bluuebunny/crossref_metadata_2025_split huggingface dataset:
Substantial fat mass loss reduces low-grade inflammation and induces positive alteration in cardiometabolic factors in normal-weight individuals
Authors: Sarin H. V. , Lee J. H. , Jauhiainen M. , Joensuu A. , Borodulin K. , Männistö S. , Jin Z. , Terwilliger J. D. , Isola V. , Ahtiainen J. P. , Häkkinen K. , Kristiansson K. , Hulmi J. J. , Perola M. 
Published: March 2019

AbstractThe accumulation of fat, especially in visceral sites, is a significant risk factor for several chronic diseases with altered cardiometabolic homeostasis. We studied how intensive long-term weight loss and subsequent weight regain affect physiological changes, by longitudinally interrogating the lipid metabolism and white blood cell transcriptomic markers in healthy, normal-weight individuals. The current study examined 42 healthy, young (age: 27.5 ± 4.0 years), normal-weight (body mass index, BMI: 23.4 ± 1.7 kg/m2) female athletes, of which 25 belong to the weight loss and regain group (diet group), and 17 to the control group. Participants were evaluated, and fasting blood samples were drawn at three time points: at baseline (PRE); at the end of the weight loss period (MID: 21.1 ± 3.1 weeks after PRE); and at the end of the weight regain period (POST: 18.4 ± 2.9 weeks after MID). Following the weight loss period, the diet group experienced a ~73% reduction (~0.69 kg) in visceral fat mass (false discovery rate, FDR < 2.0 × 10−16), accompanied by anti-atherogenic effects on transcriptomic markers, decreased low-grade inflammation (e.g., as α1–acid glycoprotein (FDR = 3.08 × 10−13) and hs-CRP (FDR = 2.44 × 10−3)), and an increase in functionally important anti-atherogenic high-density lipoprotein -associated metabolites (FDR < 0.05). This occurred even though these values were already at favorable levels in these participants, who follow a fitness-lifestyle compared to age- and BMI-matched females from the general population (n = 58). Following the weight regain period, most of the observed beneficial changes in visceral fat mass, and metabolomic and transcriptomic profiles dissipated. Overall, the beneficial anti-atherogenic effects of weight loss can be observed even in previously healthy, normal-weight individuals.
Cooling of a vial in a snapfreezing device without using sacrificial cryogens
Authors: van Limbeek Michiel A. J. , Jagga Sahil , Holland Harry , Ledeboer Koen , ter Brake Marcel , Vanapalli Srinivas 
Published: March 2019

AbstractA fresh and frozen high-quality patient bio-sample is required in molecular medicine for the identification of disease-associated mechanism at molecular levels. A common cooling procedure is immersing the tissue enclosed in a vial in a coolant such as liquid nitrogen. This procedure is not user friendly and is laborious as reducing the lag time from excision time to freezing depends on the logistic organizational structure within a hospital. Moreover snapfreezing must be done as soon as possible after tissue excision to preserve the tissue quality for molecular tests. Herein, we report an electrically powered snap freezing device as an alternative to quenching the vial in liquid nitrogen and therefore can be used directly at the location where the tissue is acquired. This device also facilitates the study of the effect of freezing conditions on the various molecular processes in the samples. Cooling experiments of a vial in the snap freezing device show that the cooling rates similar to or faster than quenching in liquid nitrogen are feasible. We performed experiments with several set point conditions and compared the results with a mathematical model.
Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy
Authors: Malik Bilal , Devine Helen , Patani Rickie , La Spada Albert R. , Hanna Michael G. , Greensmith Linda 
Published: March 2019

AbstractSpinal and bulbar muscular atrophy (SBMA) results from a CAG repeat expansion within the androgen receptor gene (AR). It is unclear why motor neurons selectively degenerate and there are currently no treatments for this debilitating disease. To uncover the causative genes and pathways involved in motor neuron dysfunction, we undertook transcriptomic profiling of primary embryonic motor neurons from SBMA mice. We show that transcriptional dysregulation occurs early during development in SBMA motor neurons. One gene found to be dysregulated, Chmp7, was also altered in vivo in spinal cord before symptom onset in SBMA mice, and crucially in motor neuron precursor cells derived from SBMA patient stem cells, suggesting that Chmp7 may play a causal role in disease pathogenesis by disrupting the endosome-lysosome system. Furthermore, genes were enriched in SBMA motor neurons in several key pathways including p53, DNA repair, WNT and mitochondrial function. SBMA embryonic motor neurons also displayed dysfunctional mitochondria along with DNA damage, possibly resulting from DNA repair gene dysregulation and/or mitochondrial dysfunction. This indicates that a coordinated dysregulation of multiple pathways leads to development of SBMA. Importantly, our findings suggest that the identified pathways and genes, in particular Chmp7, may serve as potential therapeutic targets in SBMA.
Vegfa/vegfr2 signaling is necessary for zebrafish islet vessel development, but is dispensable for beta-cell and alpha-cell formation
Authors: Toselli Chiara M. , Wilkinson Brayden M. , Paterson Joshua , Kieffer Timothy J. 
Published: March 2019

AbstractThe mechanisms underlying zebrafish pancreatic islet vascularization have not been well characterized. We sought to determine the angiogenic factors responsible for islet vascularization and assess whether an absence of endothelial cells affects beta-cell and alpha-cell formation. We used a double transgenic zebrafish Tg(fli1:EGFP; insa:tagRFP) to label endothelial cells and beta-cells, respectively. Beta-cells developed adjacent to endothelial cells and by 72 hours post fertilization (hpf) the zebrafish pancreatic islet was highly vascularized. Zebrafish beta-cells express vascular endothelial growth factors (vegf), vegfaa and vegfab. Double knockdown of vegfaa and vegfab or the primary Vegfa receptors (Vegfr2), kdr and kdrl, resulted in vessel deficient islets. While beta-cell and alpha-cell numbers remained unchanged in vessel deficient islets, insulina expression was downregulated relative to controls. Vegfaa/Vegfab-Vegfr2 signaling is necessary for proper islet vessel development, but not for the initial formation of beta-cells and alpha-cells.
Resilience of Central Pacific reefs subject to frequent heat stress and human disturbance
Authors: Donner Simon D. , Carilli Jessica 
Published: March 2019

AbstractFrequent occurrences of coral bleaching and associated coral mortality over recent decades have raised concerns about the survival of coral reefs in a warming planet. The El Niño-influenced coral reefs in the central Gilbert Islands of the Republic of Kiribati, which experience years with prolonged heat stress more frequently than 99% of the world’s reefs, may serve as a natural model for coral community response to frequent heat stress. Here we use nine years of survey data (2004–2012) and a suite of remote sensing variables from sites along gradients of climate variability and human disturbance in the region to evaluate the drivers of coral community response to, and recovery from, multiple heat stress events. The results indicate that the extent of bleaching was limited during the 2009–2010 El Niño event, in contrast to a similar 2004–2005 event, and was correlated with incoming light and historical temperature variability, rather than heat stress. Spatial and temporal patterns in benthic cover suggest growing resistance to bleaching-level heat stress among coral communities subject to high inter-annual temperature variability and local disturbance, due to the spread of “weedy” and temperature-tolerant species (e.g., Porites rus) and the cloudy conditions in the region during El Niño events.
Pet dogs’ relationships vary rather individually than according to partner’s species
Authors: Cimarelli G. , Marshall-Pescini S. , Range F. , Virányi Z. 
Published: March 2019

AbstractMost dogs worldwide are free-ranging animals that form relationships mainly with conspecifics, yet research has focused mainly on the dog-human bond, leading to the hypothesis that dogs evolved specific abilities to form a unique relationship with humans. Although widespread, this hypothesis has not, as yet, been tested. Here we compared the relationships pet dogs form with their owner and with other dogs living in the same household. Using a bottom-up approach, we analyzed dogs’ behavior in a test battery with both dog and human partners. Results revealed that pet dogs’ relationships are characterized by three components (i.e. reference, affiliation and stress). A comparison between dogs’ intra- and inter-specific relationships found that overall dogs refer more to their owner, but also that some dogs form stronger affiliative bonds with conspecifics than with their owner. Moreover, we tested how different partners could help dogs cope with a stressful situation. We found that the type of relationship, rather than the partner species, predicts how dogs react to a social threat. Our results suggest that dogs can form relationships of comparable qualities with both humans and other dogs, and that these relationships vary along multiple components across different partners.
Striatal Interneurons in Transgenic Nonhuman Primate Model of Huntington’s Disease
Authors: Lallani Shoeb B. , Villalba Rosa M. , Chen Yiju , Smith Yoland , Chan Anthony W. S. 
Published: March 2019

AbstractHuntington’s disease is an autosomal dominant neurodegenerative disorder associated with progressive motor and cognitive impairments, and the expansion of a cysteine-adenine-guanine trinucleotide (polyglutamine) repeats in exon one of the human huntingtin gene. The pathology of the disease is characterized by a profound degeneration of striatal GABAergic projection neurons with relative sparing of interneurons accompanied with astrogliosis. Here, we describe the striatal pathology in two genotypically different transgenic HD monkeys that exhibit degrees of disease progression that resembled those seen in juvenile- (rHD1) and adult-onset (rHD7) HD. The caudate nucleus and putamen underwent severe neuronal loss in both animals, while the striatal volume was reduced only in rHD1, the most severely affected monkey. The number of GABAergic (calretinin- and parvalbumin-positive) and cholinergic interneurons was also reduced in most striatal regions of these two monkeys, but to variable degrees. Overall, the density of interneurons was increased in rHD1, but not in rHD7, suggesting a relative sparing of interneurons over projection neurons in the striatum of the most affected HD monkey. The neuropil of both the caudate nucleus and putamen was invaded with reactive astrocytes in rHD1, while astrogliosis was much less severe in rHD7 and absent from control. Combined with behavioral data collected from these monkeys, our findings further demonstrate that transgenic HD monkeys share similar disease patterns with HD patients, making them a highly reliable preclinical HD animal model.
Autoreactivity profiles of influenza hemagglutinin broadly neutralizing antibodies
Authors: Bajic Goran , van der Poel Cees E. , Kuraoka Masayuki , Schmidt Aaron G. , Carroll Michael C. , Kelsoe Garnett , Harrison Stephen C. 
Published: March 2019

AbstractEpitope-focused approaches for selective clonal induction of broadly neutralizing antibodies (bnAbs) inform most current vaccine strategies for influenza virus and other rapidly evolving pathogens. The two conserved epitopes on the influenza hemagglutinin (HA) - the “stem” and the receptor-binding site (RBS) on the “head” - are the focus of the current “universal” influenza vaccine development efforts. Because stem-directed serum bnAbs are much less abundant than head-directed ones, we hypothesized that the HA stem bnAbs may be autoreactive and thus eliminated through the mechanisms of self-tolerance. We compared autoreactivity profiles of a set of stem and head-directed bnAbs. Most of the stem bnAbs we examined bound autoantigens; several showed staining of HEp-2 cells. A smaller proportion of the head-directed bnAbs were polyreactive. Gene usage did not correlate with autoreactivity. We suggest that complex foreign antigens may often have surface patches resembling some host epitope; our results indicate that HA stem epitopes resemble a host epitope more frequently than does the RBS.
Unexpected genomic rearrangements at targeted loci associated with CRISPR/Cas9-mediated knock-in
Authors: Rezza Amélie , Jacquet Christelle , Le Pillouer Amélie , Lafarguette Florian , Ruptier Charlotte , Billandon Marion , Isnard Petit Patricia , Trouttet Séverine , Thiam Kader , Fraichard Alexandre , Chérifi Yacine 
Published: March 2019

AbstractThe CRISPR/Cas9 gene editing tool enables accessible and efficient modifications which (re)ignited molecular research in certain species. However, targeted integration of large DNA fragments using CRISPR/Cas9 can still be challenging in numerous models. To systematically compare CRISPR/Cas9’s efficiency to classical homologous recombination (cHR) for insertion of large DNA fragments, we thoroughly performed and analyzed 221 experiments targeting 128 loci in mouse ES cells. Although both technologies proved efficient, CRISPR/Cas9 yielded significantly more positive clones as detected by overlapping PCRs. It also induced unexpected rearrangements around the targeted site, ultimately rendering CRISPR/Cas9 less efficient than cHR for the production of fully validated clones. These data show that CRISPR/Cas9-mediated recombination can induce complex long-range modifications at targeted loci, thus emphasizing the need for thorough characterization of any genetically modified material obtained through CRISPR-mediated gene editing before further functional studies or therapeutic use.
Magnetic field-induced rubber-like behavior in Ni-Mn-Ga particles/polymer composite
Authors: Sratong-on P. , Chernenko V. A. , Feuchtwanger J. , Hosoda H. 
Published: March 2019

AbstractSingle crystalline Ni-Mn-Ga is well known as a prototype ferromagnetic shape memory alloy (FSMA) exhibiting a giant magnetic field-induced strain (MFIS), up to 12%, due to the magnetically driven twin boundary rearrangement. The large stroke and fast magnetomechanical response make it important for actuators and sensors. Polycrystalline Ni-Mn-Ga is inexpensive and technologically easy accessible, but constrains from the grain boundaries inhibit the twin boundary motion, whereby a very low MFIS is observed. Here, we have shown for the first time that a polycrystalline Ni-Mn-Ga can be split into the magnetostrain-active single grains which, being specially assembled in a silicone polymer matrix, caused large and fully reversible MFIS of the resulting composite. We termed the unique reversibility of a large MFIS of the composite as the magnetic field-induced rubber-like behavior. The magnetostrain of individual particles was explored by the X-ray μCT 3D imaging. The results suggest novel solutions for development of the low cost magnetic actuators and sensors for haptic applications.
Effect of CHK1 Inhibition on CPX-351 Cytotoxicity in vitro and ex vivo
Authors: Vincelette Nicole D. , Ding Husheng , Huehls Amelia M. , Flatten Karen S. , Kelly Rebecca L. , Kohorst Mira A. , Webster Jonathan , Hess Allan D. , Pratz Keith W. , Karnitz Larry M. , Kaufmann Scott H. 
Published: March 2019

AbstractCPX-351 is a liposomally encapsulated 5:1 molar ratio of cytarabine and daunorubicin that recently received regulatory approval for the treatment of therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes based on improved overall survival compared to standard cytarabine/daunorubicin therapy. Checkpoint kinase 1 (CHK1), which is activated by DNA damage and replication stress, diminishes sensitivity to cytarabine and anthracyclines as single agents, suggesting that CHK1 inhibitors might increase the effectiveness of CPX-351. The present studies show that CPX-351 activates CHK1 as well as the S and G2/M cell cycle checkpoints. Conversely, CHK1 inhibition diminishes the cell cycle effects of CPX-351. Moreover, CHK1 knockdown or addition of a CHK1 inhibitor such as MK-8776, rabusertib or prexasertib enhances CPX-351-induced apoptosis in multiple TP53-null and TP53-wildtype AML cell lines. Likewise, CHK1 inhibition increases the antiproliferative effect of CPX-351 on primary AML specimens ex vivo, offering the possibility that CPX-351 may be well suited to combine with CHK1-targeted agents.
Development of thermo-responsive polycaprolactone macrocarriers conjugated with Poly(N-isopropyl acrylamide) for cell culture
Authors: Nguyen Linh T. B. , Odeleye Akinlolu O. O. , Chui Chih–Yao , Baudequin Timothée , Cui Zhanfeng , Ye Hua 
Published: March 2019

AbstractPoly(N-isopropyl acrylamide) (PNIPAAm) is a well-known ‘smart’ material responding to external stimuli such as temperature. PNIPAAm was successfully conjugated to polycaprolactone (PCL) bead surfaces through amidation reaction. Functionalization steps were characterized and confirmed by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy and Energy Dispersion Spectroscopy. PNIPAAm-conjugated PCL allowed human dermal fibroblast cells (HDF) and mesenchymal stem cells (MSC) to adhere, spread, and grow successfully. By reducing the temperature to 30 °C, more than 70% of HDF were detached from PNIPAAm-conjugated PCL macrocarriers with 85% viability. The cell detachment ratio by trypsin treatment was slightly higher than that induced by reduced temperature, however, cell detachment from PNIPAAm-conjugated macrocarriers by lowering the temperature significantly reduced cell death and increased both cell viability and the recovery potential of the detached cells. HDF attachment and detachment were also observed by Live-Dead staining and phase contrast imaging. The expression of extracellular matrix proteins such as Laminin and Fibronectin was also affected by the trypsinization process but not by the reduced temperature process. Taken together, our results showed that thermo-responsive macrocarriers could be a promising alternative method for the non-invasive detachment of cells, in particular for tissue engineering, clinical applications and the use of bioreactors.
Countershading in zebrafish results from an Asip1 controlled dorsoventral gradient of pigment cell differentiation
Authors: Cal Laura , Suarez-Bregua Paula , Comesaña Pilar , Owen Jennifer , Braasch Ingo , Kelsh Robert , Cerdá-Reverter José Miguel , Rotllant Josep 
Published: March 2019

AbstractDorso-ventral (DV) countershading is a highly-conserved pigmentary adaptation in vertebrates. In mammals, spatially regulated expression of agouti-signaling protein (ASIP) generates the difference in shading by driving a switch between the production of chemically-distinct melanins in melanocytes in dorsal and ventral regions. In contrast, fish countershading seemed to result from a patterned DV distribution of differently-coloured cell-types (chromatophores). Despite the cellular differences in the basis for counter-shading, previous observations suggested that Agouti signaling likely played a role in this patterning process in fish. To test the hypotheses that Agouti regulated counter-shading in fish, and that this depended upon spatial regulation of the numbers of each chromatophore type, we engineered asip1 homozygous knockout mutant zebrafish. We show that loss-of-function asip1 mutants lose DV countershading, and that this results from changed numbers of multiple pigment cell-types in the skin and on scales. Our findings identify asip1 as key in the establishment of DV countershading in fish, but show that the cellular mechanism for translating a conserved signaling gradient into a conserved pigmentary phenotype has been radically altered in the course of evolution.
Bone-Specific Overexpression of PITX1 Induces Senile Osteoporosis in Mice Through Deficient Self-Renewal of Mesenchymal Progenitors and Wnt Pathway Inhibition
Authors: Karam Nancy , Lavoie Jean-François , St-Jacques Benoit , Bouhanik Saadallah , Franco Anita , Ladoul Nihad , Moreau Alain 
Published: March 2019

AbstractThe cellular and molecular mechanisms underlying senile osteoporosis remain poorly understood. In this study, transgenic mCol1α1-Pitx1 mice overexpressing paired-like homeodomain 1 (PITX1), a homeobox transcription factor, rapidly develop a severe type-II osteoporotic phenotype with significant reduction in bone mass and biomechanical strength similar to that seen in humans and reminiscent of the phenotype previously observed in Sca-1 (Ly6a)-null mice. PITX1 plays a critical role in hind limb formation during fetal development, while loss of expression is associated with primary knee/hip osteoarthritis in aging humans. Through in vivo and in vitro analyses, we demonstrate that Pitx1 directly regulates the self-renewal of mesenchymal progenitors and indirectly regulates osteoclast differentiation through the upregulation of Wnt signaling inhibitors DKK1, SOST, and GSK3-β. This is confirmed by elevated levels of plasma DKK1 and the accumulation of phospho-β-catenin in transgenic mice osteoblasts. Furthermore, overexpressed Pitx1 in mice osteoblasts results in severe repression of Sca-1 (Ly6a) that was previously associated with senile osteoporosis. Our study is the first to demonstrate the novel roles of PITX1 in senile osteoporosis where PITX1 regulates the self-renewal of mesenchymal stem cells or progenitor cells through Sca-1 (Ly6a) repression and, in addition, inhibits the Wnt signaling pathway.
Development and validation of a nomogram for urothelial cancer in patients with chronic kidney disease
Authors: Chou Che-Yi , Shu Kuo-Hsiung , Chen Hung-Chun , Wang Ming-Chang , Chang Chia-Chu , Hsu Bang-Gee , Chen Tzen-Wen , Chen Chien-Lung , Huang Chiu-Ching 
Published: March 2019

AbstractUrothelial cancer (UC) is a common kidney cancer in Taiwan and patients with chronic kidney disease (CKD) are more at risk for UC than the general population. The diagnostic value of urine analysis and urine cytology is limited, especially in CKD patients. The aim of the study is to develop a nomogram to predict the risk of UC in CKD patients. We enrolled 169 UC patients and 1383 CKD patients from 9 hospitals in Taiwan between 2012 and 2015. CA125, HE4, clinical characteristics, and medical history were analyzed using multivariable logistic regression for its association with UC. A nomogram was developed to predict the risk of UC and was validated using Bootstrap. CA125 was associated with UC in CKD patients (OR: 5.91, 95% CI: 3.24–10.77) but HE4 was not (OR: 1.29, 95% CI: 0.67–2.35). A nomogram based on patients’ age, estimated glomerular filtration rate, CA125 (log transformed), smoking, exposure of environmental toxin, use of nonsteroid anti-inflammatory drugs, and use of traditional Chinese medicine was conducted. The AUC of the nomogram was 0.90 (95% CI: 0.86–0.92, p < 0.01). Serum CA125 may identify UC patients from CKD patients but has limited diagnostic value due to low sensitivity. The diagnostic value of serum CA125 level can be improved by the combination with clinical characteristics including age, renal function, and medical history.