bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of cranial neural crest cell fate by Irf6 and Twist1 interaction
Authors: Fakhouri Walid D. , Bertol Jessica Wildgrube , Xie Victoria K. , Johnston Shelby , Hubka Kelsea , Keuls Rachel , Parchem Ronald J. , Farach-Carson Mary C. 
Published: April 2020

A wide variety of common craniofacial birth defects and pediatric cancers arise from errors in the development of cranial neural crest cells (CNCC) that give rise to craniofacial skeletal and peripheral nervous systems. Identification of the genetic and environmental factors that regulate cell fate of CNCCs is crucial for uncovering the causes behind craniofacial disorders. Our lab has identified a dual‐transcription factor pathway that regulates CNCCs during EMT and migration. Initially, we identified a causative mutation in a TWIST1 binding site within an Interferon Regulatory Factor 6 (IRF6) enhancer in a multi‐generational family affected with syndromic cleft lip and palate called Van der Woude syndrome. Our subsequent animal work has shown that Twist1 and Irf6 genetically interact during early craniofacial development, and that the compound heterozygotes exhibit craniofacial abnormalities. We recently demonstrated that Irf6 is required for neural tube and CNCC development and that it interacts with Twist1 during EMT and migration of CNCCs. We also showed that TWIST1 is highly phosphorylated in CNCCs and its phosphorylation is crucial for regulating Irf6 and potentially miR10 family members in CNCC‐derived craniofacial tissues. Our recent in‐vivo and neural tube explants using dual fluorescent cell tracing system showed that Twist1 conditional knockout (CKO) in CNCCs significantly reduced cell delamination and disrupted EMT. The detached Twist1 CKO in CNCCs retained their epithelial signatures and migrated as clusters of epithelial‐like cells over significantly shorter distances. Finally, Twist1 phospho‐incompetent mice for two serine residues were recently generated to determine their impact on TWIST1 activity. Our preliminary results showed that Twist1S68A/S68A phospho‐mutant mice have craniofacial bone defects and forebrain hemorrhage.Support or Funding InformationUTHealth start‐up funds and a small grant from theRolanette and Berdon Lawrence Bone Disease Program of Texas
DNA Methylation Markers in the Diagnosis and Prognosis of Common Leukemias
Authors: Li Oulan , Yu Meixing , Zheng Lianghong , Luo Huiyan , Wei Wei , Li Zhihuan , Jiang Hua , Li Gen 
Published: April 2020

An effective and accurate diagnostic method for leukemia has not yet been developed. Using genome‐wide methylation profiling and machine learning methods, we evaluated the utility of CpG methylation status to differentiate blood from patients with acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML) from normal blood. We constructed a diagnostic prediction model that can differentiate ALL and AML blood from normal blood as well as ALL blood from AML blood with high diagnostic specificity and sensitivity by utilizing a CpG methylation panel. We then developed a methylation‐based survival classifier with 23 CpGs for ALL and 20 CpGs for AML that could successfully divide patients into high‐risk and low‐risk groups, with significant differences in clinical outcome in each leukemia type. These methylation markers have outperformed existing methods in their high sensitivity and specificity for diagnosis of ALL and AML, and have implications for the prediction of prognosis and treatment selection.Support or Funding InformationGuangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, ChinaUsing 11 markers, the methylation profile can differentiate subtype of leukemia and normal blood. Unsupervised hierarchical clustering and heatmap associated with ALL, AML and normal blood.Figure 1Methylation markers can predict five‐year overall survival of patients. A. AML training set (n=125); B. AML validation set (n=55); C. ALL training set (n=55); and D. ALL validation set (n=34).Figure 2
EVIDENCE‐BASED EXERCISE PROGRESSION ON THE DIABETIC PATIENT
Authors: Leon-Ariza Henry Humberto , Garcia-Ramos Andres Felipe , Padron-Ayala Antonietta , Rozo-Cespedes Laura , Reyes-Cruz Dario , Botero-Rosas Daniel Alfonso 
Published: April 2020

It is estimated that the worldwide prevalence of Type 2 Diabetes Mellitus by 2030 will be 522 million people, which generates a negative impact on the well‐being of the individual and population health. Within the fundamental pillars of the treatment are the changes in the lifestyle that includes physical exercise. Organizations such as the ADA (American Diabetes Association) and the ACSM (American College of Sports Medicine) suggest strength training 2 to 3 times per week, using weights, bands or machines at moderate to vigorous intensity and aerobic training 3 to 7 days, minimum 150 minutes a week with the same intensity. However, these recommendations are widespread and do not take into account the progression of the load.This work summarizes the progression of training that diabetic patients should have in order to optimize the results. It is suggested to combine the work of strength with resistance, which is related to better body composition. Training intensity should be progressively increased whenever possible, which is related to increased muscle sensitivity to insulin. The training volume should be progressively increased as well, which allows for a higher concentration of GLUT4 transporters, improving intracellular insulin signaling, and generating a reduction in plasma and intramyocellular free fatty acids that lead to better insulin sensitivity.Based on the preceding, the physiological proposal of progression includes: Performing resistance work during the first weeks of training and subsequently including endurance training until a concurrent type of training is achieved. Also, there should be an increase the training volume (total weight lifted and total covered distance ), and then increased the intensity, High‐Intensity Interval training can only be done until several weeks of adaptation are completed. Finally, the training frequency should also be increased progressively until ideally reaching seven days a week.Given the rapid physiological adaptation, the loads must be undulated, alternating the training variables, intensity, volume, time, and type of exercise, until reaching the objective. Therefore, based on the evidence, we propose in this article a dynamic training model for diabetic patients that could be implemented by physicians and corresponding health personnel.Dynamic training model for diabetic patientsFigure 1
A Novel Plug and Play Robotic Dynamometer to Assess Skeletal Muscle Contractile Function and Perform Plyometric Exercise in Live Mice
Authors: Narayan Neha , Charara Rhonda , Humbach Timothy , Schramm Dara , Teal Brittany , Winczner Kenneth J. , Pepin Marie E. , Roche Joseph A. 
Published: April 2020

OBJECTIVEOur goal was to develop a user‐friendly, all in one instrument, which can be used in longitudinal studies of mice, to assess contractile torque produced by the ankle dorsiflexor muscles and perform forced plyometric exercise on this muscle group.METHODSWe repurposed a commercial, STEM Education robotics kit, which contains a microcontroller, stepper motors and modular parts, to build a robotic dynamometer. We connected two stepper motors in parallel for optimal driving torque. The axle that connected the motors was linked in series to a torque cell and footplate. Through a commercial plug and play data acquisition device connected to a PC through a USB port, we were able to visualize real‐time data from the torque cell, and record data as needed. We wrote custom routines in the programming language of the robotics kit to perform four sets of ten stretch‐shortening plyometric contractions of the ankle dorsiflexors, at an angular velocity of 300 degrees/s, through a range of 90–160 degrees of plantar flexion and dorsiflexion. During ankle movement produced by the robotic dynamometer, the dorsiflexor muscles were tetanized with subcutaneous needle electrodes connected to an electrical stimulator. To test our rig, we studied four, healthy, 1‐yr old, male, C57BL/6J mice. We performed all testing and training of live animals under general anesthesia induced and maintained by inhaled isoflurane (2–5% to effect).RESULTSWe found that plyometric exercise performed on our dynamometer induced a significant loss of contractile torque immediately after exercise (2816 ± 222 mNmm before exercise versus 2046 ± 87 mNmm after exercise; *, p < 0.001). At 3 days post‐exercise, contractile torque was still lower than pre‐exercise levels (2322 ± 143 mNmm at Day 3; *, p = 0.002), but was significantly greater than immediate post‐exercise levels (#, p = 0.038). Histological studies (hematoxylin and eosin staining) of cross sections of the injured tibialis anterior muscle revealed that 9.6 ± 4 % of the cross sectional area was damaged (pale and disrupted cytoplasmic staining of muscle fibers).CONCLUSIONOur novel robotic dynamometer is suitable for assessing contractile function and performing forced plyometric exercise on living mice. Since our rig is made from a commercial STEM Education robotics kit, a plug and play data acquisition system, and other standard parts, it is not only user‐friendly, but is also modular in nature and therefore helps reduce machine to machine variability.Support or Funding InformationNIH R03HD091648 from NICHD and a FRAP award from EACPHS Wayne State University to JARContractile Torque and Histological DataFigure 1
Therapeutic Nrf2 Activation improves LV function in the cardiomyocyte‐specific GPER knockdown mouse
Authors: Groban Leanne , Sun Xuming , Hodge Hunter S. , Ferrario Carlos M. , Wang Hao 
Published: April 2020

BackgroundThe G protein‐coupled estrogen receptor (GPER) plays an important role in the maintenance of cardiac health partly via its link to anti‐oxidant and anti‐inflammatory pathways. The NLRP3 inflammasome is upregulated in hearts of mice with cardiomyocyte GPER gene deletion, and NLRP3 inhibition limits left ventricle (LV) dysfunction from cardiac GPER deficiency. Studies from others show that GPER mediates the inductive effect of estrogen on the transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2), the master regulator of detoxification and antioxidant systems. This in vivo animal study was designed to further confirm that lack of GPER signaling (from gene deletion or menopause) impedes Nrf2 activation, and in so doing contributes to ROS accumulation and inflammation in the cardiomyocyte. We hypothesize that chronic Nrf2 activation counteracts the adverse effects of cardiac GPER knockdown on LV function, irrespective of estrogen.MethodsMale GPER KO and WT littermates (7 months of age) were randomized to receive, via drinking water, either 8 weeks of oral treatment with the Nrf2 activator, dimethyl fumarate (KO‐DMF: n=5; WT‐DMF: n=5) at 30mg/kg/day, or its vehicle 0.08% methyl cellulose (KO‐VEH: n=5; WT‐VEH: n=5). At 9 months of age, echocardiographic indices of LV function (isoflurane anesthesia) were obtained prior to sacrifice. Data were analyzed by two‐way ANOVA for gene (GPER), treatment (DMF) and gene x treatment. P<0.05 was considered significant.ResultsSomatic characteristics (e.g. body weight, hair coat appearance) were not overtly affected by GPER knockdown nor DMF treatment. As reported previously, GPER gene deletion led to significant reductions in systolic function (% fractional shortening (FS)), myocardial relaxation (e′) and increases in filling pressure (E/e′) (gene effect: P<0.05). Chronic treatment with the Nrf2 activator significantly attenuated LV systolic dysfunction (treatment effect: P<0.05) and nearly normalized filling pressures (E/e′) in GPER KO without modifying the normal functioning heart of the WT (gene x treatment: P<0.05) (Figure
).ConclusionsThese data suggest that targeting the transcription factor Nrf2 may be a promising strategy to limit LV dysfunction as a result of cardiac oxidative stress and low‐grade inflammation from GPER deactivation (e.g., estrogen loss from ovarian extirpation or menopause).Support or Funding InformationHL051952 (CMF, LG) and AG033727 (LG)Figure 1
Differential Mesenteric Venous and Arterial Vascular Reactivity to Adenosine between Rats, Dogs, Mini‐pigs, and Human
Authors: Teng Bunyen , Mustafa S. Jamal , Teng Olivia , Muir William W. , Hamlin Robert L. 
Published: April 2020

It is well established that adenosine induces arterial vasodilation in various vascular beds. However, its effect on the venous circulation is still largely unknown. The splanchnic system receives approximately 25% of cardiac output (CO) and contains approximately 20% of total blood volume. Mesenteric (part of splanchnic system, o. d. 150–250 μm) arteries (MA) and their adjacent veins (MV) from rats, dogs, mini‐pigs and humans were isolated and mounted on a myograph (DMT Technology, USA). Vessels were preconstricted with 1 μM phenylephrine (PE) for arteries and prostaglandin F2α (PGF2α) for veins. Cumulative concentrations of 5’‐N‐Ethylcarboxamidoadenosine (NECA, 10−11 – 10−5 M), a non‐specific adenosine agonist, were applied and evaluated. Tension development was normalized to the tension induced by PE/PGF2α as %. NECA induced a concentration dependent arterial vasodilation in all 3 animals and human MA (Fig.
1). The effects were very similar in all 3 animals (maximum of 91.09±10.94% to 93.88±1.93%), however human responses were less pronounced (maximum of 59.14±4.61%). Interestingly, veins from all species responded to NECA very differently (Fig.
2). MVs from rats were the only vessels that constricted strongly in response to NECA (182.94±17.52% of pre‐constriction), which has not been previously reported (Figs.
2–
3). NECA induced vasodilation in MV from the other species varied. NECA induced vasodilation in MV from dogs were similar to MA at high concentrations (Fig.
6, 10−8 M and above). However, MV from mini‐pig (Fig.
5) and human (Fig.
6) responses were minimal (Fig.
2, maximum of 24.56±14.67% in mini‐pig and 33.54±9.61% relaxation in human) compared to 92.93±2.26% relaxation in dogs. In conclusion, although mesenteric arterial vascular reactivity responds similarly to adenosine among species, mesenteric venous vascular reactivity responses varied greatly to adenosine among species. MVs from rats were the only vessel constricted strongly in response to NECA. Caution is advised when choosing animal models for studying vascular reactivity.Figure 1Figure 2Figure 3Figure 4Figure 5Figure 6
Hepatoprotective Effect of Amygdalin (Vit B17) Against Phenolphthalein Induced liver injury; involvement of Glial fibrillary acidic protein (GFAP)
Authors: Elased Wael , Elbastawisy Yasser , Mohamed Hazem 
Published: April 2020

BackgroundPhenolphthalein (PTH) is an odorless and colorless chemical of laxative action and multiple side effects referred mostly to the production of free . It is primarily metabolized in the liver, hence its main adverse effects occur. Amygdalin (Vit B17) have antifibrotic, antiinflammatory and antitumor activities. The histopathological and functional changes in the liver together with the postulated protective hepatoprotective effect of Amygdalin were investigated in this study. Glial fibrillary acidic protein (GFAP) was considered as a marker of liver pathological changes.Material and methods30 adult male albino rats were divided into 3 groups. Group I was the control, group II received PTH alone and group III received both PTH and Amygdalin. At day 21, the levels of serum GFAP, total protein, total bilirubin and the activities of AST and ALT and liver hydroxyproline were estimated. The liver tissue samples were examined H&E, Masson’s trichrome and anti‐GFAP immunoreactive stains, and electron microscopic examination.ResultsThe liver enzymes, total bilirubin, hydroxyproline, and serum GFAP were significantly increased in group II compared with the control and in group III compared to group II. The total proteins were significantly decreased in group II in comparison to the controls and highly significantly increased in group III compared to group II. Group II showed disturbed hepatic architecture with extensive congestion, degeneration with inflammatory cell infiltration and marked collagen deposition. Group III showed preserved hepatic parenchyma and scanty inflammatory cells infiltration with decreased collagen. Group II had strong and diffuse immunoexpression and group III liver tissues were similar to the controls. The mean area percentage of GFAP immune staining showed a highly significant increased immunopositivity in group II when compared to the group I and a significant decsrease in group III compared to group II. The ultrastructure of hepatic stellate cells of group II showed dilated rough endoplasmic reticulum and loss of lipid droplets. Group III were similar to the controls.ConclusionAmygdalin treatment had a hepatoprotective effect against PTH induced liver injury and fibrosis and GFAP level could be a predictor for HSCs activation.Graphical AbstractFigure 1GFAP immune staining of the liver section of the control group (A) showing positive staining of the stellate cell and the endothelium of the sinusoids. The endothelium of the central veins is negatively stained. B: the PTH group showing strong and diffuse immunoexpression mostly perisinusoidal. C: The PTH‐Amg. group showed less marked dye expression. D: Diagram of the mean GFAP stained area percentage of the 3 animal groupsFigure 2
α‐Hederin induce gastric cancer cell death by blocking autophagic flux and triggering ER stress
Authors: Shen Weixing , Chen Haibo 
Published: April 2020

BackgroundGastric cancer (GC) is a prevalent refractory disease worldwide, especially in developing countries. α‐Hederin (α‐Hed) is a major active component of triterpenoid saponin isolated from Fructus Akebia, we found it showed significant anti‐proliferative and pro‐apoptotic activity against GC cells in a dose‐dependent manner.PurposeThis study aims to uncover the potential mechanism of α‐Hedin relation to anti‐GC activity.Study designCytotoxicity of a‐Hed to BGC‐823 and MGC‐803 cells was monitored by CCK8 and Annexin V‐FITC/PI apoptosis assay. Autophagic flux was examined by western blot analysis and the number of green fluorescent protein (GFP)‐LC3B puncta. ER Stress was also probed by western blot analysis. Cellular Reactive Oxygen Species (ROS) Detection Assay Kit was used to detect ROS level.ResultsGC cells growth was significantly inhibited and cell death was induced by α‐Hed in BGC‐823 and MGC‐803 cells. We subsequently discovered that α‐Hed promoted autophagosome formation by upregulatingthe expression of LC3‐II, Beclin‐1 and increasing GFP‐LC3B puncta formation. However, p62 was also upregulated, which was indicative of autophagic flux blockage. Comparing to α‐Hed treatment alone, the combinatorial treatment of α‐Hed and Bafilomycin A1 (Baf A1) did not obviously alter the expression of LC3‐II, suggest that α‐Hed blocked autophagic flux in GC cells. Nevertheless it was later discovered that expression of ATF6, IRE1α, and PERK were elevated after a‐Hed treatment in GC cells, which represents activation of three signaling arms of the Unfolded Protein Response. Besides, α‐Hed obviously increased cellular ROS levels in GC cells, and the ER stress‐regulated apoptosis related proteins such as CHOP, caspase‐12, and JNK also increased.ConclusionOur results suggest that α‐Hed induce GC cell death by influencing crosstalk between autophagy and ER Stress pathways.Support or Funding InformationNational Natural Science Foundation of China General Program (81973523)graphical abstractFigure 1
Molecular Basis for Acetyl‐CoA Production by ATP‐Citrate Lyase
Authors: Wei Xuepeng , Schultz Kollin , Bazilevsky Gleb , Vogt Austin , Marmorstein Ronen 
Published: April 2020

ATP‐citrate lyase (ACLY) synthesizes cytosolic acetyl‐CoA, a fundamental cellular building block. Accordingly, aberrant ACLY activity is observed in many diseases. Here we report cryo‐EM structures of human ACLY alone or bound to substrates or products. ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible actyl‐CoA synthetase homology (ASH) domains; CoA is bound at the CSH‐ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a phospho‐citryl‐CoA intermediate in the ASH domain. ACLY with acetyl‐CoA and oxaloacetate (OAA) products shows the products bound in the ASH domain, with an additional OAA in the CSH domain, which could function in ACLY autoinhibition. These structures, which are supported by biochemical and biophysical data, challenge previous proposals of the ACLY catalytic mechanism and suggest additional therapeutic possibilities for ACLY‐associated metabolic disorders.Support or Funding InformationU.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) ‐ R35 GM118090 [Marmorstein] U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) ‐ P01 AG031862 [Marmorstein]a, Two views of the ACLY structure with citrate and CoA. b, Enlarged view of CoA bound at the ASH–CSH interface, highlighting the corresponding cryo‐EM density. b and c, Close‐up view of CoA–protein interactions.d,Superimposition of ACLY bound with the extended CoA and bent CoA conformations. e, Relative enzyme activity of ACLY mutant constructs.Figure 1ACLY‐apo is suboptimal for productive CoA binding and that CoA can bind in an non‐productive conformation, but CoA cannot be converted to acetyl‐CoA until ATP and citrate substrates bind. The ACLY‐E599Q mutant in the presence of CoA, citrate and ATP reveals that a phospho‐citrate‐CoA intermediate forms prior to formation of acetyl‐CoA and OAA. Following cleavage of the phospho‐citrate‐CoA, the ACLY–OAA–acetyl‐CoA structure reveals that acetyl‐ CoA and OAA products are formed in the ASH domain.Figure 2
‘Multi‐∑QEME of Human Biodynamic Molecular Cell Sustainability in Psycho‐Neuro‐ Endo Processes’
Authors: Einstein George P. , Rahman Michael S. , Tulp Orien P. , Koynk Carla 
Published: April 2020

A healthy biological system, whether human or animal, is biodynamic aand must remain in a state of fine tuning with natural bio‐electromagnetic frequencies. A well‐tuned human body is capable of continuous adaptation. The application a controlled dose of modulated coherence quantum bio‐electromagnetic energy was investigated to determine subtle alterations within the properties of the tissue and internal organs, and bring their characteristic frequencies to corresponding levels of healthy tissues.

The Quantum of Electromagnetic wave emitted by modulated wave object and a bsorbed by a human body serves as the “messenger” so that any detrimental changes in the biological state of the body can be swiftly corrected by a natural repair of the degree of tuning‐in.Neuro‐Immune Stimulation Therapy involves the process of reversing the destructive effects of negative quantum energy within the body by the intentional transference of natural high frequency bio‐electromagnetic field resonance or positive quantum energy transference.

In this research ∑ Bio‐Psycho‐Neuro Quantum Energy model for naturally occurring heart‐brain phenomenon transfer represented in the third step of G. P. Einstein’s mathematical function for:
(3∑) Integrated Quantum Bio‐Energy Therapy (∑ IQBET) =
= ∑BEM‐Phy.QE × ∑BEM‐CHQE ×
∑BEM‐Psy.NQE
Our body serves as a receiver and can absorbed the specificBioelectromagnetic Energy for Dynamic Health.

Our Neuro ‐ Immune System has ability to accept and correctly interpret the subsequent sets of incoming signals. It can be carefully monitored and repaired when necessary through the Modulated Quantum Bio‐Electromagnetic Waves. At peak performance, the immune system is the primary defense against any disease.Dynamic Coherence of ∑ Quantum BEME Human Physiological SystemFigure 1Dynamic influences of biophotonic influences of food,nutrient, and water on the organisms master systems.Figure 2