bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Hydrodynamic Sensory System in the Skin of Cetaceans
Authors: Eldridge Sherri , Mortazavi Farzad , Rosene Douglas 
Published: April 2020

The skin’s sensory afferents have a myriad of varieties, tactile functions and specialized end‐organ receptors enabling species to exploit ecological niches. In typical vertebrate skin, from fish to humans, axons innervate relatively small discreet receptive fields, providing fine‐scale discrimination of texture or location of a pin prick.The cetacean suborders of Mysticeti (baleen) and Odontoceti (toothed) whales are fully‐aquatic glabrous‐skinned mammals, descendants of terrestrial hairy‐skinned arteriodactyls. Shaped by dynamic forces of the marine environment, nerves in the skin of cetaceans (whales, dolphins and porpoises) have adapted to assess critical aquatic information including current flow, swim turbulence, fish movement and boundary layers, as well as tactile touch, temperature and nociceptive stimuli. The anatomy of this highly‐derived sensory system was investigated in the flank skin of humpback whales (Megaptera novaeangliae, NMFS permits 14809, 15240) using antibodies against highly‐conserved molecules of physiologically‐distinct afferents identified in other mammalian species.Humpback whales inherited a genomically‐diverse suite of cutaneous axons, including low‐threshold mechanoreceptors that sense innocuous environmental signals, as well as high‐threshold thermoreceptors, chemoreceptors and nociceptors. However, during their transition from terrestrial artiodactyls into obligate marine mammals, axon morphology and organization diverged. Unlike other vertebrates, heterogenous axons in whale skin assemble into thread‐like bundles. These ensembles divide into smaller bundles, follow circuitous trajectories that form unpredictable shapes, and lack structural endings. Developmental research has shown that axonal growth in vertebrates is guided by the skin’s signaling molecules and external physical stimuli. As environmental forces are transmitted through the epidermis they convey stretch at the dermal‐epidermal junction, a mechanically unstable boundary where mechanoreceptors typically reside. While lacking these receptor endings, the whale’s polymodal axon bundles are anatomically positioned at the dermal‐epidermal junction to transduce signals. Similar axon bundles innervation is found in the odontocete Tursiops truncatus (bottlenose dolphins), evidence that this trait is a cetacean synapomorphy. The polymorphic nature of these sensory ensembles may be a tuning mechanism that targets maximal signal strength, detects functionally diverse information (hydrostatic or hydrodynamic forces) or compares attenuation of signal properties at different locations in the skin (frequency, angular velocity or amplitude).Hallmarks of a hydrodynamically‐tuned system include the capacity to detect and integrate multiple signal properties. In becoming secondarily aquatic mammals, cetaceans have reconstructed the vertebrate somatosensory plan.Support or Funding InformationNOAA Award #NA10SEC4810008.
Neuroinflammation in Alzheimer’s Disease: Friend or Foe?
Authors: Scuderi Caterina , Facchinetti Roberta , Steardo Luca , Valenza Marta 
Published: April 2020

Neuroinflammation is part of the complex immune response within the central nervous system (CNS), whose details have been partially elucidated. The CNS immune response involves elements carried from the periphery and resident elements, mainly represented by glial cells. These cells drive neuroinflammation, which can be roughly defined as an articulated physiological response characterized by the production of a plethora of inflammatory mediators that alter the microenvironment. Growing evidence shows roles for neuroinflammation in the aging brain both in healthy and pathological conditions, including Alzheimer’s disease (AD). AD is a multifactorial neurodegenerative disease of the brain, characterized, at the molecular level, by deposits of beta‐amyloid peptides in the extracellular space and of neurofibrillary tangles inside neurons. Together with abnormal protein deposits, it is now established that neuroinflammation represents the third hallmark found in AD patients’ brains. Many scientists agree that the neuroinflammatory process begins at the earliest phase of AD, bringing both positive and negative consequences. Indeed, the brain immune system recognizes the abnormal accumulation of proteins as injurious stimuli, so it initiates a physiological reaction to defend the brain that includes activation of glial cells and release of proinflammatory molecules. When these processes are protracted, they may contribute independently to neural dysfunction, cell death, thus fostering AD progression. Based on these considerations, targeting pathological gliosis seems to represent a valuable therapeutic approach. Compounds able to control glial activation with a combination of neuroprotective and anti‐inflammatory effects constitute a pool of possible therapeutic drugs to study. By using different in vitro and in vivo models of AD, I demonstrated the presence of important alterations of cerebral homeostasis caused by glial abnormalities. Obtained results have contributed to clarify the possible consequences of glia activation and of the subsequent neuroinflammation, demonstrating the presence of significant (i) alterations of the cerebral cytoarchitecture, (ii) modifications of cerebral metabolism and (iii) neuronal death. My results support the notion that targeting pathological gliosis may represent a promising and innovative therapeutic approach for several brain diseases. However, the effect of therapeutic interventions targeting glial cells depends on reaching the perfect balance between attenuating the deleterious effects and maintain the beneficial mechanisms of brain defense.Support or Funding InformationThis research was supported by the Italian Ministry of Instruction, University and Research (MIUR) to LS, and the SAPIENZA University of Rome to CS.
Cardiac Revascularization Post Myocardial Infarction Enhances Remuscularization and Improves Function
Authors: Vasconcelos Sara Nunes 
Published: April 2020

BackgroundHuman induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) offer an unprecedented opportunity to remuscularize infarcted human hearts. However, studies show that the majority of hiPSC‐CMs die post transplantation into the ischemic environment, limiting their regenerative potential and clinical application. Death of transplanted CMs occurs in the first few days post‐transplantation due to ischemia. Thus, attempts have been made to promote blood perfusion (i.e. addition of endothelial cells and/or angiogenic factors). However, these approaches require weeks for new vessels to form and to carry blood compared to the rapid death of transplanted CMs (2–3 days).PurposeOur goal was to improve the vascularization of the ischemic hearts to improve the survival of hiPSC‐CMs and increase heart remuscularization and function.MethodsWe performed left anterior descending artery (LAD) ligation in immunocompromised rats to model myocardial infarction. To improve vascularization, we used an innovative strategy consisting of ready‐made microvessels isolated from adipose tissue that form a vasculature and carry blood within the first days post subcutaneous implantation. We have co‐implanted ready‐made microvessels with hiPSC‐CMs by intra‐myocardial injection 2 weeks post LAD ligation. Cardiac function was assessed at 0, 2 and 4 weeks post‐implantation by echocardiography and by pressure‐volume loop at the endpoint (4 weeks). Immunohistochemistry and blood perfusion studies were performed at 1 and 4 weeks post‐implantation.ResultsCompared to hiPSC‐CM transplantation alone, microvessels promoted a ~600% increase in hiPSC‐CM survival with significant reduction in scar size. Echocardiography and pressure–volume (PV) loop analysis performed 4 weeks post‐MI revealed that hiPSC‐CM transplantation attenuated post‐infarct ventricular dilation and enhanced left ventricular contractility by demonstrating a significant improvement in fractional shortening (FS), ejection fraction (EF) as well as other functional parameters (end‐systolic volume, end‐diastolic volume, dP/dt max and min, Tau). Remarkably, co‐transplantation of hiPSC‐CMs with microvessels showed significantly superior functional recovery compared to hiPSC‐CMs alone in all the parameters assessed. Microvessels showed remarkable persistence and integration at both early and late time points, resulting in significantly faster blood perfusion and higher vessel density in the grafts.ConclusionThese findings provide a novel approach to cell‐based therapies for myocardial infarction whereby incorporation of ready‐made microvessels can serve as a personalized delivery system to improve functional outcomes in cell replacement therapies post‐myocardial infarction.Support or Funding InformationCanadian Institutes of Health Research (CIHR), Institute of Circulatory and Respiratory Health grant #137352 and #PJT153160. Discovery grant from the Natural Sciences and Engineering Research Council (NESERC): RGPIN 06621‐2017.
Allogeneic stem cell therapy for cardiac repair and host immune response
Authors: Dhingra Sanjiv , Abu-l-Rub Ejlal , Sequiera Glen Lester , Sareen Niketa , moudgil Meenal 
Published: April 2020

Bone marrow derived allogeneic (unrelated donor) mesenchymal stem cells (MSCs) and induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) have been found to have a high potential as candidates for cardiac repair. Unlike embryonic stem cells, there are no ethical issues involved with these two cell types. Both can help in replacing the dead cells directly/indirectly. Even though initial pre‐clinical and clinical trials showed promise for using MSCs and iPSC‐CMs, but after transplantation, these cells were found to be rejected by the recipient immune system that led to deterioration of beneficial effects of stem cell based therapies. Therefore, we aim to decipher the mechanisms responsible for the rejection of the transplanted allogeneic MSCs and iPSC‐CMs by the host immune system. The immunoprivilige of allogeneic MSCs is preserved by absence of cell surface immune antigen, major histocompatibility complex (MHC)–II. We recently found that MHC‐II expression increased in rat and human MSCs after exposure to hypoxia or after transplantation in the infarcted rat heart. MHC‐II expression is regulated by a class II transactivator (CIITA). We found that hypoxic environment led to upregulation of ATPase subunit of 19S proteasome Sug1 and its binding to CIITA, that was associated with activation of CIITA and upregulation of MHC‐II expression. As a result, MSCs became immunogenic and were rejected by host immune system. Knocking down Sug1 in MSCs preserved immunoprivilege and prevented rejection of transplanted MSCs in the infarcted heart. In case of iPS cells, we found that after differentiation to cardiomyocytes there was a significant increase in the MHC‐II expression that was associated with upregulation of immunogenicity of iPSC‐CMs. Therefore, current study provides novel mechanisms of increase in immunogenicity of allogeneic MSCs and iPSC‐CMs. This study may help in facilitating a better planning for future MSCs or iPSC based clinical trials in cardiac patients.Support or Funding InformationCanadian Institutes of Health Research
The Use of Magnetic Nanoparticles to Alter Primary Cilia Structure and Function
Authors: Nauli Surya M. , Pala Rajasekharreddy 
Published: April 2020

Primary cilia are non‐motile cell organelles with sensory functions. Abnormal cilia structure or function results in disorders, collectively termed as ciliopathies. Ciliopathies include an expanding spectrum of cardiovascular diseases, including hypertension. Microenvironment has directly implicated in an early stage of ciliopathy. Thus, the next nano‐material advances for a cilia‐targeted therapy or ciliotherapy are a desirable approach to treat ciliopathies. We report here that we have generated cilia‐targeted iron oxide (Fe2O3) nanoparticles that offer a new prototype in ciliotherapy. Live‐imaging of single‐cell‐single‐cilium analysis confirmed that the magnetic nanoparticles specifically targeted to primary cilia, making it possible to remotely control the movement and function of cilia with the external magnetic field. When these nanoparticles were loaded with fenoldopam, selected as a candidate drug prototype, the magnetic field accelerated the release of fenoldopam faster than a standard diffusion. A more sustained increase in cytosolic and intraciliary calcium (Ca2+) signaling and release of nitric oxide (NO) were observed only when magnetic field was applied. Importantly, the cardiovascular phenotypes in the ciliopathy models were improved with magnetic field. Our studies suggest that nanoparticles can be used to alter molecular and mechanical property of primary cilia.Support or Funding InformationThis work was supported by the National Institute of Health (HL131577), Congressionally Directed Medical Research Program (PR130153) and American Heart association (19IPLOI34730020)
Mechanisms of Linear Growth Acceleration in Childhood Obesity
Authors: Serrat Maria A. , Machnicki Allison L. , Song Cassaundra A. , Evans Sarah , McCloud Darby 
Published: April 2020

The obesity epidemic is alarming. Nearly one‐third of children in the Unites States are overweight or obese by the time they reach their pre‐teen years. Tall stature and accelerated bone elongation are distinctive clinical features of childhood obesity, which tend to co‐occur with painful conditions such as limb bowing, slipped epiphyses, fractures, and early onset osteoarthritis. Although linear growth rate is markedly increased, obese children paradoxically have normal circulating levels of IGF‐I, the major growth‐stimulating hormone. The causes of obesity‐induced growth acceleration remain elusive. Our lab has used a well‐established mouse model of excess dietary fat in order to examine bone elongation changes that occur with the development of juvenile obesity in young growing mice. We found, surprisingly, that brief exposure to a high‐fat diet accelerates bone elongation rate without increasing body mass or circulating IGF‐I levels. Interestingly, when we used in vivo multiphoton microscopy to measure how much systemic IGF‐I localized to growth plates in real time, we found significantly more (nearly twice as much) IGF‐I in the vasculature surrounding the growth plates of mice on a high‐fat diet relative to controls. Post‐mortem immunostaining confirmed that a high‐fat diet increased the number of activated IGF‐I receptors in the growth plate, but not total receptor number. Together, these results suggest that a high‐fat diet increases local bioavailability of IGF‐I in growth plate cartilage without altering systemic IGF‐I levels, and before changes in body mass become evident. This unique method of imaging growth factor transport in cartilage is an important advancement for addressing why linear growth is accelerated in obese children who have normal levels of systemic growth‐promoting hormones. While diets high in fat are well‐recognized for cardiovascular and metabolic complications, the role of dietary fat in bone lengthening is a novel and timely area of research. These studies may provide essential data for testing whether impeding IGF‐I actions in growth plates could be a beneficial approach for mitigating some of the deleterious skeletal consequences of childhood obesity.Support or Funding InformationSupported by the National Institute of General Medical Sciences (1P20GM121299‐01) and National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (1R15AR067451‐01).
The Neuroanatomy of HIV, How can Physical Activity Improve the Mental Health and Quality of Life in People Living with HIV
Authors: Rosario Martin G. 
Published: April 2020

Motor‐Cognitive alterations (MCAs) are associated with HIV infection and antiretroviral therapy. These MCNAs are known to be related to the frontal lobe, cognitive and motor region involvement. MCAs create a profound negative impact on their independence causing a burden to caregivers and the health care system. MCNAs dysfunctions that impact motor speed, information processing, executive functions, attention, new learning, memory, and new information retrieval are distinct and particularly prominent traits of HIV. Furthermore, recent studies focusing on the role of HIV antiretroviral medication on MCAs revealed hypertension, depression and, peripheral neuropathy are among the top main comorbidities in Hispanic people living with HIV. All the aforementioned have a profound impact in mental health and quality of life in this individuals.The intention of antiretroviral medication is to improve the immune system, cd4 immune cells, by keeping the virus from duplicating on its host, thus reducing viral load. Average values of CD4 cell count is the gold standard to assess the effectivity of antiretroviral medication. A recent report revealed the cd4 values as a better predictor for quality of life (FAHI) and perceived balance (ABC scale) in these individuals. The above‐mentioned study found a positive correlation between cd4 count and FAHI score and a moderate correlation with the ABC scale, pointing out the importance of cd4 values as a predictor for quality of life, mental health, and perceived balance.Since is imperative to maintain cd4 count in normal range especially in people living with HIV, another means to improve cd4 and in turn, mental health is exercising. Evidence suggests a combination of aerobic and resistance training three times a week helped improve fitness. A report evaluating the effects of a one‐year community‐based exercise program on the immune system and fitness in individuals with HIV found significant improvement in CD4 counts. These participants did show betterment in overall strength and cardiovascular fitness. This study concluded that participation in community‐based exercise programs can help improve the immune system (increase CD4 count) in people with HIV. Thence, clinicians should encourage individuals with HIV to participate in regular exercise and acquaint them with community/recreational programs.There is more than one path to improve mental health in people living with HIV. Taking their antiretroviral medication might keep the immune system healthy, nevertheless, alterations in mental health is still an issue. Exercise by itself has been demonstrated to boost the immune system and reduce symptoms of depression, an illness that affects most of these individuals. However, a combination of normal range of cd4 count and regular exercise gives birth to a more powerful tool to aid mental health and quality of life in people living with HIV.
Next‐gen mRNA‐enhanced Cell Therapy
Authors: Cooke John P. , Mojiri Anahita , Holgate Rhonda , Walther Brandon , Li Hongye , Stubbs Colleen , Liang Yi , Callaway Celetta , Chanda Palas , Damase Tulsi , Kettlun-Leyton Claudia , Kiss Dan , Sukhovershin Roman 
Published: April 2020

A new therapeutic field is emerging as obstacles are overcome to the clinical applications of mRNA drugs. The immunogenicity of mRNA has been reduced by the use of modified nucleosides and ultra‐purification. The stability and translatability of mRNA is increased by attention to optimizing codon use, the translational ramp, the 3′ and 5′UTRs, and by adding nuclease‐resistant secondary structure. The delivery of mRNA depends upon the application, but advances in targeted nanoparticle delivery vehicles, electro‐ or mechanoporation, microneedles and scaffolds have increased the delivery of therapeutic mRNA to the desired tissue. Because mRNA is non‐integrating, it is safer for human use than DNA‐based gene therapies.Cell therapies, including stem cell therapies for regenerative medicine, may be enhanced by mRNA‐based strategies. For example, in immunodeficient mice bearing a human B cell lymphoma, chimeric antigen receptor T (CART) cell therapy against the tumor was improved by treating the CART cells with human telomerase mRNA (hTERT mRNA). Treatment with hTERT mRNA increased telomere length of CART cells; reduced senescence of the cells with expansion; increased therapeutic cell product; and increased the anti‐tumor effect in vivo. Similarly, the ability of mesenchymal stem cells (MSCs) to induce angiogenesis in ischemic tissue was enhanced by increasing MSC telomerase activity and telomere length.Induced pluripotent stem cells (iPSCs) can be generated using mRNA encoding the Yamanaka factors, avoiding the viral integration of DNA encoding these factors. The lack of integration and its potential off‐target effects may be beneficial for iPSC‐derived cells for regenerative applications. Furthermore, mRNA encoding lineage‐determination factors can facilitate directed differentiation of these iPSCs to the therapeutic cells of choice. Alternatively, mRNA encoding the differentiation factors of choice can be administered directly to the tissue in scaffolds or nanocarriers to enhance endogenous cellular regenerative processes.Because mRNA constructs encoding any protein of interest can be generated rapidly in a cGMP fashion, and because many effective delivery vehicles are also now cGMP capable, mRNA therapeutics is a fast, flexible, and disruptive technology that has great promise in the field of regenerative medicine and cell therapy.
Moonlighting Proteins Where Changing Shape Promotes Changing Function
Authors: Jeffery Constance 
Published: April 2020

Several hundred proteins have been found to have multiple, unrelated functions. These moonlighting proteins can switch between functions through many different methods. Changes in quaternary structure and changes in conformation of a subunit are often involved. Some proteins can switch between functions when binding of a ligand causes a relatively small change in the protein conformation. For example, in some moonlighting enzymes that are also transcription factors, ligand binding can turn on the transcription factor function by causing a change in a protein’s DNA binding affinity. Other moonlighting enzymes undergo a large conformational change to uncover a previously buried functional site. Some proteins go through complete refolding of a domain or the entire protein subunit in order to perform a second function. For some proteins, called morpheeins, refolding of a protein subunit leads to an alternative quaternary structure that has a second function. Examples will be described where different subunit conformations and quaternary structures result in different protein functions.Support or Funding InformationThe author thanks the University of Illinois Center for Cancer Research for funding in support of research in the Jeffery lab.