bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immediate Effect of Abdominal and Pelvic Floor Muscle Exercises on Interrecti Distance in Women With Diastasis Recti Abdominis Who Were Parous
Authors: Gluppe Sandra B , Engh Marie Ellström , Bø Kari 
Published: April 2020

Abstract

Objective
There is a lack of consensus on which abdominal or pelvic floor muscle (PFM) exercises to recommend for the treatment of diastasis recti abdominis (DRA). The objective of this study was to investigate the immediate effect of abdominal and PFM exercises on interrecti distance (IRD) in women with DRA who are parous.

Methods
In this cross-sectional study, 38 women who were parous, with a mean age of 36.2 years (SD = 5.2), diagnosed with DRA participated. IRD was assessed with 2-dimensional real-time ultrasonography during rest and during 8 randomly ordered different exercises. A paired t test was used to compare the IRD at rest with the IRD recorded during each exercise as well as the differences between exercises. Means with 95% CI are reported.

Results
Head lift and twisted curl-up exercises significantly decreased the IRD both above and below the umbilicus. Above the umbilicus, the mean IRD difference from rest during head lift was 10 mm (95% CI = 7 to 13.2), whereas during twisted curl-up it was 9.4 mm (95% CI = 6.3 to 12.5). Below the umbilicus, the corresponding values were 6.1 mm (95% CI = 3.2 to 8.9) and 3.5 mm (95% CI = 0.5 to 6.4), respectively, but PFM contraction, maximal in-drawing, and PFM contraction + maximal in-drawing increased the IRD (mean difference = −2.8 mm [95% CI = −5.2 to 0.5], −4.7 mm [95% CI = −7.2 to −2.1], and − 5.0 mm [95% CI = −7.9 to −2.1], respectively).

Conclusions
Head lift and twisted curl-up exercises decreased the IRD both above and below the umbilicus, whereas maximal in-drawing and PFM contraction exercises only increased the IRD below the umbilicus. A randomized controlled trial is needed to investigate whether head lift and twisted curl-up exercises are effective in permanently narrowing the IRD.

Impact
To date there is scant scientific knowledge of which exercises to recommend in the treatment of DRA. In-drawing and PFM contraction leads to an acute increase in IRD, while head lift and twisted curl-up leads to an acute decrease in IRD in postpartum women. There is a need for high-quality randomized controlled trials to investigate if there is a long-term reduction in IRD by doing these exercises over time. The acute IRD increase and decrease during the different exercises is also present in a sample of women with larger separations.
A framework for mission-oriented innovation policy: Alternative pathways through the problem–solution space
Authors: Wanzenböck Iris , Wesseling Joeri H , Frenken Koen , Hekkert Marko P , Weber K Matthias 
Published: April 2020

AbstractWe aim for a better conceptualization of mission-oriented innovation policy (MIP). Our starting point is an analytical decomposition of societal problems and innovative solutions based on three dimensions of wickedness: (1) contestation; (2) complexity; and (3) uncertainty. We argue that both problems and solutions can be divergent (contested, complex, and uncertain) or convergent (uncontested, well-defined, and informed). Based on the resulting problem–solution typology, we suggest a process-oriented view on MIP and discuss three alternative pathways along which convergence between problems and solutions can be achieved to come from wicked problems to legitimate solutions. We illustrate these pathways using examples for different societal problems related to health (smoking bans), security (CCTV), and energy (wind turbines). For policy makers, locating a societal challenge in this problem–solution space, and implementing policy strategies to achieve problem and solution convergence, is expected to accelerate both the legitimacy of a mission and the resulting solutions.
Enhanced apoptogenesis and oncogene regulatory mechanism of troxerutin in triple negative breast cancer cells
Authors: Saranya Thiruvenkataswamy , Kavithaa Krishnamoorthy , Paulpandi Manickam , Ramya Sennimalai , Preethi Sivashanmugam , Balachandar Vellingiri , Narayanasamy Arul 
Published: April 2020

Abstract
Triple negative breast carcinoma (TNBC) is an aggressive form of cancer, with high rates of morbidity, mortality, poor prognosis and limited therapeutic options. The objective of the present study was to elaborate the anticancer activity of Troxerutin (TXN) in TNBC/MDA-MB-231 cells. Herein, we demonstrated the inhibitory effects of TXN on the breast cancer cell growth via induction of apoptosis. Mitochondrial membrane potential (∆Ψm), DNA damage and apoptotic nuclear changes were analyzed by flowcytometry, AO/EtBr and Hoechst staining, respectively. Furthermore, apoptotic protein and gene expressions were analyzed by western blot and reverse transcription polymerase chain reaction (RT-PCR), respectively. Our results indicated that TXN induces apoptosis as evidenced by inhibit the cell proliferation, enhanced apoptotic activation, altered mitochondrial membrane potential and elevated level of DNA damage in TNBC cells. Furthermore, the TXN inhibit anti-apoptotic protein expression with the subsequent upregulation of Cytochrome c, Caspase-9 and Caspase-3. Thus, TXN induces apoptosis in TNBC cells through inducing nuclear damage and altered apoptotic marker expressions. Therefore, TXN might be used as a potential therapeutic agent for the treatment of triple negative breast cancer.
Zebrafish as a Model System for the Interrogation of Hematopoietic Stem Cell Engraftment
Authors: Feliz Maria A , Fraint Ellen , Bowman Teresa V 
Published: April 2020

Hematopoietic stem cell (HSC) transplant is a treatment used to infuse healthy blood stem cells to patients that suffer from a range of blood disorders, such as leukemia. Although transplantations are successful nearly 85% of the time, the associated morbidity and mortality rates are still too high. To improve HSC transplantation outcomes, it is crucial to better understand all facets of HSC engraftment, which includes the seeding, expansion, and differentiation of donor HSC into the recipient. Zebrafish is an ideal animal model to study engraftment due to their small size, high fecundity, and malleable genetics. We have established a novel transplantation model using the zebrafish runx1 W84X bloodless mutant strain. These animals lack endogenous HSC and thus possess empty HSC niche available for donor cell engraftment without the need for pre‐conditioning regimens. Transplantation of donor marrow cells that ubiquitously express green fluorescent protein (ubi:GFP) into runx1 W84X homozygous mutants at two days‐post fertilization (dpf) results in robust GFP+ donor cell engraftment that sustains the blood system of the mutants into adulthood. Sham‐injected and un‐injected embryos served as negative controls. Using this model, we will image transplanted embryos daily to visualize all stages of engraftment. From 4–7 dpf, we observed seeding of GFP+ cells into all hematopoietic tissues including the thymus, caudal hematopoietic tissue, and kidney marrow (equivalent to mammalian bone marrow). We will use confocal microscopy to gain a more in‐depth view of the cell‐to‐cell interactions occurring within these niches to understand engraftment. Additionally, we will use this assay for longitudinal studies to determine what facets predict which animals will sustain high versus low donor cell chimerism. Studying this animal model could advance our understanding of human HSC transplantation outcomes.Support or Funding InformationNIH (Grant # R25‐GM104547); Cancer Research Center (Grant # P30CA013330)
Non‐Perfused Coronary Arteries Are Able to Maintain Structural Integrity in Developing Scar Tissue Following a Transmural Myocardial Infarction
Authors: Dedkov Eduard I 
Published: April 2020

IntroductionWhereas considerable effort has been devoted to identify a suitable source of contractile cells to be used for replacement of a post‐myocardial infarction (MI) scar with the newly‐formed cardiac muscle tissue, an exploration for the viable routes of arterial blood supply to the sites of regenerating myocardium remained mostly neglected. However, the presence of a sustainable blood delivery system seems imperative for survival of newly‐grown myocardium.HypothesisWe hypothesize that if the vessels of the original arterial bed, remaining in post‐MI region, will be able to maintain their structural integrity for the duration of post‐MI scar formation they can potentially be suitable for use as a natural blood delivery system to support the regenerating myocardium.MethodsA large transmural MI was induced in middle‐aged, male Sprague‐Dawley rats by permanent ligation of the left coronary artery. Post‐MI rats were euthanized 3, 7 and 14 days after occlusion and their hearts were processed to paraffin for morphological evaluation. Sham‐operated rats were used as age‐matched controls. Serial sections from each heart were stained with various histological techniques or with an anti‐smooth muscle alpha‐actin antibody. Images were captured using a Leica DM 4000B microscope and analyzed by Image‐Pro Analyzer v.7.0 software. Statistical analysis was performed using Prism 6 software package.ResultsWe found that whereas most arterioles and small arteries within an infarcted region have undergone necrosis during 3 days after MI, the medium‐sized and larger arteries appeared to preserve their structural integrity up to 14 days post‐MI. Quantitative assessment showed that surviving residual arteries continued to maintain their structural parameters, such as external diameter, lumen diameter, wall thickness and wall‐to‐lumen ratio, during 7 post‐MI days. However, in 14‐day‐old scars, some non‐perfused arteries began to demonstrate the evidence of noticeable neointimal thickening, composed of activated smooth muscle cells, that narrowed the vessel lumen and led to a significant increase in wall‐to‐lumen ratio (0.35±0.02 in post‐MI rats vs. 0.11±0.01 in sham‐operated rats, P<0.0001). Moreover, the majority of remaining vessels showed a various degree of degenerative changes, including perivascular and intravascular collagen accumulation, disintegration of internal elastic lamina and patchy disappearance of smooth muscle cells from the vessel media.ConclusionOur findings reveal that a number of large and medium‐sized coronary arteries, residing in post‐infarcted region, were capable of maintaining their structural integrity during two post‐MI weeks. This observation supports a concept that these vessels can be used as a potential route for reestablished arterial blood supply that would be necessary to facilitate the replacement of scar tissue by newly‐formed cardiac muscle.Support or Funding InformationNew Jersey Health Foundation
Myosin: Structure, Function, Regulation and Disease
Authors: Peckham Michelle , Parker Francine , Carrington Glenn , Giralt-Pujol Marta , Casas-Mao David , Scarff Charlotte 
Published: April 2020

The human myosin superfamily is made up of 12 different classes of myosin. Class 2 is the largest, and is made up of 13 genes. Of these, 9 are expressed in striated muscle and the remaining 4 in non‐muscle cells and smooth muscle. All of these myosins form filaments. In striated muscle, the filaments contain precisely 294 molecules. In contrast, non‐muscle myosins form much shorter filaments (about 30 molecules). The activity of all of these myosins is regulated by an interaction of the heads (comprising the motor domain and lever) with the first part of the coiled coil (subfragment 2, S2) to form the so‐called ‘interacting heads’ motif. Non‐muscle and smooth muscle myosin heads are additionally regulated by an interaction of the head with the tail forming region (light meromyosin, LMM).We use a combination of cell biology, and structural approaches, including electron microscopy to understand the effects of disease‐causing mutations in S2 and in LMM. Mutations in striated myosins (MyHCβ, MyHC2a) cause cardiac and skeletal muscle diseases respectively, although mutations in the distal LMM region of MyHCβ are predominantly associated with skeletal muscle disease. Mutations in non‐muscle myosin (NM2A) cause a range of bleeding disorders. We determine how specific mutations affect the myosin’s ability to form filaments, and how they affect formation of the regulated state of the myosin. For example, we use circular dichroism to determine if specific mutations affect the secondary structure of LMM. We use negative stain electron microscopy to evaluate filament formation by the LMM (fused to GST, to prevent paracrystal formation), and we use GFP‐tagged MHC to evaluate the ability of each mutant to incorporate into filaments in cultured cells, myotubes and adult rat cardiomyocytes (Parker et al. (2018) J. Mol. Biol). Together with additional structural studies, we are starting to understand how specific mutations affect myosin function, to gain a better understanding of the disease process.Support or Funding InformationThis research is supported by the Medical Research Council, MR/R009406/1 and MR/S023593/1 to MP.
A conserved role of CBP/p300 in mitochondrial stress response and longevity
Authors: Auwerx Johan , Li Terytty Yang 
Published: April 2020

Caenorhabditis elegans respond to mitochondrial stress by activating multiple stress defense pathways including the mitochondrial unfolded protein response (UPRmt). Here we show that the inhibition of CBP‐1, the C. elegans ortholog of mammalian acetyltransferases CBP/p300, either through RNA interference or by pharmacological inhibitors, robustly attenuates mitochondrial perturbation‐ induced UPRmt activation and lifespan extension. Mechanistically, CBP‐1‐mediated histone acetylation acts in conjunction with histone demethylation to transcriptionally induce a broad spectrum of UPRmt genes. In mouse and human, transcript levels of CBP/p300 systematically correlate with the expression of UPRmt genes and mitochondrial modules, as well as with longevity. Furthermore, loss‐of‐function of CBP/p300 or their pharmacological inhibition disrupts the activation of the UPRmt, the mitochondrial network and energy homeostasis in mammalian cells. These results highlight an evolutionary conserved epigenetic mechanism that protects mitochondrial function and regulates longevity through the histone acetyltransferases CBP/p300.Support or Funding InformationThis work was supported by grants from the Ecole Polytechnique Fédérale de Lausanne and the European Research Council (ERC‐AdG‐787702). T.Y.L. was supported by the “Human Frontier Science Program” (LT000731/2018‐L).
Microbiome Catabolites as Novel Modulators of Cellular Glucose and Energy Metabolism
Authors: Williamson Gary , Houghton Michael , Kerimi Asimina 
Published: April 2020

The gut microbiome supplies bioactive metabolites such as butyrate from dietary fiber to enhance the function of skeletal muscle mitochondria, and influences metabolism during exercise. Trained athletes have a distinctly different microbiome compared to sedentary individuals, since the composition and activity of the microbiota is in turn affected by muscle fitness.The gut microbiota regulate mitochondrial biogenesis through modulation of PGC‐1α, SIRT1 and AMPK, and the mitochondria regulate the gut microbiota by modulating mucosal immune responses and intestinal barrier function. Skeletal muscle is the main site of postprandial glucose disposal; the glucose transporter GLUT4 is activated by insulin by translocation to the plasma membrane from internal vesicles. In diabetic and pre‐diabetic insulin‐resistant tissues, this GLUT4 translocation is compromised. Therapeutic strategies against insulin resistance, including exercise and diet‐related interventions, aim to lower postprandial glycemia at least partly by restoring skeletal muscle glucose uptake and enhancing metabolism.Dietary phenolics can be considered as prebiotic‐type molecules, including precursors present in the unbound form as well as covalently‐attached to dietary fiber such as in cereal brans. After microbial action, many potentially bioactive phenolics are released and absorbed in the colon. These microbial products, once absorbed, interact with other tissues, including muscle and adipose cells, and stimulate the uptake of glucose by several mechanisms. For example, the microbial metabolite isovanillic acid sulfate (IVAS) stimulated a dose‐dependent increase in glucose transport in human LHCN‐M2 muscle cells through a GLUT4‐ and PI3K‐dependent mechanism. IVAS also upregulated GLUT1, GLUT4 and PI3K p85α protein, and increased phosphorylation of Akt.The stimulation of glucose uptake and metabolism provides a novel link between the diet, gut microbiota and skeletal muscle energy utilization.
Acetylation of Cytidine in Messenger RNA Regulates Translation
Authors: Oberdoerffer Shalini , Arango Daniel , Hosogane Masaki , Sturgill David , Yankova Ellie , Kouzarides Tony , Tzelepis Kostas 
Published: April 2020

Modifications within RNA nucleobases have the potential to impact all aspects of post‐transcriptional mRNA metabolism. We recently identified N4‐acetylcytidine (ac4C) as a novel modification in mRNA that is catalyzed by the enzyme NAT10. The majority of ac4C sites were found to occur within coding sequences with a general 5′ localization bias. Comparative profiling of ac4C substrate mRNAs in the presence or absence of NAT10 demonstrated a direct role for acetylation in promoting mRNA stability through enhanced translation efficiency. However, transcriptome‐wide mapping of ac4C also revealed an increased occurrence within 5′ untranslated regions (UTRs), wherein a clear relationship to gene expression was not observed (Arango et al., Cell, 2018). Here, we directly examine the function of 5′UTR acetylation in mRNA expression and uncover a putative role in the regulation of translation initiation. Ribosomal footprinting analysis performed in the presence of the initiation inhibitor harringtonine demonstrated an increased prevalence of 80S ribosomes at annotated 5′UTRs marked by overlapping acetylation. Detailed analysis in cancer relevant cellular models supports a role for ac4C in alternative initiation at well‐established non‐AUG translation start sites of known oncogenes. Altogether, our results identify a location specific role for ac4C in mRNA translation wherein coding sequence acetylation promotes translation elongation, while 5′UTR acetylation regulates translation initiation to support pro‐proliferative protein isoforms. These findings illustrate the powerful and diverse impact of the epitranscriptome on mRNA regulation.Support or Funding InformationThis work is supported by the Intramural Research Program of the NIH, the National Cancer Institute and The Center for Cancer Research.
The Role of the O‐GlcNAc Transferase Interactome in X‐linked Intellectual Disability
Authors: Wells Lance 
Published: April 2020

Both Ser/Thr phosphorylation and O‐linked beta‐N‐acetylglucosamine (O‐GlcNAc) modification occurs on thousands of nuclear and cytosolic proteins. The forces of evolution have resulted in gene duplication and divergence of substrate recognition for kinases to gain specificity. However there is only one mammalian gene encoding the O‐GlcNAc transferase (OGT). Missense mutations in this gene have been established as being causal for X‐linked intellectual disability. Working with collaborators, we have characterized several of the resulting OGT variants and found little to no defects in global O‐GlcNAc levels, enzyme kinetics, or stability. This led us to consider how is OGT regulated and targeted to substrates and whether the XLID associated variants had defects in protein‐protein interactions.It has been suggested that the N‐terminal tetratricopeptide repeat (TPR) domain of OGT, where many XLID variants occur, rather than its C‐terminal catalytic domain, is responsible for OGT substrate selection by targeting to specific complexes and subcompartments of the cell. To assess the role of the TPR domain in OGT protein interaction, we generated a BioID proximity proteomics system. Utilizing a fusion protein, TPR‐BirA*, has allowed us to identify more than 100 OGT TPR domain‐interacting proteins. We also utilized BioID to identify proteins that fail to interact with the OGT XLID variants and are in the process of identifying cell type specific differences in protein:protein interactions of the variants focusing on neural lineages. This screen to date has already produced several candidates known to be involved in neurodevelopmental disorders that represent potential mechanisms for how OGT mutations could lead to XLID. These candidates set the stage for future work elucidating the function of specific OGT TPR interactions and how they contribute to OGT function and pathophysiology.Support or Funding InformationThis work is supported in part by NICHD/NIH (R21HD097652)
Genetic and acquired heterotopic ossification are driven by a self‐amplifying positive feedback loop of Hedgehog signaling
Authors: Yang Yingzi 
Published: April 2020

Heterotopic ossification (HO), which refers to extra‐skeletal pathological bone formation, occurs as a common complication after injury or in genetic disorders. However, limited by poor understanding of the underlying cellular and molecular mechanisms, there is currently no effective treatment and surgical eviction often results in recurrence. We have found that in both genetic and injury‐induced HO, activated ectopic expression of a hedgehog ligand drives HO progression by forming a positive feedback loop that results in non‐cell‐autonomous and self‐propagation of osteoblast differentiation of wild type cells. In mouse models of progressive osseous heteroplasia (POH), a human disease caused by null mutations in GNAS that encodes Gαs, we found previously that Hedgehog signaling was activated, which is both necessary and sufficient to induce HO. We recently further found that progressively expanded ectopic bone was formed by progressively recruited wild type cells. Mechanistically, the Gnas−/− mesenchymal cells differentiate into osteoblasts and recruit wild type cells to form bone by activating expression of Hedgehog ligands. Secreted Hedgehog further induces Hedgehog expression and osteoblast differentiation in surrounding wild type cells. This self‐propagating positive feedback loop is both necessary and sufficient for ectopic bone formation and expansion and can act independently of Gαs. Importantly, Hedgehog activation was also found in fibrodysplasia ossificans progressive (FOP), Achilles tendon puncture (ATP)‐induced HO mouse models and in human HO samples. Genetic removal of Hedgehog abolished HO not only in POH, but also in FOP and aquired HO mouse models. We therefore identify a Hedgehog‐driven, self‐amplifying osteoblast differentiation as a common cellular and molecular mechanism underlying HO initiation and expansion. Our work highlights the importance of rare genetic disease studies in identifying a shared core pathological mechanism underlying a class of diseases. Our results further suggest that the Hedgehog pathway is a promising new therapeutic target for HO without affecting the normal bone.Support or Funding InformationR01DE025866 from NIDCR, R01AR070877 from NIAMS