bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pravastatin Stimulates Proliferation of Endogenous Cardiac Progenitor Cells in the Heart
Authors: SUZUKI GEN , Palka Beth A. , Canty John M. 
Published: June 2021

BackgroundWhile the HMG‐CoA reductase inhibitor pravastatin mobilizes cKit+ bone marrow‐derived progenitor cells and improves regional function in hibernating myocardium, the effect of pravastatin on resident cardiac progenitor cells (CPCs; cKit+/CD45‐ cells) is unknown.MethodsSwine with ischemic cardiomyopathy were treated with pravastatin (80mg/day, n=10) for 4 weeks and compared to untreated controls (n=6). CPCs differentiating into a myocyte lineage and proliferation were quantified by immunohistochemical colocalization with GATA4, cardiac troponin I (cTnI) and Ki67. Differentiation and proliferation pathways were assessed by western blot analysis for the Notch ligand Jagged1.ResultsPravastatin increased regional function (LAD wall thickening: 29±3% to 45±5%, p<0.01). Pravastatin increased cKit+/CD45‐ cells two‐fold but did not alter the percentage of cKit+GATA4+ or cKit+cTnI+ myocyte precursors. In contrast, pravastatin stimulated CSC proliferation with a nine‐fold increase in cKit+/Ki67+ and a three‐fold increase in the expression of Jagged1.ConclusionsThese data indicate that pravastatin up‐regulates Jagged1 in the heart and stimulates CPC proliferation but not the differentiation of CPCs into cardiac myocytes.Supported by NYSTEM and HL55324
Microglial Kv1.3 Channels as a Potential Target for Alzheimer's Disease
Authors: Jenkins David Paul , Maezawa Izumi , Wulff Heike , Jin Lee-Way 
Published: June 2021

Microglia, the major inflammatory cells of the brain, play a pivotal role in the initiation and progression of Alzheimer's Disease (AD) by either phagozytosing amyloid‐β deposits or by releasing cytotoxic and pro‐inflammatory substances in response to activation by amyloid‐β aggregates, including amyloid‐β oligomers (AβO). We here propose microglial Kv1.3 channels as a novel target for curbing the harmful effects of Aβ‐induced microglia activation. Microglia isolated from the brains of adult 5xFAD mice expressed higher levels of Kv1.3 than microglia from age‐matched control mice. We further observed strong Kv1.3 immunoreactivities in microglia associated with amyloid plaques in brains of 5xFAD mice. Proof for the functional importance of Kv1.3 in microglia comes from our observations that the Kv1.3 blocker PAP‐1 inhibits AβO‐stimulated NO production as well as microglia‐mediated neurotoxicity in dissociated cultures and organotypic brain slices. A 6‐week course of daily PAP‐1 injections also reduced the degree of microglia activation in 5xFAD mice. In contrast, Kv1.3 blockade with PAP‐1 does not affect phagocytosis of Aβ aggregates by microglia. These observations suggest that Kv1.3 blockers might preferentially inhibit microglia mediated neuronal killing without affecting beneficial functions such as scavenging of debris.Supported by NIH and Alzheimer's Association
Direct interaction of Bestrophin 3 channels with Hrc calcium‐handling protein
Authors: O'Driscoll Kate E , Hatton William J , John Steeven , Baring Martha , Britton Fiona C 
Published: June 2021

Bestrophin 3 (Best3) is a calcium‐activated chloride channel expressed in heart and other tissues. We hypothesized that Best3 channels function in a macromolecule complex similar to other cardiac ion channels.Yeast two‐hybrid assays performed on a mouse heart library, identified histidine‐rich calcium binding protein (Hrc) as a novel binding partner of Best3. Hrc is a regulator of sarcoplasmic reticulum (SR) calcium uptake, storage and release. This interaction was further determined to involve Best3 amino acids 541–669 in the cytosolic C‐terminus of the channel and the cysteine‐rich region in mouse Hrc (amino acids 665–738 aa). Specific binding between Best3 channels and Hrc was verified by co‐immunoprecipitation using mouse heart homogenates. Confocal immunofluorescence microscopy further demonstrated a strong co‐localization of Best3 and Hrc in isolated ventricular and atrial myocytes.In this study we report that cardiac Best3 channels interact with Hrc. Calcium‐activated chloride channels play a critical role in excitation‐contraction coupling in the SR by balancing charge movement during calcium release and reuptake. The direct coupling of Best3 with Hrc suggests that Best3 channels may play a role in calcium handling in the heart by functioning as a counterion channel.
The gasotransmitter hydrogen sulphide decreases Na+ transport across lung epithelial cells
Authors: Althaus Mike , Urness Kevin Douglas , Clauss Wolfgang , Baines Deborah L , Fronius Martin 
Published: June 2021

The transepithelial absorption of Na+ in the lung is crucial for the maintenance of the volume and composition of epithelial lining fluid. The regulation of Na+ transport is essential, since hypo‐ or hyperabsorption of Na+ is associated with lung diseases such as pulmonary oedema or cystic fibrosis. This study investigated the effects of the gaseous signalling molecule hydrogen sulphide (H2S) on Na+ absorption across human H441 pulmonary epithelial cells and native preparations of mouse and pig trachea. H2S rapidly and reversibly inhibited Na+ transport by all models when electrophysiologically measured in Ussing chambers. There was no effect on Na+ channels, whereas Na+/K+‐ATPase currents were decreased. Membrane abundance of the Na+/K+‐ATPase, as determined by surface biotinylation and western blot, or cellular ATP concentrations were not affected. H2S inhibited basolateral K+ channels, the inhibition of which decreased Na+/K+‐ATPase currents and Na+ absorption by H441 monolayers.Thus, H2S impairs pulmonary transepithelial Na+ absorption, due to inhibition of both Na+/K+‐ATPase activity and basolateral K+ channels. These data suggest that the H2S signaling system might represent a novel pharmacological target for interference with pulmonary transepithelial Na+ transport. This work was funded by the German Research Foundation (AL 1453/1‐1) and the German Academic Exchange Service.
Spinal VEGF induced phrenic motor facilitation is unaffected by pretreatment with repetitive acute intermittent hypoxia
Authors: Dale Erica Arden , Satriotomo Irawan , Mitchell Gordon S 
Published: June 2021

Vascular endothelial growth factor (VEGF) and VEGF receptor‐2 (VEGFR‐2) are expressed in identified phrenic motor neurons, and cervical spinal VEGF receptor activation elicits long‐lasting phrenic motor facilitation (pMF), demonstrating the potential of VEGFA to elicit respiratory plasticity. Since VEGF and VEGFR‐2 are regulated by hypoxia, we tested the hypotheses that: 1) VEGF and VEGFR‐2 are upregulated in phrenic motor neurons after repetitive exposure to acute intermittent hypoxia (3× per wk, 10 wks; 3xwAIH); and 2) 3xwAIH (4 wks) enhances VEGF‐induced pMF due to VEGF receptor up‐regulation. 3xwAIH increases VEGF (2.9±0.2 vs. 1.0±0.3; p<0.05) and VEGFR‐2 expression vs normoxic controls (8.7±0.07 vs. 1.9±0.5; p<0.05). Cervical spinal VEGFA administration elicited similar pMF in normoxic and 3xwAIH treated rats. Thus, although repetitive intermittent hypoxia up‐regulates VEGF and VEGR‐R expression in phrenic motor neurons, there was no evidence for any functional effect. Further exploration of this issue is warranted since: 1) there may be a “ceiling effect” as VEGF‐induced pMF may elicit maximal phrenic output, or 2) 4 weeks of 3xwAIH may not be sufficient time to up‐regulate the relevant proteins.Supported by: NIH NS05777 & HL080209.
Breathlessness descriptors during constant load cycling in obese men with and without dyspnea on exertion
Authors: Bernhardt Vipa , Haller Sarah F , Moran Raksa B , Babb Tony G 
Published: June 2021

During constant load exercise, some otherwise healthy obese men experience dyspnea on exertion (+DOE), while others do not (−DOE). Their subjective respiratory sensations may explain why the intensity of breathlessness is greater in +DOE.18 obese men participated and were divided based on their Ratings of Perceived Breathlessness (RPB, Borg 0–10 scale) during minute 6 of constant load (90 W) cycle exercise; ten +DOE (RPB ≥ 4) (36 yr, 39 BMI, 3.1 L/min peak V̇ O2, 104% predV̇O2) and eight −DOE (RPB ≤ 2) (34 yr, 35 BMI, 3.0 L/min peak V̇O2, 104% predV̇ O2). After the exercise, subjects filled out a questionnaire asking them to pick three of fifteen descriptors that best described the respiratory sensations they felt. Data were analyzed using z‐test proportion comparisons and clusters.Both +DOE and −DOE groups chose descriptors with similar frequency, only “I feel that I am breathing more” (+DOE 80%, −DOE 50%) and “I feel that my breathing is rapid” (+DOE 20%, −DOE 50%) differed slightly but not significantly between the groups (p=0.37). The top four clusters were ‘Breathing more’ (67% of all participants), ‘Heavy’ (44%), ‘Work/Effort’ (44%), and ‘Rapid” (33%).We conclude that obese men with and without DOE describe their respiratory sensations similarly during submaximal exercise, although their intensity of breathlessness is different.Supported by HL096782, King Charitable Foundation Trust, ALA, AHA.
Dietary fat‐induced release of diamine oxidase into intestinal lymph is mediated by histamine H4 receptor
Authors: SAKATA YASUHISA , Ji Yong , Yang Qing , Tso Patrick 
Published: June 2021

The release of histamine‐degrading enzyme diamine oxidase (DAO) into intestinal lymph is enhanced by the ingestion of nutrients, especially fat. Fat absorption also stimulates the release of histamine into lymph. We have previously reported that histamine H1 but not H2 or H3 receptor antagonist weakly inhibited lipid‐induced DAO release. The aim of this study was to determine the effect of histamine H4 receptor antagonist on the release of DAO by lipid ingestion. Intestinal lymph fistula rats (n=5) received a Liposyn bolus (4.4 kcal/3 ml) through the intraduodenal tube. The H4 receptor antagonist JNJ7777120 (37 mg/kg BW) was injected intraperitoneally 30 min before lipid infusion. Lymph was collected in cold and lymphatic DAO activity was measured by a radiometric assay. DAO protein was detected by western blot. JNJ7777120 treatment did not completely inhibit the release of DAO, but significantly reduced the peak of DAO activity (54.7±5.6 mU/ml) compared to controls (137.8±28.8 mU/ml, P=0.037). The DAO cumulative output in 1.5 hours was significantly decreased in JNJ7777120 treated rats (1.4±0.4 mg) compared to controls (4.0±0.9 mg, P=0.040). The activity data agree with the Western blot data which showed that JNJ7777120 treatment markedly decreased amounts of DAO in lymph. We conclude that lipid‐induced DAO release into lymph is mediated by histamine H4 receptor.Grant Support: NIH/NIDDK DK059360, DK092138
Exploring the Anatomical Spatial Relationships affecting the Anterior and Posterior Ethmoid Foramina (AEF & PEF) using 3‐D Geometric Morphometric Technique
Authors: Fisher Juliya , Masters Alina , Golubovskaya Yevgeniya , Pagano Anthony S. , Caceres Noel , Marquez Samuel 
Published: June 2021

Close relationships between ethmoid and maxillary sinuses, and orbital cavities have long challenged ENT surgeons. Identification of ethmoid vasculature (EV) in or adjacent to the frontal ethmoid suture line is critical in preventing intracranial entry and orbital hemorrhage during surgery. This study investigated influence of body size on spatial relationships among anterior ethmoid foramen (AEF) and posterior ethmoid foramen (PEF; which transmit arterial branches to ethmoid sinuses and meninges) and posterosuperior‐most point on the maxillary sinus roof (MSR). Ten hemi‐heads were harvested from donor bodies at SUNY Downstate. Each specimen was dissected to expose orbital cavity boundaries, infraorbital foramen, MSR, and zygomaticomaxillary suture. Landmark coordinate data were collected using a Microscribe digitizer & scaled (Procrustes scaling). Centroid size (sum of squared distances from each landmark to centroid) was used for size standardization. Results showed strong & negative correlations (p<0.05) between centroid size & distance between 1) AEF & PEF, 2) points on the orbital rim and the AEF and PEF, and 3) lateral‐most point on the orbital rim & MSR. Orbital width & height were similarly correlated with size (p<0.05) while no significance was revealed in MSR distance from the medial orbital wall. Orbital size appears to be the determining factor in changing relative positions of AEF & PEF.Grant Funding Source : SUNY Downstate Medical Center
Tracking branching variation of the axillary artery
Authors: Hartley Benjamin Rush , Marquez Samuel 
Published: June 2021

The axillary artery is divided into three parts for describing branching location. This study quantifies atypical branching in the third part, which usually gives rise to the subscapular artery and anterior and posterior circumflex humeral (CH) arteries. Rarely, the third part yields the profunda brachii artery (PBa). Tracking these branching patterns is important in accurate execution of diagnostic and surgical procedures. Further, as more arteries arise from a common trunk, more structures are at risk for ischemia via vascular insult. Axillary arterial branching was examined in 24 donors, yielding a sample size of 48 configurations. Five types of branching patterns were catalogued: Type 1 being the most common and Type 5 being the least. Pattern frequency was noted as follows: Type 1 = .563; Type 2 = .146; Type 3 = .125; Type 4 = .104; Type 5 = .063. Interestingly, the traditional “textbook” branching pattern (Type 1) was only observed in 56% percent of the sample. An unusual pattern where the PBa and both CH arteries originate from the subscapular artery was observed in over 6% of cases. As the PBa is the single source for collateral circulation of the antebrachium, disturbance to its integrity in these peculiar vascular arrangements, could have profound effects on clinical outcomes.Grant Funding Source: SUNY Downstate College of Medicine
Comparative functional morphology of the avian integument: Implications for the evolutionary history of feathers
Authors: Orellana Elise R. , Dubansky Brooke H. , Homberger Dominique G. 
Published: June 2021

The integuments of a turkey (Meleagris gallopovo) and an Amazon parrot (Amazona ventralis) differ in the arrangement of their feather muscles, which raise or depress contour feathers; the relative size of their feather tracts and apteria; and the type, distribution, and muscle attachments of their downy feathers. Common aspects, however, include smooth dermal feather and apterial muscles; dermal and subcutaneous fat layers that serve as a hydraulic skeleton for the feather follicles; and an elastic membrane that separates the fat layers and is responsible for returning the raised feathers to their resting position. Similarly, smooth dermal muscles, dermo‐subcutaneous fat tissue, and elastic membranes have been described for the integument of squamate reptiles that have imbricating scales. In contrast, the integument of crocodilian reptiles, which have plate‐like, non‐imbricating scales like dinosaurs, has lost the smooth dermal muscles and has reduced its dermo‐subcutaneous fat, but has retained an elastic layer that separates the dermis from the subcutis and is responsible for returning the stretched skin to its resting position. The comparison of avian and reptilian skin morphology illustrates an example of mosaic evolution and allows the reconstruction of the evolutionary history of the avian integument from that of a lizard‐like ancestor with imbricating scales. Funding: LSU Foundation to DGHGrant Funding Source: N.A.
The expansion and recoil mechanism of the skin of alligators and its implications for their feeding mechanism
Authors: Dubansky Brooke H , Homberger Dominique G 
Published: June 2021

Alligators are said to swallow large food items, but the assumption of an expandable throat skin has not been tested. Alligator skin can expand only through its soft‐cornified interscale skin segments. In the relaxed skin, collagenous skin ligaments in the dermis extend radially to attach to the underside of the rigid, hard‐cornified scales, which are slightly raised above the folded interscale skin. In the stretched skin, the skin ligaments assume a more circumferential orientation, thereby pulling down the scales and allowing the interscale skin to expand, while the Stratum elasticum between the dermis and subcutis is stretched. When the stretched skin is released, the Stratum elasticum returns to its resting length, thereby pushing the scales back to their raised position, allowing the interscale skin to refold, and returning the skin ligaments to their resting configuration. Maximum expansibility of the skin was found in the intermandibular region, which allows the manipulation of large food items in the oral cavity. A lack of circumferential expansibility was found in the cervical region, which limits the size of food items that can pass through the throat before they reach the narrow Isthmus thoracis. Hence, our anatomical analysis, together with observations of feeding alligators, shows that alligators do not swallow food items that are large relative to their neck size. Funding: LSU Foundation to DGHGrant Funding Source : NA
Convergence of the MicroRNA and NMD Pathways in Neurons
Authors: Shum Eleen Y , Lou Chih H , Wilkinson Miles F 
Published: June 2021

Nonsense‐mediated RNA decay (NMD) was originally identified to degrade “nonsense” mRNAs, but since then it has become clear that it also regulates ~10% of wild‐type transcripts. This regulatory role suggests that NMD itself is subject to regulation. Indeed, we recently identified a conserved regulatory circuit in mature neurons that regulates NMD through the ability of the microRNA miR‐128 to repress the NMD factors UPF1 and MLN51. Here, we report the identification of another microRNA miR‐9, which is expressed during neurogenesis, that regulates NMD by targeting UPF3B. Loss of UPF3B was recently shown to cause intellectual disability (ID) in humans. First, using reporter constructs, we obtained both gain‐and loss‐of‐function evidence that the UPF3B 3′UTR is regulated by miR‐9. Second, we found that endogenous UPF3B transcripts in cell lines are regulated by miR‐9. This miR‐9‐UPF3B circuit is likely to be physiologically relevant, as we observed that miR‐9 and UPF3B are colocalized in neurons in many regions of the mouse brain. We propose that the regulation of UPF3B by miR‐9 is important in neurogenesis. This may be disrupted in several human diseases, as mutations in human UPF3B are found not only in ID patients, but those with psychological disorders, including autism and schizophrenia.Research Supported by NIH
Amyloid beta oligomers trigger death receptors‐mediated apoptosis in cerebral endothelial cells
Authors: Fossati Silvia , Ghiso Jorge , Rostagno Agueda 
Published: June 2021

Vascular deposition of Aβ in sporadic and familial Alzheimer's disease, through poorly understood molecular mechanisms, leads to alterations in cerebral blood flow, focal ischemia, and cerebral micro‐/macro‐hemorrhages, significantly contributing to cognitive impairment. We aimed to determine the molecular mechanisms triggering apoptosis of vessel wall cells in presence of Aβ40 or its vasculotropic variants E22Q or L34V. Challenging human brain microvascular endothelial cells with both variants and wild‐type Aβ40, we showed that TRAIL death receptors DR4 and DR5 specifically mediate oligomeric Aβ induction of extrinsic apoptotic pathways. Caspase‐8 activation preceded activation of caspase‐9. The caspase‐8 inhibitor cFLIP was downregulated, and mitochondrial paths were engaged through BID cleavage. Up‐regulation of DR4 and DR5 and co‐localization with Aβ at the cell membrane suggested their involvement as initiators of the apoptotic machinery. Direct binding assays using receptor chimeras confirmed the specific interaction of oligomeric Aβ with DR4 and DR5 whereas apoptosis protection achieved through RNA silencing of both receptors highlighted their active role in downstream apoptotic pathways unveiling new targets for therapeutic intervention.Support: NIH AG30539, NS051715, American Heart and Alzheimer's Associations.
An autoregulatory feedback loop between nuclear receptor SHP and Mdm2 that controls Mdm2, SHP and p53 protein stability
Authors: yang zhihon , zhang yuxia , wang li 
Published: June 2021

MethodsImmunoprecipitation, Western blots, in vitro ubiquitination assays, luciferase reporter assays, qPCR, ChIP assays, and apoptosis assays etc.ResultsMdm2 attenuates SHP expression by promoting SHP protein ubiquitination and downregulating SHP mRNA, and SHP in turn stabilizes Mdm2 protein by abrogating Mdm2 selfubiquitination. p53 reduces SHP protein through proteasome, but not phosphorylation and acetylation, mediated SHP degradation by Mdm2, and inhibits SHP mRNA by transcriptional repression. SHP destabilizes p53 by augmentation of Mdm2 ubiquitin ligase activity toward p53. Such cross‐regulation critically depends on the physical interaction of SHP with Mdm2 through the SHPK170 residue. Consequently, SHP antagonizes p53 dependent induction of apoptosis and inhibition of tumor growth by AHPN and 3‐Cl‐AHPC in colon cancer cells.ConclusionsThe Mdm2‐SHP‐p53 interplay represents a novel component of Mdm2/p53 crosstalk that dictates p53 activity and function.This work was supported by the National Institutes of Health (DK080440) to L.W.
Role of SM22α in Angiotensin II Induced Vascular Smooth Muscle Cell Contraction
Authors: Xiao-Li Xie , Mei Han 
Published: June 2021

The major function of vascular smooth muscle cells (VSMCs) is to maintain normal vascular tone via coordinated contraction‐relaxation cycling. Angiotensin II (Ang II), a vasoactive peptide, induces vascular smooth muscle cell (VSMC) contraction. SM22α, an actin binding protein, is highly expressed in contractile VSMCs. It is unclear whether SM22α plays a role in Ang II‐induced contraction. In the present study, differentiation of VSMCs in vitro was induced by all trans retinoic acid (ATRA), and the roles of SM22α in contraction of VSMCs were assessed using specific siRNA. Knockdown of SM22α significantly attenuated the contractility in redifferentiated VSMCs, which is associated with the suppression of Ang II‐induced activation of extracellular signal regulated kinase (ERK) signaling pathway. The loss of SM22α proteins inhibited the formation of actin stress fibres. Furthermore, disruption of the actin filament network by cytochalasin D impaired the activation of ERK pathway. Overall, our results suggest SM22α regulates VSMC contraction through mediates Ang II‐induced ERK activation and actin stress fibre formation.Source of funding: This study was supported by the National Natural Science Foundation of China (31071003).