and classification have accelerated many new applications for medical image analysis. However, most deep learning algorithms have been developed using reconstructed, human-interpretable medical images. While image reconstruction from raw sensor data is required for the creation of medical images, the reconstruction process only uses a partial representation of all the data acquired. Here, we report the development of a system to directly process raw computed tomography (CT) data in sinogram-space, bypassing the intermediary step of image reconstruction. Two classification tasks were evaluated for their feasibility of sinogram-space machine learning: body region identification and intracranial hemorrhage (ICH) detection. Our proposed SinoNet, a convolutional neural network optimized for interpreting sinograms, performed favorably compared to conventional reconstructed image-space-based systems for both tasks, regardless of scanning geometries in terms of projections or detectors. Further, SinoNet performed significantly better when using sparsely sampled sinograms than conventional networks operating in image-space. As a result, sinogram-space algorithms could be used in field settings for triage (presence of ICH), especially where low radiation dose is desired. These findings also demonstrate another strength of deep learning where it can analyze and interpret sinograms that are virtually impossible for human experts.
In vitro potentiation of doxorubicin by unseeded controlled non-inertial ultrasound cavitation
Authors: Fant Cécile , Lafond Maxime , Rogez Bernadette , Castellanos Ivan Suarez , Ngo Jacqueline , Mestas Jean-Louis , Padilla Frédéric , Lafon Cyril
Published: October 2019

Ultrasound-generated non-inertial cavitation has the ability to potentiate the therapeutic effects of cytotoxic drugs. We report a novel strategy to induce and regulate unseeded (without nucleation agents) non-inertial cavitation, where cavitation is initiated, monitored and regulated using a confocal ultrasound setup controlled by an instrumentation platform and a PC programmed feedback control loop. We demonstrate, using 4T1 murine mammary carcinoma as model cell line, that unseeded non-inertial cavitation potentiates the cytotoxicity of doxorubicin, one of the most potent drugs used in the treatment of solid tumors including breast cancer. Combined treatment with doxorubicin and unseeded non-inertial cavitation significantly reduced cell viability and proliferation at 72 h. A mechanistic study of the potential mechanisms of action of the combined treatment identified the presence of cavitation as required to enhance doxorubicin efficacy, but ruled out the influence of changes in doxorubicin uptake, temperature increase, hydroxyl radical production and nuclear membrane modifications on the treatment outcome. The developed strategy for the reproducible generation and maintenance of unseeded cavitation makes it an attractive method as potential preclinical and clinical treatment modality to locally potentiate doxorubicin.
Transcriptome analysis reveals microvascular endothelial cell-dependent pericyte differentiation
Authors: Brandt Maarten M. , van Dijk Christian G. M. , Maringanti Ranganath , Chrifi Ihsan , Kramann Rafael , Verhaar Marianne C. , Duncker Dirk J. , Mokry Michal , Cheng Caroline
Published: October 2019

Microvascular homeostasis is strictly regulated, requiring close interaction between endothelial cells and pericytes. Here, we aimed to improve our understanding of how microvascular crosstalk affects pericytes. Human-derived pericytes, cultured in absence, or presence of human endothelial cells, were studied by RNA sequencing. Compared with mono-cultured pericytes, a total of 6704 genes were differentially expressed in co-cultured pericytes. Direct endothelial contact induced transcriptome profiles associated with pericyte maturation, suppression of extracellular matrix production, proliferation, and morphological adaptation. In vitro studies confirmed enhanced pericyte proliferation mediated by endothelial-derived PDGFB and pericyte-derived HB-EGF and FGF2. Endothelial-induced PLXNA2 and ACTR3 upregulation also triggered pericyte morphological adaptation. Pathway analysis predicted a key role for TGFβ signaling in endothelial-induced pericyte differentiation, whereas the effect of signaling via gap- and adherens junctions was limited. We demonstrate that endothelial cells have a major impact on the transcriptional profile of pericytes, regulating endothelial-induced maturation, proliferation, and suppression of ECM production.
Unfolding political attitudes through the face: facial expressions when reading emotion language of left- and right-wing political leaders
Authors: Fino Edita , Menegatti Michela , Avenanti Alessio , Rubini Monica
Published: October 2019

Spontaneous emotionally congruent facial responses (ECFR) to others’ emotional expressions can occur by simply observing others’ faces (i.e., smiling) or by reading emotion related words (i.e., to smile). The goal of the present study was to examine whether language describing political leaders’ emotions affects voters by inducing emotionally congruent facial reactions as a function of readers’ and politicians’ shared political orientation. Participants read sentences describing politicians’ emotional expressions, while their facial muscle activation was measured by means of electromyography (EMG). Results showed that reading sentences describing left and right-wing politicians “smiling” or “frowning” elicits ECFR for ingroup but not outgroup members. Remarkably, ECFR were sensitive to attitudes toward individual leaders beyond the ingroup vs. outgroup political divide. Through integrating behavioral and physiological methods we were able to consistently tap on a ‘favored political leader effect’ thus capturing political attitudes towards an individual politician at a given moment of time, at multiple levels (explicit responses and automatic ECFR) and across political party membership lines. Our findings highlight the role of verbal behavior of politicians in affecting voters’ facial expressions with important implications for social judgment and behavioral outcomes.
Investigating the association between neuroticism and adverse obstetric and neonatal outcomes
Authors: Axfors Cathrine , Eckerdal Patricia , Volgsten Helena , Wikström Anna-Karin , Ekselius Lisa , Ramklint Mia , Sundström Poromaa Inger , Skalkidou Alkistis
Published: October 2019

Neuroticism is not only associated with affective disorders but also with certain somatic health problems. However, studies assessing whether neuroticism is associated with adverse obstetric or neonatal outcomes are scarce. This observational study comprises first-time mothers (n = 1969) with singleton pregnancies from several cohorts based in Uppsala, Sweden. To assess neuroticism-related personality, the Swedish universities Scales of Personality was used. Swedish national health registers were used to extract outcomes and confounders. In logistic regression models, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the outcomes by an increase of 63 units of neuroticism (equalling the interquartile range). Analyses were adjusted for maternal age, educational level, height, body mass index, year of delivery, smoking during pregnancy, involuntary childlessness, and psychiatric morbidity. Main outcomes were mode of delivery, gestational diabetes mellitus, gestational hypertension, preeclampsia, induction of delivery, prolonged delivery, severe lacerations, placental retention, postpartum haemorrhage, premature birth, infant born small or large for gestational age, and Apgar score. Neuroticism was not independently associated with adverse obstetric or neonatal outcomes besides gestational diabetes. For future studies, models examining sub-components of neuroticism or pregnancy-specific anxiety are encouraged.
A Dynamic Radiographic Imaging Study of Lumbar Intervertebral Disc Morphometry and Deformation In Vivo
Authors: Byrne Ryan M. , Aiyangar Ameet K. , Zhang Xudong
Published: October 2019

Intervertebral discs are important structural components of the spine but also are significant sources of morbidity, especially for the “low back” lumbar region. Mechanical damage to, or degeneration of, the lumbar discs can diminish their structural integrity and elicit debilitating low back pain. Advancement of reparative or regenerative means to treat damaged or degenerated discs is hindered by a lack of basic understanding of the disc load-deformation characteristics in vivo. The current study presents an in vivo analysis of the morphometry and deformation of lumbar (L2-S1) intervertebral discs in 10 healthy participants while performing a common lifting act, using novel dynamic radiographic imaging of the lumbar vertebral body motion. Data analyses show uniquely different (p < 0.05) characteristics in morphometry, normal and shear strain patterns of the L5S1 discs, while the rest of lumbar discs exhibit great similarity. In particular shear strains in L2-L5 discs exhibited stronger linear correlations (R2 ≥ 0.80) between strain changes and amount of lumbar flexion-extension motion compared to L5S1 (R2 ≤ 0.5). The study therefore advances the state of knowledge on in vivo mechanical responses of the lumbar intervertebral discs during functional tasks.
Longitudinal Functional Assessment of Brain Injury Induced by High-Intensity Ultrasound Pulse Sequences
Authors: Ye Meijun , Solarana Krystyna , Rafi Harmain , Patel Shyama , Nabili Marjan , Liu Yunbo , Huang Stanley , Fisher Jonathan A. N. , Krauthamer Victor , Myers Matthew , Welle Cristin
Published: October 2019

Exposure of the brain to high-intensity stress waves creates the potential for long-term functional deficits not related to thermal or cavitational damage. Possible sources of such exposure include overpressure from blast explosions or high-intensity focused ultrasound (HIFU). While current ultrasound clinical protocols do not normally produce long-term neurological deficits, the rapid expansion of potential therapeutic applications and ultrasound pulse-train protocols highlights the importance of establishing a safety envelope beyond which therapeutic ultrasound can cause neurological deficits not detectable by standard histological assessment for thermal and cavitational damage. In this study, we assessed the neuroinflammatory response, behavioral effects, and brain micro-electrocorticographic (µECoG) signals in mice following exposure to a train of transcranial pulses above normal clinical parameters. We found that the HIFU exposure induced a mild regional neuroinflammation not localized to the primary focal site, and impaired locomotor and exploratory behavior for up to 1 month post-exposure. In addition, low frequency (δ) and high frequency (β, γ) oscillations recorded by ECoG were altered at acute and chronic time points following HIFU application. ECoG signal changes on the hemisphere ipsilateral to HIFU exposure are of greater magnitude than the contralateral hemisphere, and persist for up to three months. These results are useful for describing the upper limit of transcranial ultrasound protocols, and the neurological sequelae of injury induced by high-intensity stress waves.
A unique olfactory bulb microcircuit driven by neurons expressing the precursor to glucagon-like peptide 1
Authors: Thiebaud Nicolas , Gribble Fiona , Reimann Frank , Trapp Stefan , Fadool Debra Ann
Published: October 2019

The presence of large numbers of local interneurons in the olfactory bulb has demonstrated an extensive local signaling process, yet the identification and purpose of olfactory microcircuits is poorly explored. Because the discrimination of odors in a complex environment is highly dependent on the tuning of information by local interneurons, we studied for the first time the role of preproglucagon (PPG) neurons in the granule cell layer of the olfactory bulb. Combining electrophysiological recordings and confocal microscopy, we discovered that the PPG neurons are a population of cells expressing the precursor of glucagon-like peptide 1 and are glutamatergic; able to modulate the firing pattern of the mitral cells (M/TCs). Optogenetic activation of PPG neurons resulted in a mixed excitation and inhibition that created a multiphasic response shaping the M/TCs firing pattern. This suggests that PPG neurons could drive neuromodulation of the olfactory output and change the synaptic map regulating olfactory coding.
Diversity of Mycobacterium tuberculosis in the Middle Fly District of Western Province, Papua New Guinea: microbead-based spoligotyping using DNA from Ziehl-Neelsen-stained microscopy preparations
Authors: Guernier-Cambert Vanina , Diefenbach-Elstob Tanya , Klotoe Bernice J. , Burgess Graham , Pelowa Daniel , Dowi Robert , Gula Bisato , McBryde Emma S. , Refrégier Guislaine , Rush Catherine , Sola Christophe , Warner Jeffrey
Published: October 2019

Tuberculosis remains the world’s leading cause of death from an infectious agent, and is a serious health problem in Papua New Guinea (PNG) with an estimated 36,000 new cases each year. This study describes the genetic diversity of Mycobacterium tuberculosis among tuberculosis patients in the Balimo/Bamu region in the Middle Fly District of Western Province in PNG, and investigates rifampicin resistance-associated mutations. Archived Ziehl-Neelsen-stained sputum smears were used to conduct microbead-based spoligotyping and assess genotypic resistance. Among the 162 samples included, 80 (49.4%) generated spoligotyping patterns (n = 23), belonging predominantly to the L2 Lineage (44%) and the L4 Lineage (30%). This is consistent with what has been found in other PNG regions geographically distant from Middle Fly District of Western Province, but is different from neighbouring South-East Asian countries. Rifampicin resistance was identified in 7.8% of the successfully sequenced samples, with all resistant samples belonging to the L2/Beijing Lineage. A high prevalence of mixed L2/L4 profiles was suggestive of polyclonal infection in the region, although this would need to be confirmed. The method described here could be a game-changer in resource-limited countries where large numbers of archived smear slides could be used for retrospective (and prospective) studies of M. tuberculosis genetic epidemiology.
Long term results of single high dose Stereotactic Body Radiotherapy in the treatment of primary lung tumors
Authors: Nicosia Luca , Reverberi Chiara , Agolli Linda , Marinelli Luca , De Sanctis Vitaliana , Valeriani Maurizio , Osti Mattia F.
Published: October 2019

Stereotactic body radiotherapy (SBRT) is a standard treatment for inoperable early-stage NSCLC, with local control rates comparable to surgical series. Promising results have been achieved utilizing a high single-dose schedule. The aim of our study was to evaluate long-term local control and toxicity in a series of patients treated with SBRT delivered in a single dose of 30 Gy. 44 patients affected by early stage NSCLC were treated with SBRT delivered in a single dose of 30 Gy. Survival and prognostic factors were retrospectively evaluated. Median follow-up was 34 months (range 3–81). Three- and 5-year local progression-free survival (LPFS) were 87.8% and 87.8% respectively (median 30 months; range 6–81 months), 3- and 5-year OS and CSS were 64.9% and 36.9%, 80.9% and 65.5%, respectively. Two (4.6%) cases of grade 3 pneumonitis occurred. At the univariate analysis lesion diameter ≤ 25 mm was predictive of better 5-year LPFS (95.8% versus 56.3%; p = 0.003) and 5-year PFS (69.8% versus 27.8%; p = 0.002). The results of our study indicated a high local control, survival and tolerability after a long-term follow-up with the use of SBRT 30 Gy single dose. Further prospective studies could better define the role of this regimen.
Differentiation of Induced Pluripotent Stem Cells towards Mesenchymal Stromal Cells is Hampered by Culture in 3D Hydrogels
Authors: Goetzke Roman , Keijdener Hans , Franzen Julia , Ostrowska Alina , Nüchtern Selina , Mela Petra , Wagner Wolfgang
Published: October 2019

Directed differentiation of induced pluripotent stem cells (iPSCs) towards specific lineages remains a major challenge in regenerative medicine, while there is a growing perception that this process can be influenced by the three-dimensional environment. In this study, we investigated whether iPSCs can differentiate towards mesenchymal stromal cells (MSCs) when embedded into fibrin hydrogels to enable a one-step differentiation procedure within a scaffold. Differentiation of iPSCs on tissue culture plastic or on top of fibrin hydrogels resulted in a typical MSC-like phenotype. In contrast, iPSCs embedded into fibrin gel gave rise to much smaller cells with heterogeneous growth patterns, absence of fibronectin, faint expression of CD73 and CD105, and reduced differentiation potential towards osteogenic and adipogenic lineage. Transcriptomic analysis demonstrated that characteristic genes for MSCs and extracellular matrix were upregulated on flat substrates, whereas genes of neural development were upregulated in 3D culture. Furthermore, the 3D culture had major effects on DNA methylation profiles, particularly within genes for neuronal and cardiovascular development, while there was no evidence for epigenetic maturation towards MSCs. Taken together, iPSCs could be differentiated towards MSCs on tissue culture plastic or on a flat fibrin hydrogel. In contrast, the differentiation process was heterogeneous and not directed towards MSCs when iPSCs were embedded into the hydrogel.
Analysis of combined resistance to oxazolidinones and phenicols among bacteria from dogs fed with raw meat/vegetables and the respective food items
Authors: Wu Yifan , Fan Run , Wang Yinchao , Lei Lei , Feßler Andrea T. , Wang Zheng , Wu Congming , Schwarz Stefan , Wang Yang
Published: October 2019

The gene optrA is the first gene that confers resistance to the oxazolidinone tedizolid, a last resort antimicrobial agent in human medicine. In this study we investigated the presence of optrA and the multi-resistance genes poxtA and cfr in enterococci and staphylococci from (i) pet animals known to be fed raw meat and vegetables and (ii) the respective food items. We examined 341 bacterial isolates from cats and dogs, 195 bacterial isolates from supermarket food items and only one E. faecium collected from industrial food in Beijing during 2016. Thirty-five (6.5%) of the 537 isolates, including 31/376 (8.2%) enterococci and 4/161 (2.5%) staphylococci, were positive for optrA, while all isolates were negative for poxtA and cfr. S1-nuclease pulsed-field gel electrophoresis (PFGE) and Southern blotting confirmed that optrA was located in the chromosomal DNA of 19 isolates and on a plasmid in the remaining 16 isolates. Whole genome sequencing revealed several different genetic environments of optrA in plasmid- or chromosome-borne optrA genes. PFGE, multilocus sequence typing (MLST) and/or SNP analysis demonstrated that the optrA-carrying Staphylococcus and Enterococcus isolates were genetically heterogeneous. However, in single cases, groups of related isolates were identified which might suggest a transfer of closely related optrA-positive E. faecalis isolates between food items and dogs.
Downregulation of GRK5 hampers the migration of breast cancer cells
Authors: Sommer Ann-Katrin , Falcenberg Mathias , Ljepoja Bojan , Fröhlich Thomas , Arnold Georg J. , Wagner Ernst , Roidl Andreas
Published: October 2019

Sunitinib is a multispecific kinase inhibitor and one of its targets is the kinase GRK5, which is regulating a multitude of G protein-coupled receptors (GPCRs). In this study we demonstrate that a decreased GRK5 expression induced by knock-down experiments or sunitinib treatment hampers the migration of cancer cell lines. A proteomic analysis revealed many pathways related to cell migration which were down regulated upon the GRK5 knock-down. Furthermore, we found in MDA-MB-231 breast cancer cells that the inhibition of migration is mediated by the GPCR gastrin releasing peptide receptor (GRPR) leading to a reduced expression of migration regulating downstream targets like CDC42 and ROCK1. An in silico Kaplan Meier analysis revealed that GRK5 and GRPR overexpression reduces the distant metastasis free survival in triple-negative breast cancer (TNBC) patients. Thus, we suggest a novel anti-migratory effect of impaired GRK5 expression which induces a negative feedback loop on GRPR signalling.
A mid-Cretaceous enantiornithine foot and tail feather preserved in Burmese amber
Authors: Xing Lida , McKellar Ryan C. , O’Connor Jingmai K. , Niu Kecheng , Mai Huijuan
Published: October 2019

Since the first skeletal remains of avians preserved in amber were described in 2016, new avian remains trapped in Cretaceous-age Burmese amber continue to be uncovered, revealing a diversity of skeletal and feather morphologies observed nowhere else in the Mesozoic fossil record. Here we describe a foot with digital proportions unlike any previously described enantiornithine or Mesozoic bird. No bones are preserved in the new specimen but the outline of the foot is recorded in a detailed skin surface, which is surrounded by feather inclusions including a partial rachis-dominated feather. Pedal proportions and plumage support identification as an enantiornithine, but unlike previous discoveries the toes are stout with transversely elongated digital pads, and the outer toe appears strongly thickened relative to the inner two digits. The new specimen increases the known diversity and morphological disparity among the Enantiornithes, hinting at a wider range of habitats and behaviours. It also suggests that the Burmese amber avifauna was distinct from other Mesozoic assemblages, with amber entrapment including representatives from unusual small forms.
FTIR, Raman and AFM characterization of the clinically valid biochemical parameters of the thrombi in acute ischemic stroke
Authors: Blat Aneta , Dybas Jakub , Chrabaszcz Karolina , Bulat Katarzyna , Jasztal Agnieszka , Kaczmarska Magdalena , Pulyk Roman , Popiela Tadeusz , Slowik Agnieszka , Malek Kamilla , Adamski Mateusz G. , Marzec Katarzyna M.
Published: October 2019

The significance and utility of innovative imaging techniques in arterial clot analysis, which enable far more detailed and automated analysis compared to standard methods, are presented. The examination of two types of human thrombi is shown, representing the main ischemic stroke etiologies: fibrin–predominant clot of large vessel origin and red blood cells–rich clot of cardioembolic origin. The synergy effect of Fourier–transform infrared spectroscopy (FTIR), Raman spectroscopy (RS) and atomic force microscopy (AFM) techniques supported by chemometrics in comparison with reference histological staining was presented. The main advantage of such approach refers to free–label and non–destructive quantitative imaging of clinically valid, biochemical parameters in whole sample (FTIR–low resolution) and selected regions (RS–ultra–high resolution). We may include here analysis of lipid content, its distribution and total degree of unsaturation as well as analysis of protein content (mainly fibrin and hemoproteins). The AFM studies enhanced the vibrational data, showed clearly shape and thickness of clot features as well as visualized the fibrin framework. The extraordinary sensitivity of FTIR and RS imaging toward detection and discrimination of clinically valid parameters in clot confirms its applicability in assessment of thrombi origin.
Nucleus pulposus primary cilia alter their length in response to changes in extracellular osmolarity but do not control TonEBP-mediated osmoregulation
Authors: Choi Hyowon , Madhu Vedavathi , Shapiro Irving M. , Risbud Makarand V.
Published: October 2019

The nucleus pulposus (NP) cells adapt to their physiologically hyperosmotic microenvironment through Tonicity-responsive enhancer binding protein (TonEBP/nuclear factor of activated T-cell5 [NFAT5])-mediated osmoregulation. Primary cilia in different organs serve diverse roles including osmosensing, but its contribution to NP cell osmoadaptive response is unknown. A high percentage of cultured primary NP cells possessed primary cilia that changed length in response to osmotic stimuli. Stable silencing ofIntraflagellar Transport 88 (Ift88)orKinesin Family Member 3 A (Kif3a)to inhibit the formation of primary cilia did not affect hyperosmotic upregulation of TonEBP. While ShKif3ablocked hyperosmotic increase of TonEBP-Transactivation Domain (TAD) activity, overall the knockdown of either gene did not alter the hyperosmotic status of proximal promoter activities and transcription of key TonEBP targets. On the other hand, a small decrease in TonEBP level under hypoosmotic condition was attenuated byIft88orKif3aknockdown. Noteworthy, none of the TonEBP target genes were responsive to hypoosmotic stimulus in control andIft88orKif3aknockdown cells, suggesting the primary role of TonEBP in the hyperosmotic adaptation of NP cells. Similarly, inKif3anull mouse embryonic fibroblasts (MEFs), the overall TonEBP-dependent hyperosmotic responses were preserved. Unlike NP cells, TonEBP targets were responsive to hypoosmolarity in wild-type MEFs, and these responses remained intact inKif3anull MEFs. Together, these results suggest that primary cilia are dispensable for TonEBP-dependent osmoadaptive response.
Dissecting the evolvability landscape of the CalB active site toward aromatic substrates
Authors: Santos Yossef López de los , Chew-Fajardo Ying Lian , Brault Guillaume , Doucet Nicolas
Published: October 2019

A key event in the directed evolution of enzymes is the systematic use of mutagenesis and selection, a process that can give rise to mutant libraries containing millions of protein variants. To this day, the functional analysis and identification of active variants among such high numbers of mutational possibilities is not a trivial task. Here, we describe a combinatorial semi-rational approach to partly overcome this challenge and help design smaller and smarter mutant libraries. By adapting a liquid medium transesterification assay in organic solvent conditions with a combination of virtual docking, iterative saturation mutagenesis, and residue interaction network (RIN) analysis, we engineered lipase B from P. antarctica (CalB) to improve enzyme recognition and activity against the bulky aromatic substrates and flavoring agents methyl cinnamate and methyl salicylate. Substrate-imprinted docking was used to target active-site positions involved in enzyme-substrate and enzyme-product complexes, in addition to identifying ‘hot spots’ most likely to yield active variants. This iterative semi-rational design strategy allowed selection of CalB variants exhibiting increased activity in just two rounds of site-saturation mutagenesis. Beneficial replacements were observed by screening only 0.308% of the theoretical library size, illustrating how semi-rational approaches with targeted diversity can quickly facilitate the discovery of improved activity variants relevant to a number of biotechnological applications.
Macrophage migration inhibitory factor of Syrian golden hamster shares structural and functional similarity with human counterpart and promotes pancreatic cancer
Authors: Suresh Voddu , Sundaram Rajivgandhi , Dash Pujarini , Sabat Surendra Chandra , Mohapatra Debasish , Mohanty Sneha , Vasudevan Dileep , Senapati Shantibhusan
Published: October 2019

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that increasingly is being studied in cancers and inflammatory diseases. Though murine models have been instrumental in understanding the functional role of MIF in different pathological conditions, the information obtained from these models is biased towards a specific species. In experimental science, results obtained from multiple clinically relevant animal models always provide convincing data that might recapitulate in humans. Syrian golden hamster (Mesocricetus auratus), is a clinically relevant animal model for multiple human diseases. Hence, the major objectives of this study were to characterize the structure and function of Mesocricetus auratusMIF (MaMIF) and finally evaluate its effect on pancreatic tumor growthin vivo. Initially, the recombinant MaMIF was cloned, expressed and purified in a bacterial expression system. The MaMIF primary sequence, biochemical properties, and crystal structure analysis showed greater similarity with human MIF. The crystal structure of MaMIF illustrates that it forms a homotrimer as known in human and mouse. However, MaMIF exhibits some minor structural variations when compared to human and mouse MIF. Thein vitrofunctional studies show that MaMIF has tautomerase activity and enhances activation and migration of hamster peripheral blood mononuclear cells (PBMCs). Interestingly, injection of MaMIF into HapT1 pancreatic tumor-bearing hamsters significantly enhanced the tumor growth and tumor-associated angiogenesis. Together, the current study shows a structural and functional similarity between the hamster and human MIF. Moreover, it has demonstrated that a high level of circulating MIF originating from non-tumor cells might also promote pancreatic tumor growthin vivo.
Rapid solvent-evaporation strategy for three-dimensional cobalt-based complex hierarchical architectures as catalysts for water oxidation
Authors: Jiang Hong , Zhang Hao , Kang Qiaoling , Ma Haifeng , Tong Yinlin , Gao Feng , Lu Qingyi
Published: October 2019

It is a challenging task to seek a highly-efficient electrocatalyst for oxygen evolution reaction (OER) of water splitting. Non-noble Co-based nanomaterials are considered as earth-abundant and effective catalysts to lower overpotential and increase polarization current density of OER. In this work, we reported, for the first time, a “rapid solvent-evaporation” strategy for the synthesis of three-dimensional (3D) cobalt complex hierarchical architectures constructed by two-dimensional (2D) nanosheets. The 3D structured cobalt complexes have excellent performances in catalyzing OER with lower onset potential, overpotential, Tafel slope and better stability than commercial IrO2. Superior electrochemical performances would be beneficial from the unique 3D structure. This extremely simple method for 3D Co complex with good OER activities makes the complex be promising commercial OER catalyst to replace earth-rare and expensive IrO2.
Southwest Greenland shelf glaciation during MIS 4 more extensive than during the Last Glacial Maximum
Authors: Seidenkrantz Marit-Solveig , Kuijpers Antoon , Olsen Jesper , Pearce Christof , Lindblom Sofia , Ploug Johan , Przybyło Piotr , Snowball Ian
Published: October 2019

Although geological and modelling evidence indicate that the last glacial inception in North America was in NE Canada, little is known about the glacial response of the nearby western Greenland Ice Sheet (GIS) during the glacial advance of marine oxygen isotope stage 4 (MIS4). Our multi-proxy study of a marine sediment core collected about 60 km southwest of the Outer Hellefisk Moraines demonstrates that in the southern Davis Strait region the most extreme Greenland shelf glaciation of the last glacial cycle occurred during MIS 4, with another prominent glacial advance at 37–33 kyr BP. During those periods the GIS likely reached the Outer Hellefisk Moraines in this area. Except for these two periods, our data suggest significant advection of relatively warm Irminger Sea Water by the West Greenland Current since MIS 4. This advection likely limited the extent of the MIS2 glaciation on the SW Greenland shelf. Decreased precipitation over southwestern Greenland predicted by atmospheric models as a downstream effect of a much larger MIS2 Laurentide Ice Sheet may have played an additional role.
MicroRNA-146a-deficient mice develop immune complex glomerulonephritis
Authors: Amrouche Lucile , You Sylvaine , Sauvaget Virginia , Manda Victoria , Lamarthée Baptiste , Desbuissons Geoffroy , Tinel Claire , Rabant Marion , Nguyen Clément , Isnard Pierre , Burtin Martine , Charles Nicolas , Legendre Christophe , Terzi Fabiola , Anglicheau Dany
Published: October 2019

MicroRNAs (miRNAs) play an important role in the kidneys under physiological and pathological conditions, but their role in immune glomerulonephritis is unclear. miR-146a has been identified as a key player in innate immunity and inflammatory responses, and in the kidney, this miRNA is involved in the response of injured tubular cells. We studied the renal and immune phenotypes of miR-146a+/+ and miR-146a−/− mice at 12 months of age, and the results showed that miR-146a−/− mice developed autoimmunity during aging, as demonstrated by circulating antibodies targeting double-stranded DNA and an immune complex-mediated glomerulonephritis associated with a mild renal immune infiltrate. In addition, miR-146a−/− mice showed reduced expression of the transmembrane protein Kim1/Tim1, a key regulator of regulatory B cell (Breg) homeostasis, in the kidney and the immune cells. The numbers of memory B cells and plasmablasts were increased in miR-146a−/− mice compared with the numbers in wild-type mice, whereas Bregs were decreased in number and displayed an altered capacity to produce IL-10. Finally, we showed that miR-146a−/− mice develop an autoimmune syndrome with increasing age, and this syndrome includes immune complex glomerulonephritis, which might be due to altered B cell responses associated with Kim1/Tim1 deficiency. This study unravels a link between miR-146a and Kim1 and identifies miR-146a as a significant player in immune-mediated glomerulonephritis pathogenesis.
Functional connectivity of music-induced analgesia in fibromyalgia
Authors: Pando-Naude Victor , Barrios Fernando A. , Alcauter Sarael , Pasaye Erick H. , Vase Lene , Brattico Elvira , Vuust Peter , Garza-Villarreal Eduardo A.
Published: October 2019

Listening to self-chosen, pleasant and relaxing music reduces pain in fibromyalgia (FM), a chronic centralized pain condition. However, the neural correlates of this effect are fairly unknown. In our study, we wished to investigate the neural correlates of music-induced analgesia (MIA) in FM patients. To do this, we studied 20 FM patients and 20 matched healthy controls (HC) acquiring rs-fMRI with a 3T MRI scanner, and pain data before and after two 5-min auditory conditions: music and noise. We performed resting state functional connectivity (rs-FC) seed-based correlation analyses (SCA) using pain and analgesia-related ROIs to determine the effects before and after the music intervention in FM and HC, and its correlation with pain reports. We found significant differences in baseline rs-FC between FM and HC. Both groups showed changes in rs-FC after the music condition. FM patients reported MIA that was significantly correlated with rs-FC decrease between the angular gyrus, posterior cingulate cortex and precuneus, and rs-FC increase between amygdala and middle frontal gyrus. These areas are related to autobiographical and limbic processes, and auditory attention, suggesting MIA may arise as a consequence of top-down modulation, probably originated by distraction, relaxation, positive emotion, or a combination of these mechanisms.
Refraction and pupil diameter in 3-year- and 1-month-old children as measured by Spot Vision Screener
Authors: Tatara Shunya , Maeda Fumiatsu , Mizuno Nobuko , Noguchi Atsushi , Yaoeda Kiyoshi , Abe Haruki
Published: October 2019

Spot Vision Screener (SVS) can conduct refraction tests for both eyes within a short period. This study aims to evaluate the refraction and pupil diameters of 3-year- and 1-month-old Japanese children using SVS in regular medical checkup. We examined 2438 eyes of 1219 children (age: 3-year- and 1-month) in Fujieda (Shizuoka, Japan) to assess their refraction and pupil diameters and eye-position screening conducted by SVS. SVS successfully measured 1217 children (99.8%). Regarding the right eye refraction, the spherical power was +0.70 ± 0.55 D (median, +0.75 D), and the cylindrical power was −0.67 ± 0.49 D (median, −0.50 D). The pupil diameter of the right eyes was 5.57 ± 0.79 (median, 5.60) mm. we could obtain a large number of basic data for 3-year- and 1-month-old Japanese children. However, refraction and pupil diameter of children were not normally distributed, so careful handling of children’s basic data on the eye is necessary.
Nucleosomal dsDNA Stimulates APOL1 Expression in Human Cultured Podocytes by Activating the cGAS/IFI16-STING Signaling Pathway
Authors: Davis Shamara E. , Khatua Atanu K. , Popik Waldemar
Published: October 2019

APOL1 alleles G1 and G2 are associated with faster progression to lupus nephritis (LN)-associated end-stage renal disease (LN-ESRD) in African Americans. Increased levels of type I interferons (IFNs) and nucleosome-associated double-stranded DNA (dsDNA) fragments (nsDNA) are the hallmark of this disease. Here, we identify cyclic GMP-AMP synthase (cGAS) and interferon-inducible protein 16 (IFI16) as the major DNA sensors in human immortalized podocytes. We also show that nsDNA triggers the expression of APOL1 and IFNβ via IRF3 activation through the cGAS/IFI16-STING pathway. We demonstrate that maximal APOL1 expression also requires the activation of type I IFN receptor (IFNAR) and STAT1 signaling triggered by IFNβ produced in response to nsDNA, or by exogenous IFNβ. Finally, we show that STAT1 activation is sufficient to upregulate IFI16, subsequently boosting APOL1 expression through a positive feedback mechanism. Collectively, we find that nsDNA-induced APOL1 expression is mediated by both IFNβ-independent and dependent signaling pathways triggered by activation of the cGAS/IFI16-STING pathway. We propose that simultaneous inhibition of STING and the IFNAR-STAT1 pathway may attenuate IFI16 expression, reduce IFI16-cGAS cross-talk, and prevent excessive APOL1 expression in human podocytes in response to nsDNA.
Mode of delivery and pregnancy outcomes in preterm birth: a secondary analysis of the WHO Global and Multi-country Surveys
Authors: Thanh Bao Yen Luong , Lumbiganon Pisake , Pattanittum Porjai , Laopaiboon Malinee , Vogel Joshua P. , Oladapo Olufemi T. , Pileggi-Castro Cynthia , Mori Rintaro , Jayaratne Kapila , Qureshi Zahida , Souza Joã
Published: October 2019

Many studies have been conducted to examine whether Caesarean Section (CS) or vaginal birth (VB) was optimal for better maternal and neonatal outcomes in preterm births. However, findings remain unclear. Therefore, this secondary analysis of World Health Organization Global Survey (GS) and Multi-country Survey (MCS) databases was conducted to investigate outcomes of preterm birth by mode of delivery. Our sample were women with singleton neonates (15,471 of 237 facilities from 21 countries in GS; and 15,053 of 239 facilities from 21 countries in MCS) delivered between 22 and <37 weeks of gestation. We assessed association between mode of delivery and pregnancy outcomes in singleton preterm births by multilevel logistic regression adjusted for hierarchical data. The prevalences of women with preterm birth delivered by CS were 31.0% and 36.7% in GS and MCS, respectively. Compared with VB, CS was associated with significantly increased odds of maternal intensive care unit admission, maternal near miss, and neonatal intensive care unit admission but significantly decreased odds of fresh stillbirth, and perinatal death. However, since the information on justification for mode of delivery (MOD) were not available, our results of the potential benefits and harms of CS should be carefully considered when deciding MOD in preterm births.
Dynamically changing neuronal activity supporting working memory for predictable and unpredictable durations
Authors: Park Jong Chan , Bae Jung Won , Kim Jieun , Jung Min Whan
Published: October 2019

Diverse neural processes have been proposed as the neural basis of working memory. To investigate whether the medial prefrontal cortex (mPFC) relies on different neural processes to mediate working memory depending on the predictability of delay duration, we examined mPFC neural activity in mice performing a delayed response task with fixed (4 s) or random (between 1–7 s) delay durations. mPFC neural activity was strongly influenced by the predictability of delay duration. Nevertheless, mPFC neurons seldom showed persistent activity spanning the entire delay period and instead showed dynamically-changing delay-period activity under both the fixed-delay and random-delay conditions. mPFC neurons conveyed higher working memory information under the random-delay than fixed-delay conditions, possibly due to a higher demand for stable working memory maintenance. Our results suggest that the rodent mPFC may rely on dynamically-changing neuronal activity to maintain working memory regardless of the predictability of delay duration.
Pre-pregnancy underweight and obesity are positively associated with small-for-gestational-age infants in a Chinese population
Authors: Chen Yuan Hua , Li Li , Chen Wei , Liu Zhi Bing , Ma Li , Gao Xing Xing , He Jia Liu , Wang Hua , Zhao Mei , Yang Yuan Yuan , Xu De Xiang
Published: October 2019

The association between suboptimal pre-pregnancy body mass index (BMI) and small-for-gestational-age (SGA) infants is not well defined. We investigated the association between pre-pregnancy BMI and the risk of SGA infants in a Chinese population. We performed a cohort study among 12029 mothers with a pregnancy. This cohort consisted of pregnant women that were: normal-weight (62.02%), underweight (17.09%), overweight (17.77%) and obese (3.12%). Birth sizes were reduced in the underweight and obese groups compared with the normal-weight group. Linear regression analysis indicated that birth size was positively associated with BMI in both the underweight and normal-weight groups. Further analysis showed that 12.74% of neonates were SGA infants in the underweight group, higher than 7.43% of neonates reported in the normal-weight group (adjusted RR = 1.92; 95% CI: 1.61, 2.30). Unexpectedly, 17.60% of neonates were SGA infants in the obese group, much higher than the normal-weight group (adjusted RR = 2.17; 95% CI: 1.57, 3.00). Additionally, 18.40% of neonates were large-for-gestational-age (LGA) infants in the obese group, higher than 7.26% of neonates reported in the normal-weight group (adjusted RR = 3.00; 95% CI: 2.21, 4.06). These results suggest that pre-pregnancy underweight increases the risk of SGA infants, whereas obesity increases the risks of not only LGA infants, but also SGA infants.
A spatiotemporal analysis of the food dissemination process and the trophallactic network in the ant Lasius niger
Authors: Planckaert Joffrey , Nicolis Stamatios C. , Deneubourg Jean-Louis , Sueur Cédric , Bles Olivier
Published: October 2019

Intranidal food dissemination through trophallactic exchanges is a fundamental issue in social insect colonies but its underlying mechanisms are far from being clear. In light of the division of work, network theory and collective food management we develop a framework to investigate the spatiotemporal dynamics of the trophallactic network in starved Lasius niger ant colonies. Thanks to tracking methods we are able to record spatial locations of the trophallactic interactions in the nest. We highlight quantitative differences between the foragers and non-foragers concerning their contributions, their roles (donor/recipient) and their spatial distributions. Moreover, at the intracaste level, we show interindividual differences in all activities and we characterise their nature. In particular, within each caste, all the individuals have the same probability to start their food exchange activity but their probability to exchange differs after their first trophallactic event. Interestingly, despite the highlighted interindividual differences, the trophallactic network does not differ from a random network.