bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of the Novel Compound SMTP‐27 in a Mouse Model of Diabetic Kidney Disease
Authors: Shibata Keita , Yasuda Erika , Nishinaga Tomoka , Karasawa Sarara , Yamaguchi Tomoaki , Hashimoto Terumasa , Hasumi Keiji , Nobe Koji 
Published: April 2020

ObjectiveDiabetic kidney disease (DKD) is the most common complication of diabetes mellitus and one of the primary causes of end‐stage renal disease in many countries. Although several candidate substances have shown efficacy against DKD, no effective clinical treatment methods have been established for preventing the progression of DKD. It was recently noted that the occurrence of oxidative stress, one of the contributors to the pathogenesis of DKD, is closely related to inflammatory cell mobilization, a process that increases inflammation by inducing the production of cytokines such as interleukin‐1β and tumor necrosis factor‐α. The present study aimed to evaluate the effect of Stachybotrys microspora triprenyl phenol‐27 (SMTP‐27), which is reported to have an anti‐inflammatory effect, in a mouse model of DKD.MethodsThe right kidneys of male type 2 diabetic db/db mice (6 weeks) were removed through small flank incisions under isoflurane anesthesia to induce DKD. Male C57BL/6J mice of the same age, subjected to the same surgery, were used as the control group. DKD mice are randomly assigned to the vehicle‐treated group, SMTP‐27‐treated group (30 mg/kg), or metformin‐treated group (300 mg/kg). They were treated from six to sixteen weeks of age: SMTP‐27 injections were administered intraperitoneally once every two days, and metformin was orally administered daily. Urinary albumin (Ualb), serum creatinine (Scr), and creatinine clearance (Ccr) were measured to evaluate renal function. In addition, histological examination of an excised kidney was performed by hematoxylin‐eosin staining and periodic acid–Schiff staining to evaluate tubular regeneration and glomerular sclerosis.ResultsUalb and Scr levels were significantly higher and Ccr levels were significantly lower in type 2 diabetic db/db mice than in C57BL/6J mice. Moreover, tubular regeneration and glomerular sclerosis were significantly higher in db/db mice than in C57BL/6J mice. In the type 2 diabetes model, metformin only improved Ualb with causing antihyperglycemic effects; in contrast, SMTP‐27 significantly improved Ualb, Scr, and Ccr without inducing antihyperglycemic effects. In addition, SMTP‐27 reduced tubular regeneration, whereas metformin did not. Neither drug reduced glomerular sclerosis.ConclusionOur results showed that SMTP‐27 improved DKD without inducing antihyperglycemic effects. Thus, SMTP‐27 is a potential novel therapeutic agent for the treatment of DKD. In future studies, we plan to investigate the mechanism of action of SMTP‐27 against DKD.Support or Funding InformationThis study was supported in part by the Japan Society for the Promotion of Science KAKENHI (Grant Number 18K14958, awarded to KS; Grant Number 26460346, awarded to KN). SMTP‐27 was generously donated by TMS Co., Ltd. (Tokyo, Japan).
Correlation of Bone Density in Semi‐Aquatic and Aquatic Animals with Ecological and Dietary Specializations
Authors: Crowell Madelyn Galimore , Rahmat Sulman , Koretsky Irina 
Published: April 2020

A successful transition from a terrestrial to an aquatic environment requires the acquisition of unique adaptations that fit the distinct habitat. Pachyosteosclerosis is a combination of pachyostosis (thickening of cortical bone) and osteosclerosis (thickening of medullary bone). This accumulation of bone increases the density and weight of the animals that exhibit these characters. Pachyosteosclerosis is commonly found in aquatic and semiaquatic animals such as sirenians (sea cows), odobenids (walruses), otariids (sea lions), phocids (true seals) and cetaceans (whales). Increased bone density occurred early in the transition from a terrestrial to a marine environment, present before many of the other morphological characters such as flukes, flippers and fins and behavioral characters such as oscillatory swimming associated with aquatic life appear. Pachyosteosclerosis helps to counteract buoyancy, allowing taxa to remain submerged longer in order to feed while expending little energy. This is clearly demonstrated in sirenians, which are known to feed on sea grasses in shallow waters near the coastline. In most other aquatic mammals, such as modern cetaceans, pachyosteosclerosis is followed by an osteoporosis‐like bone lightening for increased swimming speeds that allows for the active hunting of fast‐moving prey. Pinnipeds live in a wide range of habitats (from cold to warm waters, from marine to fresh water) and demonstrate varying feeding mechanisms, ranging from filter feeding to bottom feeding to catching fast prey. Increased bone density is seen in multiple species of seals in different geological ages from the Miocene (~ 23mya) to present. The morphological and ecological significance for seals with thicker bones is that they swim slower and hunt in shallower water, while seals with lighter bones swim faster and hunt fast moving prey. Bone microstructural disparity allows different species of seals to successfully live in sympatric habitats due to their ecological and dietary specializations. Bone density is one vital character that can be used to predict the specific ecological niche and feeding preference for pinnipeds. Some early hominids, such as Homo erectus, have been shown to have increased density in the bones also. These heavier, thicker bones would make it easier for early Homo to hunt in coastal waters for littoral food sources and would compensate for the lack of stability from bipedalism.Support or Funding InformationFunding Provided by Torres Advanced Enterprise Solutions LLC and Just‐Julian Fellowship
Enhancing Strabismus Education through Interactive Learning Multimedia
Authors: Aziz Rem , Moss Heather , Claire Sheldon , Krebs Claudia 
Published: April 2020

The objective of our project was to create an interactive online educational module that integrates biomechanics of the eye with its underlying anatomy to allow for a comprehensive understanding of pediatric strabismus and its clinical detection to prevent amblyopia.Amblyopia is the leading cause of monocular vision loss in the pediatric population, affecting 3–5% of children. Untreated, it leads to irreversible visual impairment in an otherwise structurally normal eye and can have significant effects on quality of life that impact self‐esteem and restrict career opportunities due to loss of stereopsis. Majority of cases are caused by strabismus, a condition resulting in the ocular misalignment of the eye. Early intervention significantly improves vision outcomes and psychosocial well‐being of the patient, however requires prompt and skilled detection. The pediatric eye examination can be inherently challenging, particularly considering the low emphasis on ophthalmology teaching in medical school curricula. Primary care residents and undergraduate medical student trainees often report low levels of comfort performing screening eye examinations and managing common pediatric ophthalmological presentations. Integration of open educational resources such as interactive clinical skills modules can effectively advance ophthalmology education and promote prompt detection of pediatric strabismus, with the goal of mitigating serious ophthalmic complications and improving overall patient care.To effectively address these educational challenges, we have developed an innovative online module that correlates ocular anatomy to biomechanical mechanisms, and provides practical guidelines to clinical examination. The module focuses on the pediatric eye examination, evaluating for amblyopia & strabismus, and was created through an international collaboration with experts in anatomy, education, and neuro‐ophthalmology to optimize content delivery and integrate clinical relevance. It offers a variety of interactive activities to engage student learning and concludes with a set of virtual cases entailing simulated clinical examination to assess acquired knowledge. Critical feedback will be collected using a student experience survey at the beginning and end of the module to solicit response regarding effectiveness of content delivery, preference of educational media, and comfort conducting a strabismus clinical examination.This international effort aims to significantly improve confidence performing clinical examination, guide prompt amblyopia detection in the pediatric population, and prevent development of its irrevocable complications.
SPARC: Parameters of Electrical Excitation and Block of the Rat Vagus Nerve
Authors: Pelot Nicole A. , Grill Warren M. 
Published: April 2020

There is growing interest in bioelectronic medicines, where diseases are treated through electrical stimulation and block of the peripheral autonomic nervous system. Given the widespread connections of the vagus nerve from the brainstem to most truncal organs, applications include treating epilepsy, depression, obesity, heart failure, and rheumatoid arthritis. However, designing and programming the parameters of bioelectronic medicines require understanding the biophysical responses of small myelinated and unmyelinated autonomic fibers. Using in vivo electrophysiology, we quantified strength‐duration properties, activity‐dependent slowing (ADS), and responses to kilohertz frequency (KHF) signals for rapidly conducting (>2 m/s) and slowly conducting (<2 m/s) fibers in the rat vagus nerve.We stimulated the cervical vagus nerve and recorded compound action potential (CAP) input‐output curves from the abdominal vagus nerve for pulse widths from 20 to 1000 μs. Thresholds were largest for the slowest fibres (0.5 to 1 m/s), especially at shorter pulse widths. Fits to the data using standard strength‐duration equations were qualitatively similar, but the estimates of chronaxie and rheobase varied substantially.ADS describes the slowed conduction in peripheral axons resulting from persistent low frequency activity. Using a novel cross‐correlation CAP‐based analysis method, we measured ADS of ~2.3% after 3 min of 2 Hz stimulation, approximately constant across fiber conduction speeds. This is comparable to that reported for sympathetic efferents in somatic nerves, but much smaller than ADS in cutaneous nociceptors. We found greater ADS with higher stimulation frequency and non‐monotonic changes in conduction speed in select cases.KHF signals can block neural conduction in peripheral axons, and we used CAP recordings to quantify the effects of KHF signals from 10 to 80 kHz on small autonomic fibers. Block thresholds were higher for more slowly conducting fibers, and block thresholds increased monotonically with frequency, in contrast to published findings indicating that block thresholds of unmyelinated axons vary non‐monotonically with frequency. Further, there are varied reports on the time for recovery of neural conduction after KHF block; we found that the carryover effect could last tens of seconds following 25 s of KHF signal.The quantification of mammalian autonomic nerve responses to conventional and kilohertz frequency signals provides essential information for development of bioelectronic medical devices and for understanding mechanisms of action.Support or Funding InformationThis work was supported by Fulbright Canada (15122811), the Natural Sciences and Engineering Research Council of Canada (PGS M‐425353‐2012 and PGS D3‐437918‐2013), and Duke University (University Scholars Program, James B. Duke Fellowship, and Pratt School of Engineering Faculty Discretionary Fund).
Ageing signalling pathways: Quantifying the effects of protein interactions
Authors: Sadria Mehrshad , Layton Anita 
Published: April 2020

Cells adapt their metabolism and activities in response to signals from their surroundings, and this ability is essential for their survival in the face of environmental changes. In mammalian tissues a deficit of these mechanisms is commonly associated with cellular aging and degenerative diseases related to aging, such as cardiovascular disease, cancer, immune system decline, and neurological pathologies. Several proteins have been identified as being able to respond directly to energy, nutrient, and growth factor levels and stress stimuli in order to mediate adaptations in the cell. In particular, mTOR, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and in the mechanisms and metabolism of ageing of mammals. Given that the ageing process remains to be completely understood, the goal of this study is to gain insights into the interactions of the proteins in the ageing‐related signalling pathways, and how those interactions may impact longevity and related diseases. To achieve that goal, we have developed a computational model of ageing signalling pathways. Specifically, the insulin growth factor/mTOR pathway and the sirtuin pathway are represented. The model simulates the interactions among Akt, mTORC1, AMPK, NAD, and SIRT, and predicts their dynamics. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., resveratrol and curcumin), calorie restrictions, and chronic stress, and assess their functional implications on longevity and ageing‐related diseases.Support or Funding InformationThis research was supported in part by the Canada 150 Research Chair program.
Muscle Stem Cell Depletion Blunts Skeletal Muscle Adaptation to Weighted Wheel Running
Authors: Dupont Alec Marc , Englund Davis , McCarthy John , Peterson Charlotte 
Published: April 2020

Satellite cells, the resident muscle stem cell, are not required for short term skeletal muscle hypertrophy in mice when subjected to mechanical overload via synergist ablation, however, long term growth is blunted. This study aimed to further investigate the effect of satellite cell depletion on muscle adaptation using Progressive Weighted Wheel Running (PoWeR). We hypothesized that satellite cell depletion would reduce the adaptive response of skeletal muscle to the training stimulus. The Pax7‐DTA mouse model was used to deplete satellite cell content in adult skeletal muscle. PoWeR training involved adding weight to the running wheel of the mice incrementally over the 8‐week training period. Hindlimb muscles were excised at the 8‐week time point, and the plantaris was immunohistochemically analyzed. PoWeR induced an oxidative shift in fiber type distribution and increased muscle fiber cross sectional area (CSA). However, this increase in fiber CSA was blunted in mice without satellite cells. To investigate the blunted growth in satellite cell‐depleted mice, the plantaris was analyzed for extracellular matrix content and capillarization. We found that neither extracellular matrix buildup nor capillary density differed between satellite cell replete and depleted groups following PoWeR. These findings suggest that loss of satellite cells reduces the capacity for hypertrophy in response to PoWeR, but this was not due to excessive extracellular matrix accumulation. Further, satellite cells were not required for a robust fiber type shift in response to PoWeR training.Support or Funding InformationThis work was funded by the American Physiological Society’s UGSRF program and a grant from the National Institute of Health to Dr. Charlotte Peterson and Dr. John McCarthy (AR060701).
Circulating microparticles induced neutrophils chemotaxis through FOXO3a and the inhibiting role of dexmedetomidine in cardiorenal syndromes
Authors: Ou Jing-song , Yuan Hao-Xiang , Chen Cai -Yun , Li Yu-Quan , Li Yan , Xu Kang-Qing , Ou Zhijun 
Published: April 2020

RationaleCardiorenal injury, also called cardiorenal syndromes, are the common complications in cardiac surgery. We previous demonstrated that circulating microparticles from patients with valvular heart disease (vMPs) and cardiac surgery contained inflammatory components and inhibited endothelium‐dependent vasodilation. However, the effects of vMPs on cardiorenal syndromes are unclear. Neutrophils chemotaxis plays an important role in cardiorenal syndromes. In addition, dexmedetomidine (DEX) could reduce cardiorenal syndromes in cardiac surgery. However, the effect of DEX on vMPs and neutrophils chemotaxis was unknown.ObjectiveTo investigate the effects and mechanisms of vMPs on heart and kidneys and the effect of DEX on vMPs and neutrophils chemotaxis.Methods and ResultsCirculating MPs were isolated from health subjects (nMPs) and patients with VHD. vMPs stimulated the C‐X‐C motif chemokine 4(CXCL4) and C‐C motif chemokine 5(CCL5) released from cultured human umbilical vein endothelial cells (HUVECs) and induced neutrophils chemotaxis. Silencing CXCL4 or CCL5 inhibited vMPs‐induced neutrophils chemotaxis. vMPs increased the expression of forkhead box proteins 3a (FOXO3a) and decreased the phosphorylation of AKT and FOXO3a, resulting in the transport of the FOXO3a from cytoplasm to nucleus and the activation of FOXO3a signaling pathway. Silencing FOXO3a reduced the vMPs‐induced CXCL4 and CCL5 as well as neutrophils chemotaxis. vMPs enhanced the levels of CXCL4 and CCL5 in plasma, the neutrophils accumulation, but inhibited the phosphorylation of AKT and FOXO3a and increased FOXO3a, leading to the activation of FOXO3a signaling pathway in the heart and kidneys, which could be inhibited by pretreated with DEX in vivo. Pretreated with DEX also reduced vMPs‐induced CXCL4 and CCL5 and neutrophils chemotaxis in cultured HUVECs.ConclusionvMPs induced CXCL4‐CCL5 to stimulate neutrophils infiltration in the heart and kidneys, which could be inhibited by DEX via FOXO3a signaling pathway. Our findings present a novel mechanism by which vMPs induce cardiorenal injury and may provided a new basis for the application of DEX in reducing cardiorenal syndromes in cardiac surgery.Support or Funding InformationThis research was financially supported by the National Natural Science Foundation of China (Grants 81670392, 81600382, 81770241, 81830013, 81970363 and Distinguished Young Scholar Grant 81325001), International Cooperation project (2015DFA31070) from the Ministry of Science and Technology of China, Guangdong Natural Science Fund Committee (Grant 2015A030312009), the Changjiang Scholars Program from the Ministry of Education of China, the Sun Yat‐sen University Clinical Research 5010 Program, Program of National Key Clinical Specialties.
The Catalytic Features of IDH1 Mutations Can Drive Neomorphic Activity, Phenotype Severity, and Inhibitor Binding
Authors: Sohl Christal D. , Matteo Diego Avellaneda , Wells Grace , Luna Lucas , Upadhye Viraj , Quichocho Giovanni , Chambers Jennifer M. , Miller Wade , Scott David , Schiffer Jamie M. 
Published: April 2020

Isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) balance metabolite levels by catalyzing the reversible NADP+‐dependent oxidation of isocitrate to a‐ketoglutarate (αKG). Mutations in these enzymes drive many cancers such as gliomas, leukemias, and chondrosarcomas by ablating the normal reaction and, critically, by catalyzing a neomorphic reaction: the NADPH‐dependent reduction of αKG to D‐2‐hydroxyglutarate (D2HG), an oncometabolite. Most mutations affect residue R132, and the structural and chemical diversity of the mutants observed in patients, including R132H/C/G/L/S/Q, is striking. The most common mutants in IDH1 and IDH2 serve as bona fide therapeutic targets, with selective mutant IDH inhibitors currently in the clinic. Using steady‐state kinetics methods, we recently found that the catalytic efficiency of both the normal and neomorphic reactions vary widely depending on the mutation at residue 132. Importantly, we have identified one mutant, R132Q IDH1, that preserves some wild type activity, catalyzes very highly efficient D2HG production both in biochemical and cellular models, and is resistant to allosteric mutant IDH1 inhibitors. We also show intriguing evidence that the catalytic efficiency of D2HG production appears to play a role in dictating the intensity of cellular phenotypes, allowing us to relate catalytic profiles to cancer phenotype severity. Finally, using molecular dynamics simulations and structural methods, we identified an interesting pathway of water molecules that may help drive inhibitor selectivity in mutant IDH1. By establishing the molecular mechanisms of tumor‐driving IDH mutant catalysis and inhibition, we can generate tools for predicting patient prognosis and inhibitor response, and ultimately identify new targets and handles for drug design.Support or Funding InformationThis work was funded by a Research Scholar Grant, RSG‐19‐075‐01‐TBE, from the American Cancer Society (C.D.S.), National Institutes of Health R00 CA187594 (C.D.S.), U54CA132384 (SDSU) & U54CA132379 (UC San Diego), MARC 5T34GM008303 (SDSU), and IMSD 5R25GM058906 (SDSU), as well as the California Metabolic Research Foundation (SDSU).
Extracellular interaction between Neurotrophic factor‐α1 and HTR1E serotonin receptor promotes cell survival
Authors: Sharma Vinay Kumar , Xuyu Yang , Sanchez Daniel-Saiz , Kim Soo-Kyung , Goddard William A. , Loh Y. Peng 
Published: April 2020

Neurotrophic factor α1 (NFα1), classically known as carboxypeptidase E (CPE) has a non‐enzymatic role in the survival of neurons and cancer cells via binding to a putative receptor. We have identified 5‐Hydroxy tryptamine receptor 1E (HTR1E), a serotonin receptor with unknown function, as a binding partner that interacts with NFα1/CPE extracellularly to mediate cell survival. Co‐immunoprecipitation using a human LN18 cells and pull‐down assay with NFα1/CPE and HTR1E expressed in HEK293 cells confirmed interaction of these two molecules. 125I NFα1/CPE binding studies demonstrated saturable, high affinity binding to HTR1E. Molecular docking studies revealed the surface interaction between NFa1/CPE and HTR1E via 3 salt bridges, further stabilized by hydrogen bonding. We also found that HTR1E was able to activate ERK/CREB signaling upon treatment with NFα1/CPE. Pretreatment of HTR1E stable cells with NFα1/CPE followed by H2O2‐induced oxidative stress prevented a decrease in pro‐survival protein BCL2 and reduced cytotoxicity. SiRNA knock‐down of HTR1E in U118 glioblastoma cells resulted in significant inhibition of these cancer cells survival. Immunocytochemical analysis of human hippocampus indicated co‐expression of HTR1E with NFα1/CPE in CA1‐3 and dentate gyrus, and cellular co‐localization at the cell membrane in CA3 neurons. This study has uncovered a novel role for HTR1E as a binding partner for NFα1/CPE, and their interaction activates the ERK‐CREB‐BCL2 pathway to promote cell survival.Support or Funding InformationDivision of intramural research, NICHD, NIH, Bethesda, MD, USA